ischemic preconditioning
Nerve Growth Factor Gene Therapy
targeting Treg-mediated systemic immunosuppression
Scientists Turn Skin Cells into Brain Cells, Using Alzheimers Patients
combination of dextromethorphan and quinidine
cis antibody
glatiramer acetate and grafted CD115 +monocytes
nanoparticles as 'Acyl-Polycaprolactone’ and ‘magnetic iron oxide nanoparticles modified by beta-Cyclodextrin.'
Brain Wellness and Brain Fullness
HK532-IGF-1 transplantation
difluoromethylornithine (DFMO)
Calcineurin Inhibitors
neuronal pentraxin 2
radio frequency
P4 and P8
HDAC inhibitors
tau oligomers
Ultrasound therapy
Nerve Growth Factor Implant
blocking the IL-10 anti-inflammatory response
Anavex 2-73
leuprolide acetate (Lupron)
RNA-binding motif protein 3 (RBM3); 'Hibernation protein'
acamprosate and baclofen
7 new ways
Smart Soup, a Traditional Chinese Medicine Formula (rhizoma acori tatarinowii, poria cum radix pini and radix polygalae)
liraglutide and lixisenatide
TfR bispecific antibody platform
Complex therapy
NGP 555
Transcranial Magnetic Stimulation
Marijuana Compound  THC
ischemia-tolerant mesenchymal stem cells (itMSCs)
anti-APOE therapies
MSX-3(caffeine-like effects, a water-soluble A2A antagonist)
structured animal-assisted intervention (AAI) program
Reprogramming of Reactive Glial Cells
hybrid compounds of curcumin and melatonin
transthyretin (TTR)
antisense oligonucleotide (OL-1)
Holistic exercise
tubulin treatment
Young blood



Drug that boosts the brain's 'garbage disposal' slows Alzheimer's in mice
This molecule helps our brains take out the trash.


The natural removal of toxic proteins that clump together in the brain to cause Alzheimer's disease and other neurodegenerative disorders can be boosted by a drug that increases activity in the brain's 'garbage disposal', according to a new study.

Neuroscientists at Columbia University Medical Centre (CUMC) say that rolipram, a discontinued medication that was developed for its potential use in treating depression, can boost activity in the brain's proteasome system, which grinds up old proteins so they can be recycled into new ones.

"We have shown for the first time that it's possible to use a drug to activate this disposal system in neurons and effectively slow down disease," said lead researcher Karen E. Duff. "This has the potential to open up new avenues of treatment for Alzheimer's and many other neurodegenerative diseases."

Brain cells naturally clear out old or damaged proteins as part of their regular maintenance thanks to proteasomes, which are shaped like small molecular cylinders. However, sticky proteins like amyloid beta and tau proteins that contribute to the development of Alzheimer's disease impede this normal garbage disposal system, clumping together and resisting efforts to remove them.

In the study, which is reported in Nature Medicine, the researchers used a mouse model of neurodegeneration and found that tau proteins accumulate by sticking to the proteasome and slowing down the usual protein disposal process.

However, administering rolipram reactivates the proteasome and restores a normal level of protein removal. In diseased mice, the researchers found that the drug also improved memory levels to those seen in healthy mice.

Rolipram is able to do this by inhibiting an enzyme called PDE?4, and while the researchers don't fully understand how it works, the inhibition of the enzyme results in increased proteasome activity.

You can see the results in the images above, with the rolipram on the right having eliminated excess tau proteins (the bright red dots, seen in far greater number on the left image).

"We still don't know exactly where the activation is happening, but what's new is that we can modify the proteasome to increase its activity. There could be many other ways to do this," said one of the team, Natura Myeku.

And that's fortunate, because rolipram itself isn't particularly suitable for use in humans, as one of its side effects is inducing nausea. Luckily, the researchers say similar proteasome-targeting drugs also exist and don't carry such side effects, and they could go into clinical trials relatively quickly.

If such drugs are shown to be safe and to work in people like they do in mice, they could work as a kind of silver bullet to help us treat Alzheimer's and other diseases caused by the accumulation of abnormal proteins, such as Parkinson's, Huntington's, and frontotemperoral dementia.

"Treatments that speed up these cell disposal mechanisms should, in theory, only degrade abnormal proteins. We don't need to know what the toxic form of the protein is," said Duff. "In Alzheimer's disease, there are at least four different types: amyloid, tau, alpha-synuclein, and TDP43. A well-functioning proteasome can clear out everything at once."

Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling

Natura Myeku, Catherine L Clelland, Sheina Emrani, Nikolay V Kukushkin, Wai Haung Yu, Alfred L Goldberg & Karen E Duff
AffiliationsContributionsCorresponding author
Nature Medicine (2015) doi:10.1038/nm.4011
Received 07 August 2015 Accepted 17 November 2015 Published online 21 December 2015
The ubiquitin proteasome system (UPS) degrades misfolded proteins including those implicated in neurodegenerative diseases. We investigated the effects of tau accumulation on proteasome function in a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). Accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes, higher levels of ubiquitinated proteins and undegraded Ub-G76V-GFP. 26S proteasomes from mice with tauopathy were physically associated with tau and were less active in hydrolyzing ubiquitinated proteins, small peptides and ATP. 26S proteasomes from normal mice incubated with recombinant oligomers or fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin. Administration of an agent that activates cAMP?protein kinase A (PKA) signaling led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. In vivo, this led to lower levels of aggregated tau and improvements in cognitive performance.

EPPS 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid

Molecule clears Alzheimer's plaques in mice


A molecule can clear Alzheimer's plaques from the brains of mice and improve learning and memory, Korean scientists have found in early tests.
Exactly how it gets rid of the abnormal build-up is not understood.
The small Nature Communications study hints at a way to tackle the disease even once its in full swing, dementia experts say.
But there is no proof the same method would work in people - many more years of animal trials are needed first.
Currently, there is no cure for Alzheimer's disease. Treatments can lessen the symptoms, but scientists are looking for ways to prevent, halt or reverse the disease.
As the dementia progresses, more plaques (clumps of abnormal proteins and chemicals) form in the brain and healthy brain cells die off.
Scientists reason that preventing or removing the plaques might help, and many drug candidates are in development.
One still being tested, a drug called aducanumab, appears to stop the plaques from forming - but that is if it taken early enough, before the disease has advanced.
However, the South Korean researchers believe they may have found a molecule, called EPPS, that could work even if plaques have already formed.
mouse maze in the labImage copyrightSCIENCE PHOTO LIBRARY
They gave EPPS to mice (bred to have the Alzheimer's plaques) by spiking their drinking water for two weeks, and then monitored them over the next three months to see what effect it might have.
Compared with a control group of mice who received only normal water, the EPPS mice performed better on memory and learning problems (running through a maze).
The EPPS mice also had far fewer plaques in their brain at the end of the trial than they had had at the beginning. The same could not be said for the control group.
The Alzheimer's Society and Alzheimer's Research UK said it was important to remain cautious - animal study findings may never apply to humans.
Prof Tom Dening, an expert in dementia research at the University of Nottingham, said: "From a clinician's point of view, this research is of interest, but we still don't know if removing amyloid plaques is useful in humans.
"It may well be that the appearance of plaques is too far down the chain of molecular processes to be beneficial.
"We don't know if this animal work will lead to any useful agent that can be used for clinical trials."

EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques

Hye Yun Kim, Hyunjin Vincent Kim, Seonmi Jo, C. Justin Lee, Seon Young Choi, Dong Jin Kim & YoungSoo Kim
ature Communications 6, Article number: 8997 doi:10.1038/ncomms9997
Received 01 July 2015 Accepted 23 October 2015 Published 08 December 2015

Alzheimer’s disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Aβ aggregation and behavioural deficits provides strong support for the view that the accumulation of Aβ is an important mechanism underlying AD.


Experimental Alzheimer’s drug shows anti-ageing effects, surprising researchers
Human trials to begin next year.

14 NOV 2015

We know that Alzheimer’s disease is linked to ageing, in that the elderly are most susceptible to experiencing the disorder, but just how deep are the ties?

A new study by researchers in the US explains more about the relationship between ageing and Alzheimer’s, with continued testing of an experimental drug candidate called J147 revealing unforeseen benefits in the latest research. In testing on rodents, the drug surprised researchers by showing unexpected anti-ageing effects on mice.

When the animals were treated with J147 they showed better memory and cognition, healthier blood vessels in the brain, and other improved physiological features.

“Initially, the impetus was to test this drug in a novel animal model that was more similar to 99 percent of Alzheimer’s cases,” said Antonio Currais, a researcher in the Cellular Neurobiology Laboratory at the Salk Institute for Biological Studies in California. “We did not predict we’d see this sort of anti-ageing effect, but J147 made old mice look like they were young, based upon a number of physiological parameters.”

J147 takes a different approach to many other drugs developed to combat Alzheimer’s disease. “While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), none have proven effective in the clinic,” said David Schubert, senior author of the study. Instead, the treatment focuses on what the researchers say is the most obvious major risk factor for the disease: old age.

J147 was initially synthesised by using cell-based screens against old-age-associated brain toxicities. In the latest study, the researchers tested the efficacy of the treatment by tracking the progression of three groups of rapidly ageing mice. One group were young mice, one were old mice, and the final group were old mice on a diet which included J147.

In a set of experiments designed to test the animals’ memory, cognition and motor movements, the old mice fed J147 showed better performance and also displayed fewer pathological signs of Alzheimer’s disease in their brains. Further, many aspects of the J147-fed mice’s gene expression and metabolism ? including increased energy metabolism, reduced brain inflammation and reduced levels of oxidised fatty acids in the brain ? were similar to that of the younger mice.

Less leakage of blood from the microvessels in the brain was another bonus stemming from the drug. “Damaged blood vessels are a common feature of ageing in general, and in Alzheimer’s, it is frequently much worse,” said Currais.

The research, which is published in Aging, is set to continue in 2016, with the first human trials hoped to replicate these exciting effects so far seen in rodents. “If proven safe and effective for Alzheimer’s, the apparent anti-ageing effect of J147 would be a welcome benefit,” said Schubert.


New Alzheimer's treatments may arise from modeling 'heat shock proteins'

13 October 2015

One of the hallmarks of Alzheimer's disease is the abnormal clumping of beta-amyloid proteins in the brain, resulting in the death of brain cells. The discovery that small heat shock proteins prevent uncontrolled protein clumping has opened the possibility of developing drugs that emulate this effect. Now, a new study takes this a step further by revealing how small heat shock proteins interact with beta-amyloid to prevent clumping.

These electron microscope images show beta-amyloid in the absence (left) and presence (right) of alphaB-crystallin.
Image credit: Andi Mainz/TUM

The researchers, from the Technical University of Munich (TUM) and the Helmholtz Zentrum M?nchen, both in Germany, report their findings in the journal Nature Structural & Molecular Biology.

Small heat shock proteins are "helper" or "chaperone" proteins that perform a variety of roles, including the guarding of other proteins during times of stress to stop them becoming abnormal, such as folding into the wrong shape or clumping when they should not.

One reason to understand these helper proteins is the hope of using them as agents in the treatment of brain-wasting diseases such as Alzheimer's. Small heat shock proteins attach themselves to the deformed proteins before they start to aggregate and keep them in a soluble state - thus preventing the clumping.

In the case of Alzheimer's disease, the heat shock protein that stops beta-amyloid aggregating to form long fibrils that clog up brain cells is called alpha-B-crystallin. Other heat shock proteins are associated with neurodegenerative diseases such as Parkinson's disease and multiple sclerosis.

Two features stop beta-amyloid clumping
In the new study, a team led by Bernd Reif, a chemistry professor at TUM and a group leader at the Helmholtz Zentrum M?nchen, reveals precisely how the structure of alpha-B-crystallin interacts with beta-amyloid to prevent the clumping that is seen in Alzheimer's.

Using solid-state nuclear magnetic resonance (NMR) spectroscopy, the researchers identified the exact sites in the alpha-B-crystallin structure that attach to the beta-amyloid. The achievement is the result of painstaking work because of the challenges posed by the complexity of alpha-B-crystallin, as Prof. Reif explains:

"Alpha-B-crystallin exists in various different forms comprising 24, 28 or 32 subunits that are permanently being swapped. In addition, it has a large molecular weight. These factors make structure analysis very difficult."
The team found that alpha-B-crystallin uses two features of its structure to block the aggregation process. One feature allows it to attach to individual beta-amyloids to prevent them clumping into fibrils, and the other "seals" already-formed fibrils to prevent them adding more amyloids.

The discovery offers a model for researchers interested in engineering proteins that emulate these alpha-B- crystallin features to bind specifically to beta-amyloid and similar proteins.

The study follows earlier research that Medical News Today reported in March 2014 where a team led by another TUM member also found that heat shock proteins influence the aggregation of tau proteins - another hallmark of Alzheimer's.

Written by Catharine Paddock PhD
Copyright: Medical News Today

The chaperone αB-crystallin uses different interfaces to capture an amorphous and an amyloid client

Andi Mainz, Jirka Peschek, Maria Stavropoulou, Katrin C Back, Benjamin Bardiaux, Sam Asami, Elke Prade, Carsten Peters, Sevil Weinkauf, Johannes Buchner & Bernd Reif

Nature Structural & Molecular Biology (2015) doi:10.1038/nsmb.3108
Received 27 March 2015 Accepted 11 September 2015 Published online 12 October 2015

Abstract? Accession codes? References? Author information? Supplementary information
Small heat-shock proteins, including αB-crystallin (αB), play an important part in protein homeostasis, because their ATP-independent chaperone activity inhibits uncontrolled protein aggregation. Mechanistic details of human αB, particularly in its client-bound state, have been elusive so far, owing to the high molecular weight and the heterogeneity of these complexes. Here we provide structural insights into this highly dynamic assembly and show, by using state-of-the-art NMR spectroscopy, that the αB complex is assembled from asymmetric building blocks. Interaction studies demonstrated that the fibril-forming Alzheimer's disease Aβ1?40 peptide preferentially binds to a hydrophobic edge of the central β-sandwich of αB. In contrast, the amorphously aggregating client lysozyme is captured by the partially disordered N-terminal domain of αB. We suggest that αB uses its inherent structural plasticity to expose distinct binding interfaces and thus interact with a wide range of structurally variable clients.


Drug May Calm Agitation in Alzheimer's Patients

It's a combination of cough suppressant and heart medication, and experts don't yet know why it may work

By Amy Norton
HealthDay Reporter
Sept. 22, 2015

A drug that combines a cough suppressant with a heart medication might offer a safer option for calming the agitation that commonly affects people with Alzheimer's disease, an early clinical trial suggests.

The study, of 220 Alzheimer's patients, found that the drug -- called Nuedexta -- generally eased agitation symptoms over 10 weeks.

And it did not worsen patients' problems with memory, thinking and judgment, researchers reported in the Sept. 22/29 issue of the Journal of the American Medical Association.

As Alzheimer's disease progresses, people often go through periods of agitation that can range from restlessness and pacing to aggressive behavior like yelling, fighting and destroying objects.

If those issues can be managed without medication, that's always best, said Dr. Sam Gandy, a professor of neurology and psychiatry at Mount Sinai Hospital, in New York City.

But some people do end up needing medication, which currently means antipsychotic drugs that were developed for conditions such as schizophrenia and bipolar disorder.

"Those drugs basically spilled over into Alzheimer's treatment," said Gandy, who is also a spokesman for the American Federation for Aging Research.

The problem, Gandy explained, is that when given to elderly dementia patients, antipsychotics can have serious side effects, including faster mental decline and heart complications.

The new study tested the effects of Nuedexta, because it's potentially safer and is already on the market for treating a little-known neurological condition called pseudobulbar affect.

The medication is a combination of the cough suppressant dextromethorphan as well as quinidine, a drug that treats abnormal heart rhythms called arrhythmias.

Pseudobulbar affect refers to involuntary outbursts of laughing or crying that can happen to people with brain damage or certain neurological diseases, including Parkinson's, Lou Gehrig's disease and Alzheimer's.

The new findings suggest the drug also helps calm Alzheimer's-related agitation. But it's too soon to know for sure, said Anne Corbett, a dementia researcher who co-wrote an editorial published with the study.

"It's important to remember that these are early results," said Corbett, who is based at King's College London, in the United Kingdom

"A much larger clinical trial is needed before people can trust in the benefit seen here," she said.

And even though the medication did not seem to speed mental decline, it did have side effects, Corbett pointed out. Almost 9 percent of patients on the drug suffered a fall, and 5 percent developed urinary tract infections, the findings showed.

"Falls in the elderly are always a concern," Gandy agreed. Unfortunately, he added, those falls are also an expected risk with drugs that suppress the central nervous system.

For the study, researchers led by Dr. Jeffrey Cummings, of the Cleveland Clinic Lou Ruvo Center for Brain Health, in Las Vegas, recruited 220 patients with Alzheimer's-related agitation.

First, the researchers randomly assigned 93 patients to take Nuedexta, and 127 to take identical-looking placebo capsules every day for five weeks. At that point, 59 patients who were showing no response to the placebo pills were started on the real drug; another 60 remained on the placebo.

Avanir Pharmaceuticals, which makes Nuedexta, funded the research.

Over 10 weeks, patients on the drug showed a decline in a standard scale used to gauge agitation symptoms. On average, their scores dropped from the 6- to 7-point range to just below 4 points.

"That's a significant change," said Gandy, who was not involved in the study. "The effects would be noticeable and provide meaningful relief."

Since Nuedexta is already on the market, doctors have some understanding of the drug's longer-term safety, Gandy noted. "That means it could be available for widespread use in relatively short order," he said.

However, Gandy added, the U.S. Food and Drug Administration still has to weigh in.

Doctors are technically free to prescribe any approved drug "off-label," for conditions other than the officially approved use. But if Nuedexta were prescribed off-label for agitation, families would have to pay for it themselves, Gandy pointed out.

Why would a drug that combines a cough suppressant and an anti-arrhythmia medication help with agitation? It's not fully clear, Gandy said. According to drugmaker Avanir, Nuedexta is thought to act on brain areas that coordinate "emotional expression."

Both Gandy and Corbett stressed that agitation should first be managed without drugs.

In nursing homes, Gandy said, that often means separating an agitated patient from others, so they can be "reassured" and given time to calm down.

Understanding what's triggering the issue is also key, Corbett said. Sometimes it's pain or even dehydration, she explained; so making sure Alzheimer's patients are comfortable and staying hydrated can help.

Social interaction and "pleasant activities" can also head off agitation, Corbett suggested. "That must, of course, be tailored to the individual," she said, "but could involve looking at old photographs, taking a walk in the garden, or helping with cooking."

Editorial | September 22/29, 2015
Dextromethorphan and Quinidine for Treating Agitation in Patients With Alzheimer Disease Dementia
Clive Ballard, MD1; Samantha Sharp, BSc1; Anne Corbett, PhD1
[+] Author Affiliations
JAMA. 2015;314(12):1233-1235. doi:10.1001/jama.2015.10215.
Among patients with Alzheimer disease, more than 90% experience neuropsychiatric symptoms during the course of their illness1 with agitation one of the most frequent and clinically important symptoms. Agitation is not only distressing for the patient but often confers risk both to patients and to others (such as family members and caregivers). Agitation also represents a common trigger for institutionalization and presents a major management challenge for clinicians. Effective treatment options for agitation in patients with Alzheimer disease are limited, so clinical innovation in this area is a high priority.


Drug mentioned by Hippocrates may reverse Alzheimer's memory loss

Salsalate is already used for arthritis but it could bring back memories of people suffering from Alzheimer's disease

One of the world’s oldest drugs which was first mentioned by Hippocrates in the 5th Century BC could help restore memory in Alzheimer’s patients, scientists hope.
Salsalate, which comes from the same family as aspirin, was typically used to treat inflammatory conditions like rheumatoid arthritis.
But a new study suggests that it can prevent the build-up of toxic proteins in the brain and even reverse damage already done, unblocking pathways and restoring memory.
Although the effects have only been seen in mice so far, scientists believe trials could quickly move to humans because researchers already know that the drug is safe and produces few side-effects.
The US scientists say it is the first time that a drug has been shown to reverse all toxic effects of the tau protein and Alzheimer's charities said the discovery was 'promising news.'
Tau proteins accumulate in people which dementia, driving neurodegeneration and mental decline. But a low dose of salsalate appears to lower tau levels ‘rescuing’ memories and protecting the hippocampus ? a part of the brain essential for forming memories.
“We identified for the first time a pharmacological approach that reverses all aspects of tau toxicity," said Dr Li Gan, an associate investigator at the Gladstone Institutes, University of California.
"We found that salsalate reversed memory loss in a mouse model of dementia. These mice, which exhibit AD-related tau pathology, develop spatial memory loss at 7-months of age. We treated these mice with salsalate for about two months, and their memory loss is reversed.
"Remarkably, the profound protective effects of salsalate were achieved even though it was administered after disease onset, indicating that it may be an effective treatment option."

Hippocrates first described salicylates as a bitter powder extract from willow bark that eased aches and pains and reduced fevers.
The active extract salicin was first isolated by the German chemist Johann Andreas Buchner in 1828 and it can exist in two forms salsalate and aspirin.
Salsalate prevented the accumulation of tau by blocking an enzyme.
"Targeting tau could be a new therapeutic strategy against Alzheimer's disease," says co author Dr Eric Verdin, a senior investigator at the Gladstone Institutes.
"Given that salsalate is a prescription drug with a long-history of a reasonable safety profile, we believe it can have immediate clinical implications."

Salsalate, which has largely been replaced by more modern drugs, is also being looked at as a possible treatment for diabetes.
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society, said: “It’s promising news that the arthritis drug salsalate could potentially reduce the accumulation of one of the toxic proteins that characterises both Alzheimer’s disease and Frontotemporal dementia. None of the current dementia treatments target this specific protein, tau, which creates tangles in the brain that gradually destroy healthy nerve cells. While scientists are still not absolutely sure what causes Alzheimer’s or Frontotemporal dementia, the hope is that this type of treatment could be one way of slowing down the progression of the disease.
“As this drug is already prescribed to people with arthritis we know a lot about how it works and its side effects ? what we need now is confirmation of whether it works for people with dementia."

Lost memories could be restored, scientists believe
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, added: “The tau protein is implicated in a number of dementias including Alzheimer’s disease and frontotemporal dementia and is a promising target for the development of new treatments. This study identifies an important pathway regulating the tau protein in mice which will now need following up in people to explore its potential as a new treatment approach.
“Understanding more about the biology of the diseases that cause dementia is vital for identifying important biological processes to target with new treatments, and to highlight parallels with other health conditions where treatments may already exist.
"This study explores a drug previously used to treat rheumatoid arthritis, but further research will now need to explore the potential for this treatment to affect levels of the tau protein in people with Alzheimer’s and frontotemporal dementia.
"While there is potential that drugs used to treat other diseases could hold benefit in dementia, nobody should be taking such drugs until clinical trials have shown them to be safe and effective for the treatment of dementia.”
The research was published in the journal Nature Medicine.

Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits

Sang-Won Min, Xu Chen, Tara E Tracy, Yaqiao Li, Yungui Zhou, Chao Wang, Kotaro Shirakawa, S Sakura Minami, Erwin Defensor, Sue Ann Mok, Peter Dongmin Sohn, Birgit Schilling, Xin Cong, Lisa Ellerby, Bradford W Gibson, Jeffrey Johnson, Nevan Krogan, Mehrdad Shamloo, Jason Gestwicki, Eliezer Masliah, Eric Verdin & Li Gan
AffiliationsContributionsCorresponding authors
Nature Medicine (2015) doi:10.1038/nm.3951
Received 01 April 2014 Accepted 20 August 2015 Published online 21 September 2015

Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.


Hopkins, AgeneBio to launch trial of Alzheimer's drug in partnership with NIH

By Scott Dance
The Baltimore Sun

Medical Research Drug Research Drugs and Medicines Alzheimer's Disease

Researchers at Johns Hopkins and AgeneBio are testing a drug that could prevent Alzheimer's.

What could be one of the first treatments to delay or prevent Alzheimer's disease received a big boost from the National Institute on Aging, which is putting up $7.5 million to help fund the next round of trials for the drug being developed by a Baltimore start-up and the Johns Hopkins University.

The clinical trial will evaluate a drug used to treat epilepsy that has shown signs in smaller doses of calming brain hyperactivity linked to dementia.

"What this could mean for thousands of patients is they may never cross over into full-blown Alzheimer's dementia," said Jerry McLaughlin, CEO of AgeneBio, the Baltimore company founded by a Hopkins researcher who discovered that the drug might be useful in treating Alzheimer's. "We're very excited."

Alzheimer's is a degenerative brain disease that often begins with memory loss but accelerates over time, causing sufferers to lose other body functions and eventually killing them. The disease accounts for most cases of dementia, a general term for a loss in brain function.

While some treatments are available for Alzheimer's symptoms, such as memory loss or changes in behavioral or sleep patterns, the once-a-day pill researchers will test is among a small number looking to address the brain disease itself.

The institute's money, which was awarded to Johns Hopkins, will be put toward the drug's so-called Phase 3 trial over the next five years, covering about a tenth of the project's cost, according to AgeneBio.

Phase 3 trials test the effectiveness and safety of a drug or its application across a pool of a few thousand people. If such trials are successful, approval by the Food and Drug Administration is typically the next step.

For AgeneBio, the trial, which could start as soon as early 2016, could be a big step toward FDA approval and sale of the drug, McLaughlin said. The researchers expect results in 2019, which could mean they file for FDA approval that year or in 2020.

With the partnership with Hopkins and the National Institute on Aging ? a division of the National Institutes of Health ? AgeneBio joins the likes of Eli Lilly, Genentech and Novartis, which are also working with the NIH on treatments to prevent or cure Alzheimer's.

The drug, known as AGB101, is composed of a proprietary low-dose formulation of levetiracetam, an FDA-approved treatment for epilepsy. In the Alzheimer's trial, subjects will receive one-fifth to one-12th the amount of levetiracetam prescribed to patients with epilepsy.

Michela Gallagher, the Krieger-Eisenhower professor of psychological and brain sciences at Hopkins and director of the university's Neurogenetics and Behavior Center, conducted the research that suggested the drug could be applied to Alzheimer's.

Two decades ago, it was thought that brain overactivity observed in patients with dementia was the brain overcompensating for whatever was causing Alzheimer's. But Gallagher and colleagues' work showed that hyperactivity in the brain was instead causing it to atrophy.

"If you brought overactivity down and it was serving a beneficial function, you would expect their memory performance would get worse, but it didn't," Gallagher said of tests on animal subjects.

In rat trials, Gallagher tested various treatments to calm the brain activity. While most other epilepsy drugs didn't work, levetiracetam was effective. The drug is considered an "atypical" anti-epileptic because it doesn't dull broader central nervous system activity.

Those findings became the basis of AgeneBio, which Gallagher founded in 2008. While it was briefly based in Indiana, the company moved to Baltimore last year and now has offices at the Johns Hopkins at Eastern campus in Waverly.

An earlier study of the drug, published this year, found that low doses calmed the overactivity in the brain and improved memory performance in subjects who were experiencing memory loss and were considered to be pre-dementia.

Now, Hopkins researchers plan to test the drug on hundreds of patients around the world, focusing on those who are showing signs of unusual memory loss or confusion but who don't yet have Alzheimer's.

The grant pays a share of Hopkins' costs for running the trial, while AgeneBio will cover the bulk of the expenses and also must make its data public as part of the deal. The university is a minority investor in AgeneBio but does not otherwise benefit financially from the partnership, McLaughlin said.

AgeneBio, which employs four people and has so far raised $18 million in investment, will seek more investors or a partnership with a pharmaceutical company to help fund its Phase 3 efforts, McLaughlin said.

"We believe this news, this validation from the NIH, will provide a lot of value," he said.

The need for effective Alzheimer's treatment is great, said Elizabeth Li, a spokeswoman for the Greater Maryland chapter of the Alzheimer's Association.

Last year, Alzheimer's was estimated to cost $214 billion, including $150 billion to Medicare and Medicaid, but the federal government allocated $566 million to Alzheimer's research, she said. The association bills itself as the largest private funder of Alzheimer's research, and it contributed $14 million to 88 research projects last year, she said.

"Right now there is no way to prevent, cure or slow Alzheimer's disease," Li said.

That presents an opportunity for AgeneBio.

"We feel excited about the opportunity to potentially bring this therapeutic to patients," McLaughlin said. "It has this real opportunity to delay the onset of Alzheimer's dementia."

ischemic preconditioning

'Conditioning' blood flow could deter dementia, GRU researcher says

GRU doctor's 'conditioning' cuts off blood flow in limb
By Tom Corwin
Staff Writer
Sunday, Sept. 13, 2015

Briefly cutting off blood flow in the arm could help stave off dementia caused by a chronic lack of blood in deeper parts of the brain, the second-most common cause of the condition, a researcher at Georgia Regents University says.

The daily “conditioning” technique relies on a seemingly contradictory medical principle called the hormesis effect that dates back to the ancient Greeks but that most doctors probably don’t know, said Dr. David Hess, the chairman of GRU’s De?part?ment of Neurology and the principal investigator on the study.
Lack of blood flow to parts of the brain over time can lead to what is called vascular cognitive impairment, Hess said. It is the second-leading cause of dementia after Alzheimer’s disease and can make that disease worse when someone has both problems, he said.
“Vascular causes of dementia are a major contributor to dementia,” Hess said. “Not only do they give you dementia by itself, but they also appear to accelerate Alz?heimer’s.”
Studies have found some of the best predictors of whether someone will have dementia later in life are those things that put them at higher risk of stroke: high blood pressure, high cholesterol and smoking, Hess said.
“Everything that leads to stroke leads to dementia, implying that these are shared risk factors and common processes,” Hess said.
Even without some of these risk factors, aging itself weakens the smaller blood vessels in the brain and they can degenerate over time, he said. That can lead to a lack of blood flow, particularly in deeper parts of the brain such as the white matter around the ventricles, and that can lead to damage visible on an MRI scan, Hess said.
“Almost everybody, by the time they hit 70, have evidence of white matter damage in their brains, presumably from the small (blood) vessel disease,” he said. “If we live long enough, we’re all going to get it.”
That damage, called leukoaraiosis, can lead to vascular cognitive impairment, Hess said. The damage will begin to affect the person by essentially severing communication between areas of the brain responsible for different things, such as movement and speech, and making coordination difficult, he said.
“(Patients) tend to be slow, they can’t multitask, they can’t stay on task, they can’t focus, they can’t concentrate,” Hess said. “That will lead to more severe dementia later on.”
There is no good treatment yet for it, but there might be ways to combat it.
A lot of research has shown that short periods of cutting off blood flow, known as ischemic preconditioning, can help organs adapt to longer and larger periods of loss. It is what might help the body improve during periods of intense physical exercise, as muscles and blood vessels appear to make adaptive changes, different studies have found.
This relies on something called the hormesis effect, where small amounts of something bad, such as a toxin, could have a beneficial result or help the body become conditioned to withstand a larger dose, Hess said.
“What we think is happening is any kind of minor insult is basically stimulating the organism to induce endogenous (internal) protective mechanisms,” he said. “Small doses protect, larger doses kill.”
Doing the same thing for the brain would be tricky, but it might be possible to cut off blood flow in a limb and achieve the same results, Hess said.
In what’s being called remote ischemic “conditioning,” a blood pressure cuff is used to cut off blood flow in a limb for minutes at a time in mice on a daily basis for two weeks, even after artificially inducing blood flow loss in the brain. Hess’ preliminary research found an improvement in blood flow, cognitive performance and even preventing the accumulation of proteins associated with Alz?hei?mer’s known as amyloid beta.
If it were done in people, it might involve inflating a blood pressure cuff four to five times for five minutes at a time on a daily basis for some time, he said. The idea would be to target those with the damage who have only a mild impairment in order to try to keep it from progressing, Hess said.
“I think we’re looking more at arresting it,” he said. “It’s not clear that these white matter lesions are reversible. They seem to just progress, so we’d really be looking at stopping progression.”
There is some evidence that can happen. A large multicenter European study of patients with that white matter damage found that those who exercised more had less dementia and did better than those who had not.
“It kind of makes sense,” Hess said. “We know that physical exercise seems to reduce your risk of Alzheimer’s, reduces your risk of cognitive decline.”
Using the blood pressure cuff conditioning could be “an exercise equivalent,” he said. “The mechanisms have much in common.”


For Alzheimer's patients, resveratrol brings new hope

By Carina Storrs
September 11, 2015

(CNN)Over the years, resveratrol, an antioxidant found in grapes, chocolate and red wine, has been touted as a possible antidote to Alzheimer's disease, cancer, diabetes and many other conditions. Now, the first study in people with Alzheimer's suggests that the compound, when taken in concentrated doses, may actually have benefit in slowing progression of this disease.

Researchers at 21 medical centers across the United States looked at the safety and effectiveness of taking high doses of resveratrol in an experimental pill -- equal to the amount found in 1,000 bottles of red wine -- in people with mild to moderate Alzheimer's.

The researchers looked at several biomarkers of Alzheimer's, and found that people who took up to four pills a day for a year had higher levels of amyloid-beta proteins in their spinal fluid than those who took a placebo (control) pill.

Although accumulation of amyloid-beta in the brain is a hallmark of Alzheimer's disease, patients actually have lower levels of this protein outside of the brain. The study finding suggests that resveratrol could help change the balance from amyloid-beta buildup in the brain to circulating protein in the body.

Even if concentrated forms of resveratrol pills like the kind used in this study were available, it's too soon to recommend going out and getting some just yet.

"The study is encouraging enough that we should certainly go ahead and do a [larger] clinical trial because we showed that it is safe and does have significant effects on Alzheimer's biomarkers," said Dr. R. Scott Turner, professor of neurology at Georgetown University Medical Center and lead investigator of the study, which was published on Friday in the journal Neurology.

The main goal of the current study, which included 119 patients, was to find out whether high doses of resveratrol could be safe. The only small concern they found was that patients taking resveratrol lost about two pounds during the one-year study, and weight loss is already a problem with Alzheimer's, Turner said. In comparison, the control group gained about 1 pound.

Much more research is needed
The study was not big enough to answer some important questions, such as whether patients taking resveratrol actually had lower levels of amyloid-beta plaques in their brain, and most importantly, whether they experienced less decline in their mental faculties.

A large, phase 3 clinical trial getting at these issues could start in as soon as a year, Turner said. (The current study was a phase 2 trial, typically meant to evaluate safety and get an early look at efficacy of a new drug.)

Even for the relatively small number of participants in the study, the researchers did see indication that resveratrol could improve cognition. Patients in this group had slight improvements in their ability to carry out daily tasks, such as remembering to brush their teeth. And anecdotally, patients who took resveratrol told the researchers that they felt like they were maintaining their mental ability. (Neither the participants nor the researchers knew who was taking resveratrol and who was taking placebo.)

"To really get a better feel of how effective this could be you really need to do larger studies for longer periods of time (such as several years)," said James A. Hendrix, director of global science initiatives at the Alzheimer's Association, a research and advocacy organization. "Other potential therapies we've had had some early exciting results and then they didn't pan out in later trials," he added.

If resveratrol does pan out in further research, it may add to the medications that are currently available, such as Aricept and Exelon, which slow, but do not halt, progression of the disease, Hendrix said.

Ultimately, it will probably be a combination of several drugs, as well as diet, exercise and social and mental stimulation that help stave off the rapid mental decline that is often associated with Alzheimer's, he added.

Antioxidant may be most effective in combination
This is one of the first studies to look not only at these biomarkers, but also the metabolites of resveratrol in spinal fluid, to show that resveratrol is probably getting into the brain, said Dr. Giulio M. Pasinetti, who is the Saunders Family Chair and professor in neurology at the Icahn School of Medicine at Mount Sinai. However, he added that changes in biomarkers may not necessarily lead to mental and behavioral improvements, which larger studies will address.

In addition, resveratrol on its own might not end up working as well as a combination of resveratrol and other polyphenol compounds found in red wine, grape juice and grape seed extract, which could help people at risk of Alzheimer's and those who already have mild symptoms, Pasinetti said.

The current study used high doses of resveratrol to increase the chances that enough of the compound got into the brain to have an effect. But for now, the best way to get resveratrol is probably through diet. One glass of red wine a day could help those with mild Alzheimer's, "but no more than that," Turner said.

There is probably little benefit in taking currently available resveratrol supplements, even if they claim to contain levels similar to the ones used in this study. "The things that are on the market are not regulated, and you don't know how much is in them," Turner said. "There could be 500 milligrams, which is what they advertise [researchers gave participants in the study four 500 milligram pills a day] or there could be zero," he said.

Previous research has suggested that people who consume diets rich in resveratrol do not have lower rates of cancer, heart disease and other conditions.

Nerve Growth Factor Gene Therapy

Alzheimer's Disease: Gene Therapy May Promote Neuronal Growth
Early results from a small trial show promise

by Kristina Fiore
Staff Writer
MedPage Today

A gene therapy that boosts nerve growth factor (NGF) production in cholinergic neurons was safe and appeared to promote neuronal growth in a small study of patients with early Alzheimer's disease, researchers reported.
All 10 patients in the trial -- which started in 2001 -- showed a trophic response to the growth factor delivered via gene therapy, Mark Tuszynski, MD, PhD, of the University of California San Diego and the San Diego Veterans Affairs clinic, and colleagues reported online in JAMA Neurology.

"In every case, all cholinergic neurons showed growth," Tuszynski told MedPage Today. "We consistently achieved [growth] in every patient who had the procedure."
Tuszynski's group appears to be doing the only gene therapy for Alzheimer's disease. Most therapeutic efforts in the field have focused on the accumulation of amyloid in the brain, but after several failed trials of antibodies targeting accumulation of that protein, researchers have begun to ask whether it's time to explore other therapeutic targets.
NGF gene therapy instead attempts to directly target the neurodegeneration that manifests clinical symptoms. It does not target amyloid.
Tuszynski said his group chose NGF because it stimulates the cholinergic neurons that are impaired so early on in the Alzheimer's disease process. The protein helps to prevent cell death and neurodegeneration.
But why gene therapy instead of just delivering NGF? It's important to keep potent growth factors under control to thwart potential side effects, Tuszynski said.
"It's a better way to go [since] it's simple, efficient, and now we know it's safe," he told MedPage Today, adding that it's also a matter of convenience. "In theory, you could give it once in a person's lifetime and be done. They won't have to take medications."
For their trial, the researchers enrolled 10 patients with early Alzheimer's in what was the first attempt at gene delivery to slow neurodegeneration.
The first eight patients had ex vivo gene therapy, which involves inserting NGF genes into skin fibroblasts and implanting those altered cells into the brain. The final two patients had in vivo gene therapy, in which an adeno-associated viral vector serotype 2 (AAV2) carrying NGF genes were injected into the brain.
The researchers autopsied all 10 brains after patients died. They found that the neurons responded to the therapy in all patients, as evidenced by axonal sprouting toward the NGF source, neuronal hypertrophy, and activation of cell signaling.
Although there are concerns about systemic effects of growth factors in the body, the researchers reported no serious adverse events.
"This is the largest opportunity to date to show that at an anatomical level, [gene therapy delivering NGF] is safe," Tuszynski said. "Growth factors are very potent in the nervous system, and if they're broadly distributed, they can cause off-target adverse effects. But we saw none in these 10 patients."
One patient survived 7 years, and there was evidence that the implanted NGF genes continued to be expressed at that time, he added.
Some researchers not involved in the study told MedPage Today that the data provide encouraging support for the potential of gene therapies that deliver growth factors, but that large clinical trials are needed to see whether this therapy has a meaningful clinical effect.
Others were quick to applaud the work for moving beyond amyloid and into other targets that likely play a role in the Alzheimer's disease process.
"The cholinergic basal forebrain appears to be one of the earliest tangled areas, and [neurofibrillary] tangling may index oxidative stress, inflammation, mitochondrial decline, and perhaps other metabolically undesirable aspects of aging that are being accelerated in the Alzheimer's brain," Douglas Watt, PhD, of the Alzheimer's center at Quincy Medical Center in Boston who was not involved in the study, told MedPage Today.
"From this perspective, it does make sense that nerve growth factor may counter-balance whatever is going on to create early tangling in these cholinergic regions," Watt said.
He added that the "clear implication" of the research is that researchers "really shouldn't be looking at treatments in isolation but in combination."
That includes "anti-inflammatory, pro-plasticity, mitigating sex steroid declines, promoting insulin sensitivity in the brain, correcting circadian imbalances, promoting better mitochondrial function, proving dietary patterns, improving aerobic fitness, reducing social stress and social isolation, etc.," Watt said. "And yet we've had decades of applying single factor therapies in relationship to Alzheimer's disease -- and the vast majority of these have shown minimal to no benefit at all."
Tuszynski noted that a phase 2 multicenter randomized sham-surgery-controlled trial of AAV2-NGF gene delivery is completed and will publish soon.
He and his group also published work on gene therapy with brain-derived neurotrophic factor (BDNF) targeting cortical neurons in animal models in Nature Medicine in 2009, and they are now slated to start human clinical trials in 12 to 18 months, he added.
Tuszynski is the founder of Ceregene but has no present financial interest in the company.
Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Original Investigation | August 24, 2015
Nerve Growth Factor Gene Therapy Activation of Neuronal Responses in Alzheimer Disease
Mark H. Tuszynski, MD, PhD1,2; Jennifer H. Yang, BS1; David Barba, MD3; Hoi-Sang U, MD3; Roy A. E. Bakay, MD4; Mary M. Pay, NP1; Eliezer Masliah, MD1; James M. Conner, PhD1; Peter Kobalka, MD1,5; Subhojit Roy, MD, PhD1,5; Alan H. Nagahara, PhD1
[+] Author Affiliations
JAMA Neurol. Published online August 24, 2015. doi:10.1001/jamaneurol.2015.1807

Importance Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment.

Objective To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset.

Design, Setting, and Participants Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined.

Main Outcomes and Measures Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay.

Results Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P?<?.05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)?mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed.

Conclusions and Relevance These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.

targeting Treg-mediated systemic immunosuppression

Brain's immune system ‘key to reversing dementia’

ALZHEIMER’S disease could be halted and even reversed by altering the brain’s immune system, groundbreaking research says.

Aug 18, 2015

Leading neurobiologist Professor Michal Schwartz said the findings were “very exciting” ? and showed for the first time that a diseased brain was able to fight the debilitating condition.

Scientists saw a significant drop in the symptoms of dementia when they reduced the cells that prevent the immune system from reacting.

The study by experts at the Weizmann Institute of Science in Israel and published in journal Nature Communications, offers hope of a drug for the disease which affects about 850,000 people in Britain.

Mice were genetically engineered with human genes that are linked to dementia and made to learn the location of a platform in a rodent "swimming pool”

Scientists then blocked the action of regulatory T cells which consequently allowed immune cells to enter the brain.

As a result, inflammation and clumps of “plaque” on the brain were reduced and the mice performed better in cognitive tests.

Prof Schwartz said: “Those who were given the therapy were almost as good at memorising the platform as normal mice ? even though they already had symptoms of dementia.

“It means the therapy not only halted the condition but reversed it.”

The most common form of dementia, Alzheimer’s disease affects the body’s central nervous system.

Inflammation, damage to brain cells and abnormal protein build-up can cause devastating memory loss and inability to respond to the environment.

Researchers said the work highlighted the possibility of T cells as drug targets for future Alzheimer’s treatment.

Prof Schwartz said: “The concept is very exciting.

“We already have several molecules we believe could perform the same function in humans and we hope we will be able to reveal these in pre-clinical experiments by the end of the year.”

Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology

Kuti Baruch, Neta Rosenzweig, Alexander Kertser, Aleksandra Deczkowska, Alaa Mohammad Sharif, Amit Spinrad, Afroditi Tsitsou-Kampeli, Ayelet Sarel, Liora Cahalon & Michal Schwartz
AffiliationsContributionsCorresponding authors
Nature Communications 6, Article number: 7967 doi:10.1038/ncomms8967
Received 21 April 2015 Accepted 01 July 2015 Published 18 August 2015

Abstract? Introduction? Results? Discussion? Methods? Additional information? References? Acknowledgements? Author information? Supplementary information
Alzheimer’s disease (AD) is a neurodegenerative disorder in which chronic neuroinflammation contributes to disease escalation. Nevertheless, while immunosuppressive drugs have repeatedly failed in treating this disease, recruitment of myeloid cells to the CNS was shown to play a reparative role in animal models. Here we show, using the 5XFAD AD mouse model, that transient depletion of Foxp3+ regulatory T cells (Tregs), or pharmacological inhibition of their activity, is followed by amyloid-β plaque clearance, mitigation of the neuroinflammatory response and reversal of cognitive decline. We further show that transient Treg depletion affects the brain’s choroid plexus, a selective gateway for immune cell trafficking to the CNS, and is associated with subsequent recruitment of immunoregulatory cells, including monocyte-derived macrophages and Tregs, to cerebral sites of plaque pathology. Our findings suggest targeting Treg-mediated systemic immunosuppression for treating AD.


Novato's Buck Institute battles looming Alzheimer’s tsunami

Actor Peter Falk, best known for his lead role in the television series "Columbo," had Alzheimer's disease. (publicity photo, 1973)

The North Bay Business Journal
August 17, 2015, 5:01AM

Editor’s note: This is the first of two stories on the Buck Institute for Research on Aging’s studies on Alzheimer’s disease ? costs and emerging drugs. Part two next week examines how researchers treat Alzheimer’s with dozens of “targets,” and new data that show three types of Alzheimer’s.

Alzheimer’s ? a scary, progressive disease ? darkened the brains of President Ronald Reagan, composer Aaron Copeland, artist Norman Rockwell, writer E.B. White, actors Rita Hayworth, Peter Falk and Charlton Heston, and boxer Sugar Ray Robinson. Rita Hayworth, star of Gilda (1946), dance partner of Fred Astaire and spouse of Orson Welles for four years, was diagnosed with Alzheimer’s in 1980 at age 62; she died of the disease in 1987. Her daughter, Princess Yasmin Aga Khan, founded the Rita Hayworth Gala, an annual Mother’s Day benefit for the Alzheimer’s Association held in New York and Chicago that has raised some $65 million.

The disease, a focus of research at Novato-based Buck Institute for Research on Aging, ruins neurons and incrementally sabotages its victims’ mental acuity, blurring especially short-term memory. Some victims eventually cannot recognize their own family members or lose the ability to swallow.

Nearly a third of 2.6 million Americans who die each year have Alzheimer’s, nearly 85,000 attributed to it. The wily disease contributes to deaths from pneumonia and malnutrition. Direct costs of caring for Alzheimer’s patients will exceed $225 billion in 2015, half covered by Medicare.

Now afflicting 5 million Americans, Alzheimer’s is expected to hit some 13 million Americans and cost more than $1 trillion by 2050. In that year, Medicare will spend more than $450 billion ? a quarter of its projected budget and threatening its solvency ? on the disease.

Scientists at the Buck Institute, on a budget of only $32.5 million, are racing to learn about Alzheimer’s and tame the brain disorder that wrecks memory and thinking, and causes enormous suffering in victims and their families.

Alzheimer’s manifests as a complex disease with several dozen contributing factors. Research that looks at the disease as a gestalt ? an organized system that is more than the sum of its parts ? holds particular promise (see part two next week). This multivariable approach to science is radical, far from the one-factor-at-a-time clinical studies the Food and Drug Administration usually supports.

“The process is inherently dynamic,” subject to evolution, according to Dr. Dale E. Bredesen, the Buck Institute’s first CEO, who returned to full-time research in 2008. Bredesen, a pioneer in Alzheimer’s research, also directs the Easton Center for Alzheimer’s Research at UCLA.

Alzheimer’s strikes twice as many women as men. Once they have dementia, women decline twice as fast as men, according to studies cited by the Alzheimer’s Association in Chicago.

Early-onset Alzheimer’s, which strikes by age 40 or 50, was depicted by Julianne Moore in the movie Still Alice. Early Alzheimer’s, which is linked to a genetic mutation and accounts for roughly 5 percent of cases, was the subject of a joint research project between Buck Institute and BioMarin Pharmaceuticals, a biotechnology company in San Rafael. The project ended when BioMarin, with some $700 million in revenue, concluded that the drugs under study would be too expensive to manufacture.

“That BioMarin collaboration ended” about a year ago, Bredesen said. “There were very practical issues: Can you make enough drug? Can you make it pure enough? Can you make it easily enough, cheaply enough? The drug worked beautifully in animal models. It turned out to be not so easy to make. It had a lot of disulfide bridges (a bond between sulfur atoms).”

More common forms of Alzheimer’s descend typically after age 65. The potential market for a drug to treat Alzheimer’s is huge, estimated at $10 billion to $20 billion. Until recently, research has produced several Alzheimer’s drug failures.
Bredesen oversees the Buck Institute’s first clinical trial in Australia on a drug code-named FO3, which binds three receptors involved in cognitive function. The Phase 1b/2a clinical trial involves 36 patients with amnestic mild cognitive impairment.
“We’re still early,” Bredesen said. “It depends on how quickly people get enrolled.” Results could be available by fall 2016.
Funding for the $2 million to $3 million trial is from several sources: the Ellen and Douglas Rosenberg Foundation; Bechtel Foundation; the Alzheimer’s Association; and former Buck Institute board member Hussam Abu Issa.
He considered doing an FO3 clinical trial here, but at issue is whether it would be Phase I (testing healthy volunteers for dose ranging) or Phase II (testing patients to assess efficacy and safety.) “It’s already available in Australia,” he said, “Here we would have to get an IND (investigational new drug application.) It will be helpful to have results there.”
Bredesen and colleagues tested FO3 “head-to-head in mice” against Aricept (donepezil hydrochloride) and Namenda (memantine), both used to treat dementia. “It was far superior to either one,” Bredesen said.
“We have new information on FO3 that’s quite exciting and not yet published,” Bredesen said. “It looks like FO3 has efficacy beyond what we originally thought, a novel mechanism of action as well. We’re hoping this will be something that will be tested in the U.S. if we have partnership with (Culver City-based) NantWorks,” he said. “We’re doing drug development in this general area with NantWorks.” That project in the United States is at least a year away, Bredesen said.
NantWorks was founded in 2011 by Dr. Patrick Soon-Shiong, a controversial surgeon and medical researcher estimated by Forbes in 2014 to have net worth of about $12 billion.
FO3 affects the processing of amyloid deposits (misfolded proteins) in the brain, which can form a sticky plaque that some scientists associate with Alzheimer’s symptoms. Amyloid beta peptides are “a component of a much bigger system,” Bredesen said. “There is a metabolic control and a network of signals and structural components.”

A synapse requires proper lipids as well as the right signals. “The CEO of a company has to take a lot of things into account to determine whether to build that next building,” Bredesen said. “Do they have the personnel, the permits, the cash, the interest, the product? There are different forms of input. The brain is doing that same thing ? am I going to make and keep a memory? Do I have the right hormonal signals, the right anti-inflammatory signals, the right vitamins, nutrition?”

As people age, their bodies assess moment by moment “what size and sort of system you are capable of supporting,” Bredesen said, based on mitochondrial function (cellular energy), nutritional support, exercise, DNA and other factors. It’s like “downsizing a company,” he said, when the brain decides not to store certain memories due to Alzheimer’s. “Am I capable of supporting a 10,000-person company or just a 1,000-person company?”
Amyloid beta “is part of the downsizing,” he said. If connected neurons are deprived of their nerve growth factor and brain-derived neurotrophic factor, a protein coded by BDNF genes, the neurons send out amyloid beta “as part of the signal, saying, we are not supported for a major connection anymore. We’re downsizing,” Bredesen said.
In effect, the brain jettisons memories it considers extraneous.
“People have spent their careers to focus on” amyloid beta, Bredesen said, “without realizing it is part of a much bigger system.”
“Take a young woman, 40 years old” who gets a hysterectomy, he said. Her estrogen drops to zero, and her chances of getting Alzheimer’s disease doubles. “You have stripped away one of the things that is supportive” of fresh memory storage.
“Here’s what’s really fascinating to me as a neuroscientist,” Bredesen said. “Bacteria have quorum sensing,” a chemical regulation of gene expression in response to fluctuations in cell-population density.
The bacteria seek to know if there are sufficient nutrients, based on how many other bacteria of the same kind are in the vicinity. “They emit a chemical,” Bredesen said. “When the chemical hits a certain concentration, it will stick to itself.”
In the brain, that sticky substance is amyloid, he said. “When we make amyloid in our brains, we are quorum-sensing for synapses. We’re saying, can we support this large number of synapses? As they start to fail, you start to make amyloid to say, wait a minute, you have exceeded the threshold of what you can support. You are getting to an age where you can’t support this number” of neurons.
Drugs that inhibit production of amyloid are “silly,” Bredesen said. “The amyloid is just there because you can’t support that large network any more. Don’t stop the amyloid, but provide support for the network” of neurons.

“We have to think of Alzheimer’s in a very, very different way,” he said. “We need to bring eastern medicine, western medicine. There’s going to be a future new type of doctor ? traditional Chinese doctor with the western doctor,” who is good at DNA and proteins, but not grasping the whole picture of patient health. “Traditional Chinese doctors knew nothing about DNA or protein,” Bredesen said. “They understood that you need to treat the body as a concert, a whole symphony. That’s the doctor we need to create,” he said, one who “understands a patient’s genome, quorum-sensing, where amyloids are coming from. Then you treat the whole thing, and you get results. That’s chronic medical treatment going forward.”
A 10-minute doctor’s appointment may not be enough with a complex disease. “You’ve got to be Sherlock Holmes,” Bredesen said. “Why is this person on the wrong side of that balance?”
Editor’s note: Don’t miss next week’s part 2, a look at Bredesen’s new research, and details of how he reverses Alzheimer’s symptoms.

Scientists Turn Skin Cells into Brain Cells, Using Alzheimers Patients


You are looking at freshly-made human neurons, or brain cells. But they used to be common skin cells. And their existence could change how we treat Alzheimers.

Using a special mix of small molecules, two groups of scientists in China have successfully turned human skin cells into neurons. They hope that their technique could one day help rejuvenate failing tissues in the brains of Alzheimers patients.

The two teams in China focused on strategies for converting skin cells to neurons, with one group focusing on skin cells from mice and the other on humans. Results of their work are published in two papers today from the journal Cell Stem Cell. The team working on human cells drew their samples from Alzheimers patients, because one possible end goal of this research would be to produce working brain cells that could supplement failing tissues in the brains of people with dementia.

If someone became ill with Alzheimers, doctors might one day use this technique to take a small skin sample and generate new, healthy brain tissue for them. Because the tissues had been made from the patient’s own body, there would be no risk of rejection.

The technique worked in both mice and humans, though we are very far from converting this breakthrough into a working therapy for Alzheimers. Still, the results are promising, especially because they don’t require expensive and difficult genetic engineering techniques.

Peking University cell biologist Hongkui Deng, who worked on the mouse study, said in a release:

The small molecules that are used in this chemical approach are cell permeable; cost-effective; and easy to synthesize, preserve, and standardize; and their effects can be reversible. In addition, the use of small molecules can be fine-tuned by adjusting their concentrations and duration, and the approach bypasses the technical challenges and safety concerns of genetic manipulations, which may be promising in their future applications.
Even more exciting is the possibility that the small molecule mixture could be tweaked to induce skin cells to turn into very specific kinds of neurons.

Shanghai Institutes for Biological Sciences researcher Jian Zhao worked on the human study. She said:

It should be possible to generate different subtypes of neurons with a similar chemical approach but using slightly modified chemical cocktails. It also needs to be explored whether functional neurons could be induced by chemical cocktails in living organisms with neurological diseases or injury.
Her final comment is the most intriguing yet. She’s hinting at the idea that we might be able to use these small molecules ? which she calls “chemical cocktails” ? in a living person to convert their cells into fresh neurons on the spot. Imagine growing neurons right on your arm, then transplanting them into your brain or spinal cord to heal an injury.

Medicine of the future might help us heal ourselves, by giving us new ways to control how our cells grow.

Read the full scientific papers [paper one and paper two] at Cell Stem Cell.

Image of chemical induced neurons courtesy of Gang Pei and Jian Zhao

Contact the author at annalee@gizmodo.com.
Public PGP key
PGP fingerprint: CA58 326B 1ACB 133B 0D15 5BCE 3FC6 9123 B2AA 1E1A

Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons

DOI: http://dx.doi.org/10.1016/j.stem.2015.06.003 |

?Chemical screening identifies a small molecule cocktail for reprogramming
?Functional mature neurons can be induced from fibroblasts with chemicals alone
?BET family protein inhibition suppresses the fibroblast-specific program
?The neurogenesis inducer ISX9 is required for induction of neuronal genes

Recently, direct reprogramming between divergent lineages has been achieved by the introduction of regulatory transcription factors. This approach may provide alternative cell resources for drug discovery and regenerative medicine, but applications could be limited by the genetic manipulation involved. Here, we show that mouse fibroblasts can be directly converted into neuronal cells using only a cocktail of small molecules, with a yield of up to >90% being TUJ1-positive after 16 days of induction. After a further maturation stage, these chemically induced neurons (CiNs) possessed neuron-specific expression patterns, generated action potentials, and formed functional synapses. Mechanistically, we found that a BET family bromodomain inhibitor, I-BET151, disrupted the fibroblast-specific program, while the neurogenesis inducer ISX9 was necessary to activate neuron-specific genes. Overall, our findings provide a “proof of principle” for chemically induced direct reprogramming of somatic cell fates across germ layers without genetic manipulation, through disruption of cell-specific programs and induction of an alternative fate.

Received: March 9, 2015; Received in revised form: May 11, 2015; Accepted: June 8, 2015;
? 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.


Medscape Medical News s
TTP488: From Futility to Fast Track for Alzheimer's
Pauline Anderson
July 30, 2015

WASHINGTON, DC ? An investigational Alzheimer's disease (AD) drug that a few years ago might have ended up in the disposal heap ? or at least in the recycling bin ? is now fast tracked for regulatory approval.

The change in direction could be due to its novel neuro?anti-inflammatory mode of action, the strength of its eventual statistical significance, or the fact that there are so few promising pharmaceutical interventions for dementia.

In any case, the drug, TTP488 (Azeliragon, vTv Therapeutics Inc), initially failed a futility analysis but is now fast tracked by the US Food and Drug Administration (FDA), with a phase 3 study already underway.

The lesson is that futility analyses in AD trials may be "misleading," says Marwan Sabbagh, MD, director, Banner Sun Health Research Institute, Sun City, Arizona, and principal investigator for the phase 3 program now investigating TTP488. "They argue for conducting the full analysis plan even when futility criteria are met."

Dr Sabbagh gave an overview of findings with this drug during an oral presentation here at the Alzheimer's Disease International Conference (AAIC) 2015.

Inhibits RAGE

TTP488 works by inhibiting the receptor for advanced glycation end-products (RAGE). "This small orally active molecule blocks RAGE and therefore in consequence reduces the downstream effects," which include vascular dysfunction, metabolic dysregulation, and amyloid deposition, said Dr Sabbagh.

At high levels of expression, RAGE has been correlated with disease severity and progression, and it affects normal microglial and endothelial cells, said Dr Sabbagh. In a RAGE knockout model, mice resist amyloid β plaque formation but are otherwise normal.

Dr Sabbagh provided results of a phase 2b trial of TTP488 that was discontinued a few years ago after a futility analysis. The study included 399 patients with a Mini-Mental State Examination (MMSE) score of 14 to 26 who were receiving background therapy of cholinesterase inhibitors and/or memantine. There was 80% power to detect a treatment effect on the AD Assessment Scale-Cognitive Subscale (ADAS-cog) with a prespecified difference of 3 points.

These patients were randomly assigned to one of three groups: a 60-mg/day load followed by a 20-mg/day maintenance dose; a 50-mg/day load followed by a 5-mg/day maintenance dose, or placebo.

A year after all patients had been randomly assigned, researchers used a decision tree to apply the futility analysis, said Dr Sabbagh.

"Basically, what we said was that if there was conditional probability of less than 10% that there would be a difference between treatment and placebo, there would be a decision to terminate the study. If the conditional probability was greater than 20%, then the study would continue unabated; and if there was somewhere between 10% and 20%, there were secondary triggers that were to be applied."

At that 12-month analysis, the conditional probability of a difference between treatment and placebo was determined to be 9.3%. Researchers decided to terminate the study, and patients discontinued dosing at their next visit.

Dr Sabbagh pointed out that while not a consideration in the futility decision algorithm, there was a 2.3-point difference in median values between the 5-mg dose of the drug and placebo on the ADAS-cog.

And, had the conditional probability reached 10%, the 12-month mean ADAS-cog between-group difference for the 5-mg dose would have been 1.34.

At the end of the 18-month study, the final protocol planned analysis showed that the study did indeed meet its prespecified endpoint, with a 3.1 difference in ADAS-cog of treatment over placebo, with an impressive P value of .008.

Multiple Models

"This was looked at in multiple mathematical statistical models and every single one of them was positive," said Dr Sabbagh. "That is to say that the protocol planned analyses using different methodologies to cope with missing data all showed a statistically significant difference in ADAS-cog favoring 5 mg of treatment over placebo."

An on-treatment analysis, which included all patients with on-treatment data plus 45 days and accounting for a half-life of roughly 18 days, showed a statistically significant value (P = .03) favoring treatment over placebo, with a mean difference of 2.7 points on the ADAS-cog.

A post hoc analysis of patients with mild AD (MMSE score, 21 to 26) showed a between-group ADAS-cog difference of as many as 4 points (P = .018).

This subgroup analysis also found that the difference in the Clinical Dementia Rating sum of the boxes (CDR SB) was statistically significant for the treatment group (a difference of 1 point; P = .02).

How can the "discordance" between these positive results and the prediction of the futility analysis be explained? According to Dr Sabbagh, it was from the use of a statistical model that included only a small sample of participants.

The futility analysis "was based on a single snapshot, a single variable, and a single statistical model that was different from the protocol planned in the final analysis," he said.

"In essence, hindsight is 20/20, and if we were to do it over again, we would not have seen the futility trigger met."

Asked by a delegate whether the parameters for the futility analysis could have been changed, Dr Sabbagh said he "anguishes" over this issue. "I love to speculate about the 'shoulda, woulda, coulda,' but the bottom line is that it was applied. At the end of the day, if we could do it again, I would say there would be no futility analysis, but it is what it is, and that was what was applied at the time."

Now, a phase 3 trial under an FDA-agreed special protocol assessment has gotten under way. The 18-month trial will include 800 patients with an MMSE score of 21 to 26 who will be enrolled in one of two studies, each of which will have two groups: 5 mg/day of the drug or placebo.

The higher dose of the drug has been discontinued because of toxic effects, including confusion, falls, and a greater ADAS-cog decline not seen with the lower dose or placebo.

Weighing in on the topic, Maria Carrillo, PhD, chief science officer, medical and scientific relations, Alzheimer's Association, told Medscape Medical News that TTP488 is "very promising" despite the futility analysis not showing a difference in relation to placebo.

"When the researchers followed the patients out at 18 months, meaning the subjects didn't get any drug for 6 months, they actually found a significant benefit."

She pointed out that the drug company, vTv Therapeutics Inc, is trying to raise money to continue with the research after Pfizer "dropped it." The company has filed a registration statement with the Securities and Exchange Commission.

As the principal investigator for the phase 3 program, Dr Sabbagh is a paid consultant but does not have commercial proprietary ownership in the company. Dr Sabbagh receives research support from Lilly, Avid, Navidea, Functional Neuromodulation, Neuronix, Merck, Takeda, AstraZeneca, Roche, and Genentech. He is an advisor for Biogen Lilly, vTv therapeutics, Avid, and Piramal. He receives royalties from TenSpeed/Random House.

Alzheimer's Association International Conference (AAIC) 2015. Oral presentation 04-09-03. Presented July 22, 2015.


This 29-year-old CEO's Alzheimer's drug is one critical clinical trial away from getting approval

Lydia Ramsey
Today at 7:12 AM ? ? ?

It’s incredibly difficult to bring a new pharmaceutical drug to market: about 95% of drugs in clinical trials never get approval. For Alzheimer’s disease, that percentage changes to 99%.

But Vivek Ramaswamy, a 29-year-old former Wall Street hedge fund manager, told investors at a meeting Wednesday that his company Axovant is “a single confirmatory study away” from getting FDA approval for his mild-to-moderate Alzheimer’s disease treatment, currently called RVT-101.

Pharmaceutical giant GlaxoSmithKline started developing the drug, but couldn’t get it off their hands fast enough ? it had done poorly on its own in clinical trials. That is, except one, which combined the drug with Aricept, a widely used drug already available on the market and used to treat Alzheimer’s symptoms like memory loss and confusion. Together, the two together slowed the loss of cognition and ability to perform daily tasks than when Aricept was taken alone.

Ramswamy latched on to that one study. Axovant got the rights to the compound in December 2014, paying only $US5 million for it. Since then, the company had its initial public offering in June ? the biggest in biotech history at $US1.4 billion, according to Forbes.

It plans to launch the phase 3 trial by the end of the year, building off the results of its recent phase 2b study which were announced earlier this week.

Axovant is in the business of late-stage drug development, which means they don’t research and develop their own drugs from scratch. This cuts years off the costly drug development process.

The phase 3 study will again use Aricept, generically known donepezil. The hope is to make RVT-101 a pill that’s taken once a day.

But it’s not out of the woods yet. Just because a study has success up through phase 2b does not mean the FDA is ready to hand over approval. But doctors have shown support for the drug. It’s not a huge medical advance, but it is a step in the right direction. Ramswamy said in a meeting with investors they hope to file for FDA approval by 2017.

combination of dextromethorphan and quinidine.

Jul 22 2015, 1:06 pm ET

Drug Helps One of Worst Alzheimer's Symptoms - Agitation

A drug that combines a cough suppressant with a medication to fight heart arrhythmias might offer some peace for one of the most troubling symptoms of advanced Alzheimer's disease - agitation - researchers reported Wednesday.

The drug is already approved to treat uncontrollable laughing, crying or other outbursts caused by head injuries and degenerative disease such as amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig's disease. The symptom is called pseudobulbar agitation.

It's a combination of dextromethorphan - a cough suppressant - and the anti-arrhythmic drug quinidine.

A trial in Alzheimer's patients showed it improved nearly half of them, researchers told the Alzheimer's Association International Conference.

"This is one of the most tough symptoms for families to manage," said Dr. Jeffrey Cummings of the Cleveland Clinic center for brain health in Las Vegas, who led the study.

"These are people who will shout or slam doors or strike out or in some way make very difficult for the caregiver to take care of them."

It's hard to measure improvements in behavior, but on a scale that measures agitation, patients who got the drug improved from a 7 on the scale to about 3.5, Cummings said.

Cummings said he was giving the drug to a patient outside of the clinical trial. "The caregiver said to me, 'He came back to us'. I thought that was such a powerful, powerful statement," Cummings told a news conference.

It's a rare glimpse of light for caregivers of Alzheimer's patients, who can become inexplicably agitated, kicking, screaming, cursing and struggling. Agitation is the main reason that Alzheimer's patients must be moved to specialized care facilities, taking them away from family and familiar surroundings. And residential care can be extremely expensive.

"Hard-to-manage care situations, wandering off and challenges with the bathroom are the primary reasons families are forced to move their loved ones into institutional care centers," said Maria Carrillo, chief science officer for the Alzheimer's Association.

The dextromethorphan works in the brain. The quinidine simply stops the body from breaking it down, raising the effectiveness, Cummings said. Researchers testing the drug for pseudobulbar agitation noticed it also seemed to relieve agitation, and decided to try it for Alzheimer's.

Earlier, researchers released details of trials showing that drugs called monoclonal antibodies might work in the very early stages of Alzheimer's to remove the brain-clogging amyloid deposits that underlie the diseases. But if they work at all, it's only going to be in patients who don't have severe symptoms yet, said Dr. David Knopman, an Alzheimer's specialist at the Mayo Clinic who was not involved in the research.

There's nothing comparable to offer patients with advanced dementia, or their caregivers. Antipsychotics can be used to treat agitation but experts and regulators discourage the practice, saying it's dangerous.

More than 5 million Americans have Alzheimer's now and that will balloon as the current Baby Boom generation gets older. The Alzheimer's Association predicts 28 million cases of Alzheimer's by 2050.

cis antibody

Beth Israel researchers discover potential brain injury, Alzheimer's cure

Jul 16, 2015
Jessica Bartlett
Boston Business Journal
Neurons can become tangled due to a misshapen protein, the hallmark of Alzheimer's and other neurodegenerative diseases.

Researchers at Beth Israel Deaconess Medical Center have developed an antibody that can target and treat the beginning causes of Alzheimer’s and other debilitating neurodegenerative diseases.

In the exciting research, funded partially by the National Institutes of Health and published this week in the journal Nature, researchers first found that a brain protein, known as the tau protein, can become misshapen as soon as 12 hours after a traumatic brain injury.

Previous research has also shown that abnormal development of the tau protein underlies Alzheimer’s and other neurodegenerative diseases.

“Healthy tau protein is found in the brain and serves to assemble and support microtubules, the ‘scaffolding systems’ that give neurons their unique shape and are integral to memory and normal brain functioning,” said co-senior author Dr. Kun Ping Lu, chief of the division of translational therapeutics in the Department of Medicine at BIDMC and professor of medicine at Harvard Medical School, in a release.

Receive Boston Business Journal's Morning Edition and Afternoon Edition newsletters and breaking news alerts.

Yet a traumatic brain injury ? such as from a concussion or from military-related blasts, or in the beginning stages of Alzheimer’s, the tau protein becomes tangled and unable to function.

This tangled protein can soon spread to other neurons. The tangled neurons are unable to transport mitochondria ? which provides energy for neuron functions ? leading to widespread neuron death.

In addition to tracking the development of this distorted protein, researchers also created an antibody that can target these problematic proteins, acting like a lock and key.

“We have developed a potent monoclonal antibody that can prevent the onset of widespread neurodegeneration by identifying and neutralizing this toxic protein and restoring neurons’ structural and functional abilities,” Lu said.

To conduct the study, researchers first confirmed that this protein was present in diseased human brain cells, and that misshapen tau proteins were the cause of neurodegenerative diseases.

The authors then simulated contact sport and blast-related injuries in mice, finding that the formation of disrupted tau proteins depended on how severe the injury was or how frequently injuries occurred. In mild concussions, the tau protein was only moderately disrupted. But repetitive concussions or a severe blast or impact caused persistent and longstanding changes to the protein.

Researchers then used an antibody to eliminate the toxic tau protein, preventing the neurons from dying and tangles from spreading, and restoring brain structure and function.

Researchers hope to next develop ways to identify when this distorted protein is present in humans, and develop the antibody for human use.

The work has promising implications for the 5 million Americans and 30 million people worldwide that suffer from Alzheimer’s disease.

The findings could also help identify and treat those at risk for chronic traumatic encephalopathy (CTE) ? which has been found to be in the brains of boxers, American football players and blast-exposed veterans and is characterized by risk-taking, aggression and depression.

“Alzheimer’s disease and chronic traumatic encephalopathy are terrible diseases that progressively rob individuals of their memory, judgment and ability to function,” said study coauthor Dr. Alvaro Pascual-Leone, chief of the division of cognitive neurology at BIDMC and professor of neurology at Harvard Medical School. “We need to learn more about CTE’s causes in order to develop better ways of diagnosing and treating it, and this study offers us a promising early intervention to prevent the pathologic consequences of this disease ...These findings additionally offer us a new way to approach Alzheimer’s disease.”

Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy

Nature (2015) doi:10.1038/nature14658 Received 17 June 2014 Accepted 11 June 2015 Published online 15 July 2015

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer’s disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term ‘cistauosis’, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer’s disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.

glatiramer acetate and grafted CD115 +monocytes

July 7, 2015

Enriched blood cells preserve cognition in mice with features of Alzheimer's disease

Cedars-Sinai researchers have successfully tested two new methods for preserving cognition in laboratory mice that exhibit features of Alzheimer's disease by using white blood cells from bone marrow and a drug for multiple sclerosis to control immune response in the brain.

Under the two approaches, immune cells from outside the brain were found to travel in greater numbers through the blood into the brain. The study showed measurable benefits in mice, an encouraging step toward further testing of these potentially powerful strategies in human trials.
Researchers point out that the brain's own immune cells are critical for its healthy function. During the progression of Alzheimer's disease, these cells are found to be defective. In this study, the researchers discovered that immune cells infiltrating the brain from the blood effectively resisted various abnormalities associated with the condition.
"These cells appear to work in the brain in several ways to counter the negative effects associated with Alzheimer's disease," said Maya Koronyo-Hamaoui, PhD, assistant professor of neurosurgery and biomedical sciences at Cedars-Sinai, and the senior author of the article published in Brain, a journal of Oxford University Press.
"The increasing incidence of Alzheimer's disease and the lack of any effective therapy make it imperative to explore new strategies, especially those that can target multiple abnormalities in such a complicated disease," Koronyo-Hamaoui added.
In Alzheimer's disease, a protein fragment known as amyloid-beta builds up at the synapses of neurons - the point where neuron-to-neuron communication occurs. As a result, synapses are lost and cognitive function becomes severely impaired.
Immune cells in the brain that are exposed to increasing concentrations of the toxic protein fragment deteriorate and lose their ability to attack and clear away the buildup. Over time, these cells themselves go awry, contributing to harmful inflammation and becoming toxic to the neurons.
During the course of the disease, cells that support the brain's structure and function also fail at the cellular and molecular levels, steadily impairing memory and learning functions.

In efforts to boost an effective immune response, the Cedars-Sinai scientists have devised ways to "recruit" white blood cells known as monocytes from bone marrow to attack the protein fragments and preserve the synapses.
The researchers evaluated two such methods and their therapeutic potential. In one, they extracted a specific type of monocytes from the bone marrow of healthy young mice and injected the cells into the tail veins of sick mice once a month. A second group of sick mice received weekly under-the-skin injections of glatiramer acetate, an FDA-approved drug used for the treatment of multiple sclerosis; the drug has been shown to foster the migration of white blood cells from the bloodstream to the brain. A third group received both treatments.
All three groups experienced a substantial decrease in Alzheimer's-like pathology and symptoms.
The varied approaches were effective in "recruiting" protective monocytes to "lesion sites" in the brain, removing protein fragments and reducing harmful inflammation through the secretion of chemicals that regulate immunity at the molecular level, said Koronyo-Hamaoui, the head of Cedars-Sinai's neuroimmunology laboratory at the Maxine Dunitz Neurosurgical Institute and a faculty member in the Department of Neurosurgery and Department of Biomedical Sciences.
In this study, glatiramer acetate was further found to profoundly affect monocytes' function, she added.
"This study provides the evidence that a subgroup of unmodified monocytes, extracted from the bone marrow of healthy mouse donors and grafted into the bloodstream, can migrate into the brains of sick mice, directly clear abnormal protein accumulation and preserve cognitive function," said Yosef Koronyo, the article's first author and a research associate in the Department of Neurosurgery.
Koronyo added that the study gives unprecedented details about monocyte numbers migrating into brain lesion sites and the compounds they secrete, and shows that the body's natural monocytes can have direct effects on the integrity of synapses.
Explore further: Nanotechnology identifies brain tumor types through MRI 'virtual biopsy' in animal studies
More information: Brain, "Therapeutic effects of glatiramer acetate and grafted CD115+ monocytes in a mouse model of Alzheimer's disease," published online June 6, 2015. DOI: dx.doi.org/10.1093/brain/awv150
Journal reference: Brain
Provided by Cedars-Sinai Medical Center

Therapeutic effects of glatiramer acetate and grafted CD115+ monocytes in a mouse model of Alzheimer’s disease

Yosef Koronyo , Brenda C. Salumbides , Julia Sheyn , Lindsey Pelissier , Songlin Li , Vladimir Ljubimov , Michelle Moyseyev , David Daley , Dieu-Trang Fuchs , Michael Pham , Keith L. Black , Altan Rentsendorj , Maya Koronyo-Hamaoui

DOI: http://dx.doi.org/10.1093/brain/awv150 First published online: 6 June 2015


Weekly glatiramer acetate immunization of transgenic mice modelling Alzheimer’s disease resulted in retained cognition (Morris water maze test), decreased amyloid-β plaque burden, and regulation of local inflammation through a mechanism involving enhanced recruitment of monocytes. Ablation of bone marrow-derived myeloid cells exacerbated plaque pathology, whereas weekly administration of glatiramer acetate enhanced cerebral recruitment of innate immune cells, which dampened the pathology. Here, we assessed the therapeutic potential of grafted CD115+ monocytes, injected once monthly into the peripheral blood of transgenic APPSWE/PS1ΔE9 Alzheimer’s disease mouse models, with and without weekly immunization of glatiramer acetate, as compared to glatiramer acetate alone. All immune-modulation treatment groups were compared with age-matched phosphate-buffered saline-injected control transgenic and untreated non-transgenic mouse groups. Two independent cohorts of mice were assessed for behavioural performance (6?8 mice/group); treatments started in 10-month-old symptomatic mice and spanned a total of 2 months. For all three treatments, our data suggest a substantial decrease in cognitive deficit as assessed by the Barnes maze test (P < 0.0001?0.001). Improved cognitive function was associated with synaptic preservation and reduction in cerebral amyloid-β protein levels and astrogliosis (P < 0.001 and P < 0.0001), with no apparent additive effects for the combined treatment. The peripherally grafted, green fluorescent protein-labelled and endogenous monocytes, homed to cerebral amyloid plaques and directly engulfed amyloid-β; their recruitment was further enhanced by glatiramer acetate. In glatiramer acetate-immunized mice and, moreover, in the combined treatment group, monocyte recruitment to the brain was coupled with greater elevation of the regulatory cytokine IL10 surrounding amyloid-β plaques. All treated transgenic mice had increased cerebral levels of MMP9 protein (P < 0.05), an enzyme capable of degrading amyloid-β, which was highly expressed by the infiltrating monocytes. In vitro studies using primary cultures of bone marrow monocyte-derived macrophages, demonstrated that glatiramer acetate enhanced the ability of macrophages to phagocytose preformed fibrillar amyloid-β1?42 (P < 0.0001). These glatiramer acetate-treated macrophages exhibited increased expression of the scavenger receptors CD36 and SCARA1 (encoded by MSR1), which can facilitate amyloid-β phagocytosis, and the amyloid-β-degrading enzyme MMP9 (P < 0.0001?0.001). Overall, our studies indicate that increased cerebral infiltration of monocytes, either by enrichment of their levels in the circulation or by weekly immunization with glatiramer acetate, resulted in substantial attenuation of disease progression in murine Alzheimer’s models by mechanisms that involved enhanced cellular uptake and enzymatic degradation of toxic amyloid-β as well as regulation of brain inflammation.

Alzheimer’s disease
behavioural neurology

?Abbreviations ADtgAlzheimer's disease double transgenic APPSWE/PS1ΔE9BMbone marrowGAglatiramer acetateGFPgreen fluorescent proteinMoBMbone marrow-derived CD115+ monocytesMФBMmonocyte-derived macrophages
? The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com

nanoparticles as 'Acyl-Polycaprolactone’ and ‘magnetic iron oxide nanoparticles modified by beta-Cyclodextrin.'

2 nanoparticles produced for Alzheimer's disease treatment

Mehr News Agency
Sun 5 July 2015 - 12:10

TEHRAN, Jul. 05 (MNA) ? Researchers of Biomedical Engineering Department at Amirkabir University of Technology have developed 2 nanoparticles that can be used in treating Alzheimer's disease.

Mojtaba Ansari, the project manager, referred to the causes of this memory loss disease, saying “in cases of Alzheimer's disease, a kind of protein called Amyloid beta aggregates in the spaces between the brain's nerve cells, causing a loss of synapses - contact points via which nerve cells relay signals to one another - and a parallel deterioration in brain function in the ability to remember.”

“In this study we managed to develop a kind of nanoparticle that prevents the aggregation and toxicity of beta-amyloid proteins,” he said.

Noting that the results of the study can be used in two different fields, Ansari explained, “part of the results can be used to create a medicine and in another part, the nanoparticles can be used as blood purifier to remove the pathogens since the nanoparticles can attach themselves to the amyloid proteins and prevent their aggregation in brain's nerve cells.”

Ansari identified the two developed nanoparticles as 'Acyl-Polycaprolactone’ and ‘magnetic iron oxide nanoparticles modified by beta-Cyclodextrin.'

“We obtained good results at the laboratory phase and hope that the research can be effective in developing new therapeutic strategies for treating Alzheimer's,” said the Iranian researcher.

Alzheimer's disease is the most common form of dementia, accounting for 60 to 80 percent of dementia cases. It is a progressive disease, where dementia symptoms gradually worsen over a number of years. Alzheimer's disease has no current cure, but treatments for symptoms are available and research continues.

Brain Wellness and Brain Fullness

Jun 30, 2015

Korean Healthtech Startup Closing In On Cure For Alzheimer's

Gregory Curley ,

Korea’s startup landscape remains partial to gaming. Demand has been growing at such a staggering clip that the industry now accounts for 90% of the country’s mobile app revenues. The government is also providing financial assistance ? to the tune of $90 million ? to help shoulder rising demand. But though many welcome such incentives, the figures indicate that the trend is nearing its saturation point, and suggest that it may be time for the country’s fleet of young entrepreneurs to be leveraging their talents in a slightly different direction, one that favors long-term sustainability, and a means of overcoming the alarming rate of failure that startups and small businesses have been receiving as of late.

One healthtech startup in Seoul’s affluent Gangnam district feels that product technology is not only a more beneficial direction to take, it’s a necessity for South Korean startups if they want to achieve longevity.

Headed by its co-founders, CEO Kiwon Lee and COO Seungyeong Kim, Ybrain has developed medical wearable devices for patients suffering early onset Alzheimer’s and is building a mobile healthcare platform for detailed analytics for disease diagnosis and personalized treatments and services. They have already been approved by the FDA for clinical trials, and have secured $4.2 million in Series A funding round last summer from several leading Korean VCs.

“Our technology is basically a very non-invasive form of brain stimulation through a series of activations,” says Lee. “Our ambition is to challenge one of the toughest problems humanity faces today. Cancer is nearing a cure. But we don’t yet have a cure for Alzheimer’s, even with today’s most advanced medical technology.”

The venture was triggered from an injury Lee’s father suffered that left him intellectually impaired. With a team comprised of experts, all with extensive experience within the medical industry, and some of whom have loved ones affected by Alzheimer’s, Ybrain’s wearable medical devices are intended to treat both patients with neurological impairment and patients wishing to maximize brain function.

“The reason we are operational today is because there is opportunity to challenge technology and find a cure,” asserts Lee.

The company will release two devices: Brain Wellness and Brain Fullness to treat disorders and enhance brain function, respectively. There are 96 patients currently being treated for depression, to testing the product. Ybrain is currently seeking KFDA approval to get their devices to the market by early 2016 to cure depression.

“Our devices increase the brain’s resting state ever so slightly so neurons can fire signals on their own with very little intervention,” Lee says. “This minimally invasive approach is favorable for those against taking pills to combat symptoms.”

Neurological modulation involves providing a push for the brain’s synapses to function optimally. Lee points out that they are not only out to treat a series of degenerative neurological disorders but also aid in the improvement of normal neurological functioning, conditioning the brain to work at higher levels.

“Essentially, Ybrain’s wearable tech sends out a weak electronic signal to minimally increase the brain’s resting phase so that neurons can send signals on their own, more naturally without any failure,” Lee explains.

Ybrain’s patented technology couldn’t come at a more opportune time. The Obama administration recently set aside close to $3 billion in funding for its Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Lee is confident that their technology will allow for the study and treatment at a fraction of the cost.

“Our patented headsets can be worn at home and monitored from a lab, and will help alleviate a series of neurological disorders, including addiction, trauma, dieting, and schizophrenia,” says Lee. “This will allow for us to gather large amounts of data; the number of brain waves through our technology and use that information at nearly one tenth the cost.”

Two products are to hit the market next year: a diagnostic platform that will work in tandem with the wearable to help doctors pinpoint the root of neurological disorders, and a wearable brain wave product ? the first of its kind ? for depression.

“The U.S. government claims that they can save up to 80% of its medical cost through these wearable technologies,” says Lee. “This gave us pause and made us assess the benefits we can give consumers.”

Despite Ybrain’s ambitions, they are not alone in the race for a cure; several other companies with similar strategies will soon have products available to patients in need. However, Lee is quick to point out that his technology provides a much more favorable method of tackling one of the world’s deadliest diseases.

“Many of our competitors products are heavy and awkward, difficult to operate, and only operational by experts,” Lee asserts. “When we started the company we felt that everyone should be able to use it by themselves. Our device is connected to our platform, so brain management, neuromodulation can be operated remotely and closely studied to assess brain wave patterns.”

Kim is also quick to point out that Korean startups are missing the bigger picture, and that young entrepreneurs going against the grain should not be dissuaded by hype and submit to current startup trends.

“It takes a lot of time, money, and energy to prove that our technology actually cures neurological disorders,” Kim notes. “But if you have big purpose and big dreams, big investors will express interest.”

Such high hopes are certainly inspiring and enough to question the government’s recent appropriation of funds to an industry already teeming with developers, and to spark debate as to where the future of Korea’s current line of startups may lead.

Gregory Curley is a freelance writer and founder of GBC Media, a global marketing communications company based in Seoul, South Korea.

HK532-IGF-1 transplantation

Neuralstem's HK532-IGF-1 neural stem cells therapy for Alzheimer's disease presented at ISSCR Annual Meeting

June 27, 2015

Neuralstem, Inc. (NYSE MKT: CUR), a biopharmaceutical company using neural stem cell technology to develop small molecule and cell therapy treatments for central nervous system diseases, announced that the poster "Human Neural Stem Cells Expressing IGF-1: A Novel Cellular Therapy for Alzheimer's Disease" was presented yesterday at the International Society for Stem Cell Research (ISSCR) Annual Meeting in Stockholm, Sweden.

In the poster, researchers from the University of Michigan presented data that mice with an animal model of Alzheimer's disease (AD), transplanted with HK532-IGF-1 cells in the peri-hippocampus, performed better on hippocampal-dependent behavioral tasks than untreated mice, demonstrating both enhanced learning cognitive processes and memory consolidation. Researchers also reported a beta-amyloid plaque reduction in both the cortex and hippocampus of the mice that received the stem cells. Amyloid plaque is one of the two hallmarks of AD.

These results indicate that HK532-IGF-1 transplantation can impact learning and memory deficits, as well as Alzheimer's pathology. The researchers found the results to be encouraging and recommend further study. HK532-IGF-1, Neuralstem's second stem cell line, is a proprietary line of cortical neural stem cells engineered to express insulin-like growth factor-1 (IGF-1), which has been shown to have wide-ranging neuroprotective properties.


Jun. 25, 2015

Alzheimer's breakthrough FDA gives OK to RTP firm to test new drug in patients

Research Triangle Park, N.C. ? T3D Therapeutics, a young Research Triangle Park company started with loan help from the North Carolina Biotechnology Center, has received approval from the Food and Drug Administration to test its lead drug candidate in patients with Alzheimer’s disease.

“This is a significant milestone for our company,” said CEO John Didsbury.

T3D plans to begin a phase two-a study this summer on the heels of the FDA’s approval of its Investigational New Drug application.

The drug candidate, T3D-959, is a potential therapeutic for Alzheimer’s disease, designed to be given orally once a day. The molecule passed a phase one clinical trial for safety and tolerability in healthy volunteers, and in pre-clinical studies using an Alzheimer’s animal model it showed positive effects on memory, motor function, inflammation, neuronal cell death, beta amyloid production and tau (protein) alteration.

Unlike most Alzheimer’s therapies in development that target one disease pathway, such as beta amyloid plaques or tau bundles, T3D-959 acts on multiple pathologies, including a likely trigger for the disease, insulin resistance in the brain. As a dual nuclear receptor agonist, T3D-959 may regulate many genes involved in Alzheimer’s and could be a powerful insulin sensitizer, anti-inflammatory and neuroprotectant, offering a greater potential to slow, stop or reverse disease progression, the company reports.

The phase two-a clinical study will evaluate T3D-959 in 36 patients with mild-to-moderate Alzheimer’s disease. In addition to evaluating safety, the study will examine changes in cerebral glucose metabolism and neural (brain cell) connectivity.

The company has been selected by the Alzheimer’s Association to present its pre-clinical results of T3D-959 at the upcoming Alzheimer’s Association International Conference in Washington, D.C., July 18 through 23.

T3D Therapeutics is a privately held company established in 2013 to develop therapeutics for the treatment of Alzheimer’s and other central nervous system disorders.

NCBiotech awarded T3D a $50,000 Company Inception Loan in 2013 and a $250,000 Small Business Research Loan in 2014. Earlier this year the company won a $1.8 million phase two Small Business Innovation Research grant from the National Institute on Aging to further develop T3D-959.

(C) NC Biotechnology Center


Pioglitazone drug significantly decreases risk of dementia

June 23, 2015

Patients with type 2 diabetes have a dysfunctional sugar metabolism because the essential hormone insulin does not work effectively. Once the disease reaches an advanced stage, the body stops producing insulin altogether, which means that it has to be administered externally. Type 2 diabetes most commonly occurs in late adulthood, and it has long been known that it can affect the patient's mental health: Patients have a greater risk of developing dementia than non-diabetics. However, how does antidiabetic medication influence this risk? Neurologist Michael Heneka and the demographers Anne Fink and Gabriele Doblhammer investigated this issue in the current study. Their work is based on data from the years 2004 to 2010 provided by the German public health insurance company AOK. These data set comprises information about diseases and medication related to more than 145,000 men and women aged 60 and over.

Long-term treatment reduced dementia risk

The analysis confirmed previous findings that diabetics have an increased risk of developing dementia. However, it was also found that this risk can significantly be modified by pioglitazone. This drug is taken as tablets. It is applied in short-term as well as in long-term treatment of diabetes as long as the body is still capable of producing its own insulin.

"Treatment with pioglitazone showed a remarkable side benefit. It was able to significantly decrease the risk of dementia," says Doblhammer. "The longer the treatment, the lower the risk." Risk reduction was most noticeable when the drug was administered for at least two years. Diabetics given this treatment developed dementia less often than non-diabetics. Doblhammer: "The risk of developing dementia was around 47 percent lower than in non-diabetics, i.e. only about half as large."

Metformin - another frequently prescribed antidiabetic drug - also lowered the risk of developing dementia. However, the effect was lower than that of pioglitazone.

Protection against nerve cell damage

Pioglitazone improves the effect of the body's own insulin. Moreover, laboratory tests have long indicated that it also protects the nerve cells. The current results are therefore no surprise to neuroscientist Michael Heneka. "Pioglitazone is an anti-inflammatory drug that also inhibits the deposition of harmful proteins in the brain," he says.

However, Heneka emphasizes that the exact mechanisms are not yet understood: "Our study suggests that pioglitazone has a preventive effect. This happens when the drug is taken before symptoms of dementia manifest. Thus, it protects in particular against Alzheimer's, the most common form of dementia. The causes for this, whether pioglitazone only has this protective effect in diabetics or if it would also work in non-diabetics - all these questions have yet to be answered. The next logical step would therefore be clinical studies. These studies would specifically investigate the effect of pioglitazone and other antidiabetics on dementia."

DZNE - German Center for Neurodegenerative Diseases


Heptares Initiates Clinical Study With First Selective Muscarinic M1 Receptor Agonist For Improving Cognition In Patients With Alzheimer’s Disease

First Human Trial of Novel Small Molecule Drug Derived From Heptares GPCR-Focused Structure-Based Drug Design Platform

London, UK and Boston, MA, USA, 9 December 2013 ? Heptares Therapeutics, the leading GPCR structure-guided drug discovery and development company, announces that it has initiated a Phase 1 clinical study of HTL9936, the first fully selective muscarinic M1 receptor agonist to enter clinical development. HTL9936 is an orally available, small molecule drug candidate discovered using the Heptares GPCR structure-based drug design (SBDD) platform. Heptares plans to develop HTL9936 as a novel treatment for improving cognitive function (memory and thinking abilities) in patients with Alzheimer’s disease and other diseases associated with dementia and cognitive impairment.

“We are excited to initiate clinical development of HTL9936, a first-in-class agent with the potential to become an important new medicine for improving cognitive function in patients with Alzheimer’s disease and other potential indications including schizophrenia and Lewy body dementia,” said Malcolm Weir, CEO of Heptares. “In addition, the initiation of this clinical trial with HTL9936 marks an important milestone for Heptares, as we evolve into a clinical-stage business with a rich portfolio of novel GPCR-targeted agents advancing through Phase 1 and 2a clinical trials in the near-term.”

M1 receptor agonism is a well-validated mechanism of action for treating cognitive impairment and a valuable pharmacological profile that the pharmaceutical industry has endeavored to create for decades. The principal challenge has been to engineer selective compounds that activate the M1 receptor subtype without also activating the M2 or M3 receptors, which are associated with undesirable side effects. All previous compounds have been discontinued due to inadequate selectivity. Using a new structure-guided approach, Heptares scientists determined the x-ray crystal structure of the M1 receptor for the first time and leveraged unique insights into the receptor to identify new chemistries with fully selective M1 agonist profiles.

The Phase 1 study will evaluate the safety, tolerability and pharmacokinetics of HTL9936. In addition, the clinical pharmacodynamics of the drug will be investigated in a series of studies over the next year. This study aims to recruit more than 100 healthy volunteers including elderly people at a single clinical centre in the UK. Initial results are expected in mid-2014

About Alzheimer’s Disease and Other Disorders of Cognitive Impairment

Today there is significant unmet medical need and heavy economic burden across multiple diseases characterised by cognitive impairment and dementia. In Alzheimer’s disease, currently available drugs provide limited and transient effects on cognition. Healthcare costs associated with the epidemic of AD, including nursing home care, continue to grow dramatically and new therapies with better and more durable efficacy are urgently needed. In addition, an estimated 80% of schizophrenics suffer from cognitive impairment and 1.3 million patients in the US suffer from Lewy body dementia. Currently there are no approved therapies for treating cognitive impairment in schizophrenia or for treating Lewy body dementia.

difluoromethylornithine (DFMO)

Alzheimer's Disease could be prevented by immune system tweak

14 Apr 2015

New research raises the prospect that statin-like drugs could be given to the middle-aged to ward off dementia
Alzheimer’s Disease could be prevented or cured by a new drug which reboots the immune system to stop devastating memory loss, scientists believe.

A new study has shown for the first time that immune cells play a crucial role in the formation of sticky plaques which clump between brain cells, preventing them from functioning correctly.

Usually the body protects the brain from these plaques. But US scientists have found that in Alzheimer’s Disease the immune cells in the brain seem to go haywire, producing a molecule which actually reduces the immune response and consumes an important brain nutrient.

However a drug which blocks that molecule is already being tested in cancer patients, and researchers discovered that it stops the formation of plaques. It raises the prospect that statin-like drugs could be given to the middle-aged to ward off dementia.

Animal tests have already shown that the drug, difluoromethylornithine, (DFMO) stops mice developing Alzheimer’s and improved memory in creatures who already had the disorder.

Charities said that is could open new doors for the prevention and treatment of dementia.

"It's surprising, because suppression of the immune system is not what the field has been thinking is happening in Alzheimer’s Disease," said Matthew Kan from Duke University School of Medicine, which carried out the study.

“Instead, scientists have previously assumed that the brain releases molecules involved in ramping up the immune system, that supposedly damage the brain.

"All of this suggests to us that if you can block this process, then you can protect, the mouse, at least, from Alzheimer's disease.”

Around 850,000 people in Britain have been diagnosed with dementia and 60,000 people die each year, mostly though Alzheimer’s disease.

The brains of people with Alzheimer's show two hallmark signs, ‘plaques’ and ‘tangles’. Plaques are the build-up of sticky proteins called beta amyloid, and tangles are twisted strands of a protein called tau.

Researchers found that most immune cells stay the same with the onset of Alzheimer’s, but one type, called microglia start producing a molecule called CD11c which suppress the immune system and eats up the important brain protecting nutrient called arginine.

The molecule was found in the highest quantities in regions of the brain involved in memory and where neurons had died.

"We see this study opening the doors to thinking about Alzheimer's in a completely different way, to break the stalemate of ideas in Alzheimer’s," said Dr Carol Colton, professor of neurology at Duke University.

“That the drug worked is a strong indication that we may be on an interesting and worthwhile track for better understanding how the Alzheimer’s pathology is started.

“There is the possibility that other agents based on this drug could be developed for safe and effective use to stop the early onset of Alzheimer’s.”

Dementia charities said the research was promising but advised maintaining a healthy diet and exercising.

“These early findings could open new doors for future treatment development for Alzheimer’s, said Dr Laura Phipps of Alzheimer’s Research UK.

“Current research suggests that the best way to maintain a healthy brain throughout life is to ensure a balanced diet, not smoke, keep mentally and physically active and exercise regularly, and to keep blood pressure and cholesterol in check.”

Dr James Pickett, Head of Research at Alzheimer’s Society said: “This study in animals joins some of the dots in our incomplete understanding of the processes that cause Alzheimer’s disease, in particular around the role played by the immune system.

“Importantly, these new findings reflect earlier observations that arginine is reduced in the brains of people with Alzheimer’s disease.”

The research was published in the Journal of Neuroscience.

Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer's Disease

Matthew J. Kan1,
Jennifer E. Lee2,
Joan G. Wilson2,
Angela L. Everhart2,
Candice M. Brown3,
Andrew N. Hoofnagle4,
Marilyn Jansen2,
Michael P. Vitek2,
Michael D. Gunn1,5, and
Carol A. Colton2

The Journal of Neuroscience, 15 April 2015, 35(15): 5969-5982; doi: 10.1523/JNEUROSCI.4668-14.2015


The pathogenesis of Alzheimer's disease (AD) is a critical unsolved question; and although recent studies have demonstrated a strong association between altered brain immune responses and disease progression, the mechanistic cause of neuronal dysfunction and death is unknown. We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes, and age-dependent hippocampal neuronal loss. Using this mouse model, we studied longitudinal changes in brain immunity in relation to neuronal loss and, contrary to the predominant view that AD pathology is driven by proinflammatory factors, we find that the pathology in CVN-AD mice is driven by local immune suppression. Areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c+ microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine. Pharmacologic disruption of the arginine utilization pathway by an inhibitor of arginase and ornithine decarboxylase protected the mice from AD-like pathology and significantly decreased CD11c expression. Our findings strongly implicate local immune-mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.

Calcineurin Inhibitors

Transplant anti-rejection drug protects against Alzheimer's, study

By Stephen Feller
June 8, 2015

GALVESTON, Texas, June 8 (UPI) -- A drug that suppresses the immune system to prevent transplant recipient patient's bodies from rejecting their new organs may prevent Alzheimer's disease.

Researchers made the discovery while reviewing data which showed that dementia and Alzheimer's occurs among transplant patients at much lower rates than in the general population.

Calcineurin, an enzyme which regulates communication between brain cells and memory formation, plays a major role in the formation of toxic protein aggregates that target and disrupt the brain cells responsible for memory among Alzheimer's patients.

"These data clearly show that the prevalence of dementia and Alzheimer's in our transplant patient group is significantly lower, in fact almost absent, when compared to national data from the general population," said Luca Cicalese, a professor in the department of surgery, in a press release.

Calcineurin inhibitor-based medications, such as Tacrolimus or cyclosporine, are taken by transplant recipients to suppress the immune system and prevent rejection of the new organs. Researchers must still find a way block calcineurin, potentially benefitting Alzheimer's patients, without affecting the immune system.

"We are currently working on devising treatment strategies to obtain the same beneficial effects in AD humans using low doses of calcineurin inhibitors that result in minimal or no immunosuppression, thus limiting possible undesired side effects," said Giulio Taglialatela, Professor and Vice Chair for Research in the department of neurology and director of UTMB's Mitchell Center for Neurodegenerative Diseases.

The study is published in the Journal of Alzheimer's Disease.

Volume 47, Number 2, IN PRESS

Short Communication

Giulio Taglialatela, Cristiana Rastellini, Luca Cicalese (Handling Associate Editor: Elizabeth Head)

Reduced Incidence of Dementia in Solid Organ Transplant Patients Treated with Calcineurin Inhibitors

Abstract: Experimental evidence suggests that the protein phosphatase calcineurin mediates the action of amyloid-β (Aβ) oligomers, the most toxic amyloid species thought to drive initial cognitive decline in Alzheimer’s disease (AD). However, there is currently no evidence that inhibition of calcineurin could prevent the onset of AD in humans. Here, we report for the first time that individuals chronically treated with calcineurin inhibitors to prevent solid organ transplant rejection have a significantly lower incidence of AD/dementia as compared to the general population. This result prompts further clinical development of calcineurin inhibition as a viable treatment for AD.





会場 :福岡国際会議場(福岡市)
演題 :アルツハイマー型認知症モデルマウスの認知機能に対するヤムスゲニン(R)含有トゲドコロ末の効果
内容 :アルツハイマー型認知症モデルマウスにヤムスゲニン(R)含有トゲドコロ末を経口投与した。一定期間飼育後の認知機能を評価した結果、記憶障害の発症前および発症後において、ヤムスゲニン(R)含有トゲドコロ末に認知機能低下を予防・改善する作用があることを確認した。



タカラバイオ株式会社: http://www.takara-bio.co.jp




neuronal pentraxin 2

Study: Specific protein may slow memory loss due to Alzheimer's

Neuronal pentraxin 2 serves as “bulldozer” allowing new brain connections

Erin Jordan, The Gazette
May 24, 2015 | 9:02 pm

AMES ? A new study by an Iowa State University researcher shows a protein may slow memory loss and reduce brain atrophy caused by Alzheimer’s disease.

Auriel Willette, a researcher in food science and human nutrition, found evidence that higher levels of a little-studied protein called neuronal pentraxin 2 may slow cognitive decline in Alzheimer’s patients by improving the connections between neurons in the brain.

“Neuronal pentraxin 2 remodels existing synapses communicating between neurons,” Willette said. “It also clears away old cells or digested proteins.”

He compared the protein to a bulldozer that removes debris to make room for new buildings.

About 5 million Americans are currently living with Alzheimer’s disease, but that number is expected to rise to 14 million by 2050, the Centers for Disease Control and Prevention reported. The progressive disease is the leading cause of dementia.

Willette analyzed data from the Alzheimer’s Disease Neuroimaging Initiative, a national collection of brain images and spinal fluid samples, to create three study groups: people without Alzheimer’s disease, people with mild cognitive impairment who may develop Alzheimer’s disease and people with full-blown Alzheimer’s disease.

He found participants with higher levels of neuronal pentraxin 2 showed little or no memory loss after two years. He also learned elevated levels of the protein were linked to less atrophy in the medial temporal lobe, which is the part of the brain first to show atrophy in Alzheimer’s disease.

Neuronal pentraxin 2 is naturally produced in the body, primarily by neurons, which are nerve cells that carry electrical impulses and chemicals signals to the rest of the body.

Engaging in new or complex mental tasks may promote the production of protective proteins like neuronal pentraxin 2, Willette said. Exercise also has been found to increase the number of connections between nerve cells in older rats and mice, the National Institutes for Health reported.

People taking antidepressants or who have consumed alcohol have higher levels of neuronal pentraxin 2, Willette said.

While he doesn’t recommend drinking or taking antidepressants to boost protein levels, Willette said there may be drug therapies that could elevate neuronal pentraxin 2 levels for people at risk of Alzheimer’s. Diet may also be a factor, although there is little research in this area, he said.

Willette will present his study at the Psychoneuroimmunology Research Society‘s annual scientific meeting, June 3 to 6 in Seattle.


China's new Alzheimer's disease drug applies for clinical tests

English.news.cn 2015-05-24 16:44:31

GUANGZHOU, May 24 (Xinhua) -- China will begin clinical tests on a new drug for Alzheimer's disease (AD), after animal tests showed positive results.

AD16, developed by Guangzhou Institute of Biomedicine and Health (GIBH) under the Chinese Academy of Sciences, has proven effective in improving the memory and cognitive abilities of guinea pigs, Hu Wenhui, head of the development team, told Xinhua on Sunday.

Hu said AD16 functions as an anti-neuroinflammatory agent and can alleviate damage caused by amyloid beta protein on neurons, thus, slowing the disease's progression.

Alzheimer's affects tens of millions of elderly people worldwide, yet there is no effective cure. The cause of the disease is poorly understood, although scientists have linked it to a build-up of the amyloid beta protein in brains.

radio frequency

Man invents possible breakthrough treatment for Alzheimer’s

By Jocelyn Maminta Medical/Health Reporter
May 22, 2015

FARMINGTON, Conn. (WTNH) ? What inventor Eric Knight has been working on for five and a half years could be the key to managing Alzheimer’s Disease, a devastating illness that touches the lives of a growing number of us and robs a person of their memory.

Knight now has the patent for technology that he says could be one of the biggest breakthroughs in medical science.

“Hopefully history in the making right here,” he told WTNH-TV.

He created the prototype of a unique device designed to keep Alzheimer’s Disease from progressing. It’s a bicycle helmet with postcard-sized antennas facing inward towards the brain.

“This would turn Alzheimer’s from a terminal illness to a chronic illness and a managed illness,” Knight said.

It’s based on medical research that used radio frequency to dissolve “plaque build-up” in the brain of mice with Alzheimer’s.

“The intent is to do what in the brain?”

“To provide these radio waves to break up the beta amyloid plaques that really gum up the neurological activity of the brain cells,” the inventor said. “So that’s what they had discovered with their analysis in testing with mice, and so what I’ve done is scale it up for use for humans.”

The a-ha moment came when he applied data from working on the first privately-funded rocket into space to come up with his device.

“You know, I can take those same antennas that are flexible around the rocket, flip them around and have them flex inward, and broadcast the same sort of RF inward as a therapeutic to the brain,” said Knight.

Power supplied or battery operated.

“People could use this device one hour a day, two hours a day, and it would maintain the brain health over a long period of time,” he said.

It’s not a cure, but potentially a way to manage Alzheimer’s. To push it along, he is not charging researchers a fee to use his patent.

“My thought is what is the quickest way to get this into the marketplace through clinical trials into the hands of the people who need it,” Knight said. “The quickest way is to get it into the hands of those who have the medical expertise to be able to test it and research it and get it through the pipeline as fast as possible.”

Jennifer Walker with Alzheimer’s Association of Connecticut says new research is always exciting news and that she looks forward to seeing how it will work in the human brain.

The Alzheimer’s National Plan is to have a treatment, cure, or both by the year 2025.

It took two and a half years for the government to issue Eric Knight a patent for his technology. The okay came just two days ago.

For more about Knight’s technology, click here.


Information from: WTNH-TV


Alzheimer's drug developed by Triad company moving into final trial phase

May 20, 2015,
Owen Covington
Triad Business Journal

A promising drug targeting Alzheimer's disease and developed by a High Point pharmaceutical company is heading into a final phase of clinical trials.

The move into Phase 3 testing of azeliragon by vTv Therapeutics, formerly TransTech Pharma, comes nearly two years after the successful completion of Phase 2 trials during which the drug showed results in slowing cognitive decline among patients with mild or moderate Alzheimer's disease.

vTv Therapeutics will begin enrolling its first patients in what it's calling STEADFAST, Single Trial Evaluating Alzheimer's Disease Following Addition to Symptomatic Therapy. It's a placebo-controlled trial that expects to enroll 800 patients in the U.S. and Canada who will then receive 18 months of treatment.

"We are excited to reach this next significant milestone in the development of azeliragon as a potential therapy to slow the decline of cognition and function in patients with Alzheimer's disease by enrolling our first patients in our Phase 3 trial," said vTv President and CEO Steve Holcombe.
Azeliragon tries to minimize the effects of Alzheimer’s on the brain by restoring the balance of amyloid protein through a pathway called the “receptors for advanced glycation endproducts,” or “RAGE.” Those proteins are essentially a waste product of the metabolic process, and scientists believe amyloid build-up leads to Alzheimer’s.
Holcombe said the only drugs on the market for Alzheimer's now target the early symptoms of the disease.

"There are no disease-modifying therapies on the market at this point, and that's what we're hoping our drug will prove to be," Holcombe said.
vTv began working on the drug, then known as TTP488, with pharmaceutical giant Pfizer as a development partner, but that partnership ended with vTv becoming the sole rights-holder to of the drug.

Following positive results in Phase 2, which typically involves a smaller pool and is designed to see if the drug has any therapeutic effect at all, the drug was granted "fast track" status by the Food and Drug Administration. That was based largely on the high demand for the development of Alzheimer's treatments, which vTv notes affects 5 million Americans.
"The key was meeting with the FDA and getting an agreement as to what kind of studies we could run that if successful, would result in the drug being approved," Holcombe said.
That streamlines the process of the trial yields positive results, with azeliragon moving straight into applying for registration and then to market, Holcombe said.
"You sort of have your pre-approval," he said.
That was followed by selecting contract research organizations to administer the trial as well as selecting sites for the studies, with about 100 sites within the U.S.
As for the name change, Holcombe said the company is disclosing few details about that. The management is the same, the company hasn't been sold, but vTv is now the company that holds all the assets and operations of TransTech Pharma he said.

Records show that vTv Therapeutics was registered as a limited liability corporation last month in the state of Delaware. TransTech Pharma had been incorporated in North Carolina.
Moving to Phase 3 with azeliragon is another piece of good news for vTv, which in March announced a new licensing agreement with Calithera Biosciences for one of its cancer treatment programs. vTv and High Point Pharmaceuticals, a sister company spun off in 2008, could could see an infusion of more than $100 million for vTv if the research generates a licensed product.


GliaCure Initiates Phase 1b Dosing in Alzheimer's Patients

04 May 2015

BOSTON, MA, USA I May 4, 2015 I GliaCure, a privately-held biotechnology company focused on the development of novel therapies for neurological and neuropsychiatric disorders based on glial targets, announced that it has initiated dosing of Alzheimer's patients in a Phase 1b clinical trial of its lead product candidate, GC021109, a compound developed as a potential disease-modifying treatment. GliaCure's innovative approach to treating Alzheimer's disease is innovative in that it both promotes the clearance of amyloid and stimulates anti-inflammatory actions through a single target, an approach that has recently been supported by research studies from independent groups.

"We are optimistic that our Phase 1b study will demonstrate that GC021109 is both safe and well tolerated in early stage Alzheimer's patients," stated GliaCure board member Joe Zakrzewski. "Data from this study will prove invaluable as we move forward with the design our Phase 2 trial."

GliaCure's Phase 1b trial, which began recruiting volunteers in February 2015, includes multiple ascending dosing of 36 subjects and is intended to demonstrate safety and tolerability of GC021109. The study is co-funded by the Alzheimer's Drug Discovery Foundation (ADDF). More information about the study can be found at https://clinicaltrials.gov/ct2/show/NCT02386306?term=gliacure&rank=1.

About GliaCure, Inc.

GliaCure is a privately held company that is pioneering the development of novel therapeutics aimed at treating neurological and neuropsychiatric disorders of the brain. The company's approaches are based on glial targets, a cell type in the brain that has previously been overlooked in drug discovery. The dual phagocytic and anti-inflammatory actions of the GliaCure's lead clinical candidate, GC021109, have the potential to serve as a disease-modifying treatment for Alzheimer's disease and to affect other disorders, including psoriasis, Parkinson's disease, multiple sclerosis and glaucoma. GliaCure has an exclusive license to the GC021109 compound and related technology from Tufts University. GliaCure also has a pipeline program for the development of therapeutics for astrocytic targets related to sleep disorders and depression. The company is based in Boston and is headed by Professor Philip G. Haydon, who also holds the position of Annetta and Gustav Grisard Professor and Chair of Neuroscience at Tufts University.

SOURCE: GliaCure


Volume 59, Issues 4?5, September?October 2010, Pages 268?275

Multiphoton in vivo imaging of amyloid in animal models of Alzheimer’s disease


Amyloid-beta (Aβ) deposition is a defining feature of Alzheimer’s disease (AD). The toxicity of Aβ aggregation is thought to contribute to clinical deficits including progressive memory loss and cognitive dysfunction. Therefore, Aβ peptide has become the focus of many therapeutic approaches for the treatment of AD due to its central role in the development of neuropathology of AD. In the past decade, taking the advantage of multiphoton microscopy and molecular probes for amyloid peptide labeling, the dynamic progression of Aβ aggregation in amyloid plaques and cerebral amyloid angiopathy has been monitored in real time in transgenic mouse models of AD. Moreover, amyloid plaque-associated alterations in the brain including dendritic and synaptic abnormalities, changes of neuronal and astrocytic calcium homeostasis, microglial activation and recruitment in the plaque location have been extensively studied. These studies provide remarkable insight to understand the pathogenesis and pathogenicity of amyloid plaques in the context of AD. The ability to longitudinally image plaques and related structures facilitates the evaluation of therapeutic approaches targeting toward the clearance of plaques.


Aberdeen scientists developing Alzheimer’s drug that could transform the lives of sufferers

3 May 2015
by Andrew Clark
Professor Claude Wischik

A drug being developed in Aberdeen could transform the lives of millions of Alzheimer’s sufferers.

LMTX has the potential to offer dementia patients “15 years” of extra lucidity and final trials on it are being carried out.

The drug could be on the market within two years.

Magnetic resonance imaging technology pioneered in the north-east helped prove its effectiveness on the human brain. And Aberdeen University’s maths department is helping to handle the huge volumes of data from worldwide tests.

Professor Claude Wischik who is spearheading development of LMTX, said: “If all goes well, 2017 could be when we see this drug in the pharmacies and on the street.”

About LMTX for Alzheimer’s

LMTX?, TauRx's second-generation Tau Aggregation Inhibitor (TAI), offers a major advance over existing treatments for Alzheimer’s, which only transiently address the symptoms and cannot slow disease progression. LMTX? acts by reducing levels of aggregated or misfolded Tau proteins, which are associated with the progressive neurodegeneration of Alzheimer’s disease. LMTX? shares the same active ingredient (methylthioninium (MT)) and mode of action as rember?, TauRx’s first generation TAI, but is designed to have improved bioavailability and tolerability. Phase 2 clinical trials of rember? showed a 90% reduction in the rate of Alzheimer’s progression over 2 years. These results provided the first clinical demonstration that a new therapy targeting protein aggregation could dramatically reduce the rate of progression of this deadly disease.

The LMTX? family also has activity against synuclein aggregation, another protein misfolding disorder leading to Parkinson’s disease, offering potential for development in this indication as well.

The Phase 2 clinical trial results reported by Professor Claude Wischik and colleagues at the University of Aberdeen suggest that a treatment based on Tau aggregation pathology could delay the progression of cognitive decline in mild to moderate Alzheimer’s. This is being further validated in several large Phase 3 clinical trials.


Scientists discover protective molecule against Alzheimer’s

14 hours 57 minutes ago

Adelaide and Chinese scientists have made a ground breaking molecular discovery in their work to find a cure for Alzheimer’s Disease.

Published today in the prestigious international journal Molecular Psychiatry, the research is a joint collaboration between scientific groups led by Professor Xin-Fu Zhou (photo)at the University of South Australia and Professor Yanjiang Wang at China’s Third Military Medical University.

Prof Xin-Fu Zhou, who is UniSA’s Research Chair in Neurosciences, says the discovery of one of the mechanisms of Alzheimer’s Disease opens the door to further research into potential treatments.

“Currently, only a few drugs help with the symptoms of Alzheimer’s Disease and there is no cure,” he says.

Alzheimer’s Disease accounts for nearly 70 per cent of all dementia cases. Dementia affects a staggering 44 million people around the world, with more than 342,000 Australians living with dementia. Without a medical breakthrough, the number of Australians with dementia is expected to be almost 900,000 by 2050

“Alzheimer’s Disease is one of the most devastating diseases currently facing society,” Prof Zhou says.

“Its effects are devastating on the individual, their carer and family, and the economic burden on health and aged care systems will only increase without urgent further research.”

Prof Zhou and Prof Wang’s Molecular Psychiatry article is titled p75 ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s Disease.

“Alzheimer’s Disease is a kind of metabolic disease which produces too much toxic metabolic product and causes breakdown of nerve connectivity,” Prof Zhou says.

“Neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration.

“Fortunately, people normally have mechanisms which produce sufficient amounts of nerve protective factors which can prevent the damage of toxic metabolites to the brain.

“The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and precursors of neutrophins and mediates the toxicity of the neurodegenerative signals. However, the shedding of its extracellular domain (P75ECD) of p75 from the cell surface is a neuroprotective event and physiologically regulated.”

Profs Zhou and Wang discovered that in Alzheimer’s Disease, the full length p75 which causes nerve damage is increased but the level of neuroprotective p75ECD in the brain and cerebral spinal fluid is reduced to the abnormality in the process of p75ECD shedding.

They showed that restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brains of mice reversed the behavioural deficits and Alzheimer’s Disease-type pathologies, such as Aβ deposit, apoptotic (cell death) events, neuroinflammation, Tau phosphorylation, and the loss of dendritic spine, neuronal structures and synaptic proteins. They also showed p75ECD can reduce amyloidogenesis by suppressing β-secretase expression and activities.

“Our data demonstrates that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for Alzheimer’s Disease,” Prof Zhou says.

“Further studies are required to validate p75ECD as a drug candidate and diagnostic marker in preclinical and clinical trials.”

Contact for interview: Prof Xin-Fu Zhou email xin-fu.zhou@unisa.edu.au

Media contact: Kelly Stone office (08) 8302 0963 mobile 0417 861 832 email Kelly.stone@unisa.edu.au

Molecular Psychiatry advance online publication 28 April 2015; doi: 10.1038/mp.2015.49

p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s disease

X-Q Yao1,10, S-S Jiao1,10, K Saadipour2,10, F Zeng1, Q-H Wang1, C Zhu1, L-L Shen1, G-H Zeng1, C-R Liang1, J Wang2, Y-H Liu1, H-Y Hou3, X Xu4, Y-P Su5, X-T Fan6, H-L Xiao7, L-F Lue8, Y-Q Zeng9, B Giunta3, J-H Zhong2, D G Walker8, H-D Zhou1, J Tan3, X-F Zhou2,9 and Y-J Wang1


In Alzheimer’s disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer’s patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.

P4 and P8

April 29, 2015

Novel approach blocks amyloid production in Alzheimer's mouse model

Offering a potential early intervention for Alzheimer's disease (AD), researchers at University of California, San Diego School of Medicine and Cenna Biosciences, Inc. have identified compounds that block the production of beta amyloid peptides in mice. The study is reported April 29 in PLOS ONE.

If the results ultimately translate to human treatment, the most promising compound - a peptide dubbed P8 - could be administered to individuals at high risk of developing the disease, long before the tell-tale signs of dementia occur and perhaps with few side effects, due to the compound's highly specific mode of action.

"Our approach is completely different from any current approaches that target beta amyloid," said lead author Nazneen Dewji, PhD, associate adjunct professor in the Department of Medicine. "We are blocking the actual production of beta amyloid in a new way. It's very promising because it means that, in principle, we can stop the disease in its tracks."

The build-up of beta amyloid plaques is widely believed to cause irreversible brain damage, resulting in a host of cognitive and motor impairments broadly associated with AD, which accounts for about 60 to 80 percent of all cases of dementia in the United States.

Because of the currently perceived role of beta amyloid in disease progression, several investigational drugs have targeted the enzymes that cleave beta amyloid from its larger precursor protein, the aptly named amyloid precursor protein (APP).

"These drugs, however, have largely failed in clinical trials," said Dewji, "mostly because they are responsible for cleaving other proteins besides APP. Inhibiting or modifying their activities creates many undesirable effects in the cell."

The P8 compound does not act on enzymes, but rather binds to APP and in so doing, prevents the larger protein from being processed into smaller amyloid peptides. The compounds are derived from a fragment of a membrane protein known as presenilin 1 that is known to interact with APP to produce beta amyloid. The highly specific binding between the APP and P8 was measured using both biophysical methods and optical imaging techniques.

"Our approach is different, specific and interferes with only the reaction that produces beta amyloid, as opposed to drugs that target the enzymes responsible for its cleavage from APP, which can affect multiple reactions in cells," said Dewji, who is also president and CEO of the La Jolla-based biopharmaceutical company Cenna, where the drug candidates are being developed.

In addition to cell culture experiments, researchers also conducted experiments with mice, engineered to produce large amounts of the human beta amyloid early in life.

Their experiments showed that a two-week course of treatment with either P8 or another compound called P4 resulted in, on average, a greater than 50 percent reduction in plaque accumulation, as compared with mice who received no treatment.

"We now have a new approach for the treatment of Alzheimer's disease that can arrest the production of beta amyloid very early and specifically," she said. "It's a real chance at a successful treatment for Alzheimer's disease."

Other co-authors include Eliezer Masliah, Edward Rockenstein, Martha Harber, and Taylor Horwood, UC San Diego; and Mihyun Kim, UC San Diego and Cenna Biosciences.

Explore further: Is the amyloid hypothesis the right path to find a treatment for Alzheimer's disease?

Journal reference: PLoS ONE

Provided by University of California - San Diego

Peptides of Presenilin-1 Bind the Amyloid Precursor Protein Ectodomain and Offer a Novel and Specific Therapeutic Approach to Reduce ?-Amyloid in Alzheimer’s Disease

Nazneen N. Dewji ,

Published: April 29, 2015
?DOI: 10.1371/journal.pone.0122451


β-Amyloid (Aβ) accumulation in the brain is widely accepted to be critical to the development of Alzheimer’s disease (AD). Current efforts at reducing toxic Aβ40 or 42 have largely focused on modulating γ-secretase activity to produce shorter, less toxic Aβ, while attempting to spare other secretase functions. In this paper we provide data that offer the potential for a new approach for the treatment of AD. The method is based on our previous findings that the production of Aβ from the interaction between the β-amyloid precursor protein (APP) and Presenilin (PS), as part of the γ-secretase complex, in cell culture is largely inhibited if the entire water-soluble NH2-terminal domain of PS is first added to the culture. Here we demonstrate that two small, non-overlapping water-soluble peptides from the PS-1 NH2-terminal domain can substantially and specifically inhibit the production of total Aβ as well as Aβ40 and 42 in vitro and in vivo in the brains of APP transgenic mice. These results suggest that the inhibitory activity of the entire amino terminal domain of PS-1 on Aβ production is largely focused in a few smaller sequences within that domain. Using biolayer interferometry and confocal microscopy we provide evidence that peptides effective in reducing Aβ give a strong, specific and biologically relevant binding with the purified ectodomain of APP 695. Finally, we demonstrate that the reduction of Aβ by the peptides does not affect the catalytic activities of β- or γ-secretase, or the level of APP. P4 and P8 are the first reported protein site-specific small peptides to reduce Aβ production in model systems of AD. These peptides and their derivatives offer new potential drug candidates for the treatment of AD.

HDAC inhibitors

April 29, 2015

Scientists uncover surprising new details of potential Alzheimer's treatment

Taking a new approach, scientists from the Florida campus of The Scripps Research Institute (TSRI) have uncovered some surprising details of a group of compounds that have shown significant potential in stimulating the growth of brain cells and memory restoration in animal models that mimic Alzheimer's disease.

The new study points to promising new directions using a known therapeutic strategy for Alzheimer's disease?a disorder that will affect nearly 14 million Americans by 2050, according to the Alzheimer's Association.

The study, which was led by TSRI Associate Professors Courtney Miller and Gavin Rumbaugh, appears online ahead of print in the journal Neuropsychopharmacology.

This new study builds on previous findings from Miller and Rumbaugh demonstrating the memory-rescuing potential of inhibiting histone deacetylases (HDACs), a family of signaling enzymes that act like molecular switches, silencing gene expression by controlling access to the cell's nuclear cache of tightly compacted DNA. Mutations in HDACs genes have been associated with health problems including cancer, inflammatory and autoimmune diseases, metabolic disorders and loss of memory function.

Miller and Rumbaugh note that current efforts by many research teams focus on developing "isoform-selective" HDAC inhibitors?for example, select members of Class 1 HDACs such as HDAC 1, -2 or -3?in order to limit the potential for unwanted side effects. However, the Scripps Florida researchers wondered if some of the potential of memory rescue could be lost with this increased selectivity.

To investigate, in the current study, the Scripps Florida team used inhibitors initially developed by Professor Joel Gottesfeld, a molecular biologist on TSRI's La Jolla campus, and subsequently by biotech firm Repligen Corporation, to attack more than one form of Class 1 HDAC at the same time in a mouse model of Alzheimer's disease.

"We wanted to find out which inhibitors were the most selective and the most effective in restoring memory function," Miller said. "We found the key to memory restoration was the growth of new synapses (synaptogenesis), which required simultaneous inhibition of multiple HDACs."

"We found evidence that better synapse growth was associated with less specific inhibition of Class 1 HDACs," Rumbaugh added. "There was a clear correlation between synapse building? which may lead to improved network power?and memory restoration by the different HDAC inhibitors."

Interestingly, memory was not enhanced in normal animals by chronic pretreatment with multiple HDAC inhibitors, suggesting a diseased brain responds to these compounds differently than a healthy brain.

Explore further: Team finds drug that helps Huntington's disease-afflicted mice?and their offspring

More information: "Pharmacological Selectivity within Class I Histone Deacetylases Predicts Effects On Synaptic Function and Memory Rescue," 10.1038/npp.2015.93 www.nature.com/npp/journal/vao… full/npp201593a.html

Journal reference: Neuropsychopharmacology

Provided by The Scripps Research Institute

Neuropsychopharmacology (3 April 2015) | doi:10.1038/npp.2015.93

Pharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory Rescue

Gavin Rumbaugh, Stephanie E Sillivan, Emin D Ozkan, Camilo S Rojas, Christopher R Hubbs, Massimiliano Aceti, Mark Kilgore, Shashi Kudugunti, Sathyanarayanan V Puthanveettil, J David Sweatt, James Rusche and Courtney A Miller

Histone deacetylases (HDACs) are promising therapeutic targets for neurological and psychiatric disorders that impact cognitive ability, but the relationship between various HDAC isoforms and cognitive improvement is poorly understood, particularly in mouse models of memory impairment. A goal shared by many is to develop HDAC inhibitors with increased isoform selectivity in order to reduce unwanted side effects, while retaining procognitive effects. However, studies addressing this tack at the molecular, cellular and behavioral level are limited. Therefore, we interrogated the biological effects of class I HDAC inhibitors with varying selectivity and assessed a subset of these compounds for their ability to regulate transcriptional activity, synaptic function and memory. The HDAC-1, -2, and -3 inhibitors, RGFP963 and RGFP968, were most effective at stimulating synaptogenesis, while the selective HDAC3 inhibitor, RGFP966, with known memory enhancing abilities, had minimal impact. Furthermore, RGFP963 increased hippocampal spine density, while HDAC3 inhibition was ineffective. Genome-wide gene expression analysis by RNA sequencing indicated that RGFP963 and RGFP966 induce largely distinct transcriptional profiles in the dorsal hippocampus of mature mice. The results of bioinformatic analyses were consistent with RGFP963 inducing a transcriptional program that enhances synaptic efficacy. Finally, RGFP963, but not RGFP966, rescued memory in a mouse model of Alzheimer’s Disease. Together, these studies suggest that the specific memory promoting properties of class I HDAC inhibitors may depend on isoform selectivity and that certain pathological brain states may be more receptive to HDAC inhibitors that improve network function by enhancing synapse efficacy.


Alzheimer's 'breakthrough': Addenbrooke's Hospital recruits first humans for testing diabetes drug

Patients over 50 with early Alzheimer's recruited for research in Cambridge after study finds drug Liraglutide might reverse some damage caused in later stages of disease

By Laura Donnelly, Health Editor
21 Apr 2015

Men and women with early Alzheimer’s disease are being recruited to a trial for a drug which could be the first treatment to reverse progression of the condition.

Scientists say that if the ?5m study is successful, it will herald the most significant breakthrough in the treatment of dementia for more than 30 years.

A landmark study last autumn on mice found that the drug Liraglutide, which is already used in the treatment of diabetes ? appeared to reduce the damage caused by dementia and result in memory improvements.

Mice with late-stage Alzheimer's given the drug performed significantly better on an object recognition test and their brains showed a 30 per cent reduction in the build-up of toxic plaques.

The new study, led by Imperial College London, will recruit more than 200 men and women in their 50s, with early onset Alzheimer’s disease, to a year-long trial during which their brains will be scanned and their memory function tested.

If the drug is found to reverse damage to the brain, or to stall disease progression, the drug could be the first treatment to prevent Alzheimer’s disease, and offered more widely within five years, scientists said.

Alzheimer's disease is the most common cause of dementia; it is predicted there will be more than 520,000 people in the UK with the disease in 2015.

Currently there are no drugs on the market for Alzheimer’s disease which can stall or reverse progress of the condition. Treatments on offer can only mask symptoms for a certain period of time.

The new trial by Imperial College London and Addenbrooke’s Hospital in Cambridge, follows a study led by Lancaster University, which last year found improvements in memory and reductions in amyloid plaques in the brains of mice who were given the drug daily.

The drug works by increasing insulin production, reducing the amount of sugar in the blood and helping food pass more slowly through the stomach.

Previous research has also suggested that insulin may protect the brain and repair damaged neurons.

Dr Paul Edison, Clinical Senior Lecturer at Imperial College London and Consultant Physician at Hammersmith Hospital who is leading the new study, said if successful, the treatment would “dramatically change” the treatment of patients with dementia.

"We're hoping this will improve their memory function in people and their quality of life and that their memory will improve,” he said. “We're hoping we will be able to delay the progression of the disease."

Previous studies have shown that people with diabetes have a much greater risk of getting Alzheimer’s disease.

The discovery was made after scientists found a link between Alzheimer's and diabetes. Patients with diabetes have a far greater risk of the degenerative condition.

Dr Edison said that the brains of patients with diabetes appeared to share some mechanisms with those of patients with Alzheimer’s disease.

Animal tests in the laboratory found that giving the diabetes drug to patients with dementia led to “a significant improvement in memory” and improvements in brain function, he said.

The multi-centre study will also involve patients from King's College London, Oxford, Birmingham, Bristol, Brighton and Southhampton.

If the first trials succeed, they will be followed by a study in a larger population, researchers said.

Dr Edison said he hoped the process would be speeded up, because Liraglutide is also shown to be safe and effective as a treatment for diabetes.

However, there is growing concern that Britain’s regulatory processes stand in the way of drugs being “repurposed” for another use.

Charities have raised concerns that patients with eye disease have been denied cheap drugs which can prevent blindness because they were licensed as a cancer treatment, and are only licensed for a new purpose if manufacturers seek approval.

Dr Simon Ridley, head of research at Alzheimer’s Research UK, said the latest steps were “encouraging” but said it was too early to say whether the drug would constitute a breakthough treatment for dementia.

He said: ““Earlier research in mice has suggested that liraglutide may be able to act against Alzheimer’s disease, but positive results from animal studies ? a vital first step in research ? do not always translate into benefits for people. Clinical trials are crucial to understand whether a treatment could help people with Alzheimer’s disease, so it’s encouraging to see this drug taken forward for human trials.”

He said it was vital that a number of different approaches were tested, with more funding needed to deliver the best chance of success in finding a treatment which is capable of stopping the disease in its tracks.



Drug discovery yields new hope for Alzheimer’s

9 April, 2015
Luxemburger Wort

(AFP) A drug that's already being used to treat strokes could hold promise in the fight against Alzheimer's disease.

Scientists from the University of South Australia and Third Military Medical University in China discovered that a drug called Edaravone could alleviate the progressive cognitive symptoms of Alzheimer's.

Available in some Asian countries, Edaravone is used to treat ischemic stroke, the most common kind that occurs due to blood clots.

When tested on mice, the drug improved functions of learning and memory by several different mechanisms, according to lead author Professor Xin-Fu Zhou of UniSA.

He says the multi-faceted approach could be key in treating Alzheimer's because several pathways require targeting to keep symptoms at bay.

"Edaravone can bind the toxic amyloid peptide which is a major factor leading to degeneration of nerve cells," says Professor Zhou.

The drug is said to be a scavenger that attacks free radicals, thereby suppressing oxidative stress similarly to the work of antioxidants.

Oxidative stress, says Professor Zhou, is the main cause of brain degeneration.

It can also hinder production of amyloid beta, a series of amino acid peptides that play a key role in the progression of Alzheimer's as the main component of the amyloid plaques that form in the afflicted brain.

What's more, the drug restrains the Tau hyperphosphorylation that generates disruptive tangles in the brain cells.

Human clinical trials must occur before healthcare professionals should consider prescribing Edaravone to Alzheimer's patients, says Professor Zhou.

The paper was published in Proceedings of the National Academy of Sciences.

In August, researchers at Yale University in the US discovered another drug that reverses cognitive deficits of Alzheimer's in mice.

It's called TC-2153 and it works by inhibiting the undesirable effects on learning and memory of a protein called STtriatal-Enriched tyrosine Phosphatase (STEP).

Their paper was published in the journal PLOS One.

Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits

Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved March 10, 2015 (received for review December 4, 2014)


Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.

tau oligomers

UTMB Scientists Use Immunotherapy to Reduce Memory Problems with Alzheimer's Disease

By: Raul Reyes
Friday, March 27, 2015

A new study from the University of Texas Medical Branch at Galveston has revealed that a single dose of an immunotherapy reverses memory problems in an animal model of Alzheimer’s disease. The article appears in the March 25 issue of the Journal of Neuroscience.

Researchers have been working for decades to map out how Alzheimer’s disease wields its devastating effects. Although it’s known that two molecules ? tau and amyloid beta ? are considered responsible for the disease’s progression, the relationship between these two proteins and resulting memory problems has remained unclear.

Brain cells depend on tau protein to form highways for the cell to get nutrients and get rid of waste. In some neurodegenerative diseases such as Alzheimer’s disease, the tau protein changes into a more toxic form referred to as an oligomer. When this happens, molecular nutrients can no longer move to where they are needed and the brain cells eventually die.

Scientists from UTMB have previously shown their anti-tau oligomer immunotherapy reduced levels of tau oligomers and reversed memory deficits in an animal model of Alzheimer’s. In the current study, it came as a surprise that the immunotherapy also reduced amyloid beta oligomer levels, suggesting that the detrimental effects of amyloid beta are dependent on the presence of toxic forms of tau.

“Our findings with this immunotherapy study indicate a link between tau oligomers and amyloid beta,” said lead author and associate professor of neurology, Rakez Kayed. “Because of this relationship, removing tau oligomers with our immunotherapy may also decrease the harmful effects amyloid beta and mitigate memory deficits.”

What sets Kayed's therapy apart from other tau immunotherapy drugs is that his targets only the toxic oligomer form of tau and leaves the normal tau alone and able to carry out its typical functions.

These findings provide strong evidence of the benefits of targeting tau oligomers with immunotherapeutic approaches as an Alzheimer’s disease treatment.

The other authors of this paper include UTMB’s Diana Castillo-Carranza, Marcos Guerrero-Munoz, Urmi Sengupta, Caterina Hernandez, Alan Barrett and Kelly Dineley.

This paper was supported by the Cullen Trust, the Alzheimer’s Drug Discovery Foundation, the UTMB Mitchell Center for Neurodegenerative Disease, the UTMB Sealy Center for Vaccine Development and these studies were completed as part of an interdisciplinary research team funded by The Moody Project for Translational Traumatic Brain Injury.

Article written by Raul Reyes
Raul Reyes, director of media relations at UTMB, has an extensive background in communications with more than 30 years experience in journalism. Before joining UTMB in 2007, he was an editor at The New York Times and also worked as an editor at the Dallas Morning News and the San Antonio Express-News. When he and his wife, Linda, worked at the Houston Chronicle in the 1980s, they used to dream about living and working in Galveston. Some things do come true. Raul is at UTMB and Linda edits a couple of Dallas magazines from their home in Galveston

Journal of Neuroscience

Tau Immunotherapy Modulates Both Pathological Tau and Upstream Amyloid Pathology in an Alzheimer's Disease Mouse Model

Diana L. Castillo-Carranza1,2,3,
Marcos J. Guerrero-Mu?oz1,2,3,
Urmi Sengupta1,2,3,
Caterina Hernandez1,2,3,
Alan D.T. Barrett4,
Kelly Dineley1,2,3, and
Rakez Kayed1,2,3,4

Author contributions: D.L.C.-C., A.D.T.B., K.D., and R.K. designed research; D.L.C.-C., M.J.G.-M., U.S., and C.H. performed research; D.L.C.-C., M.J.G.-M., U.S., C.H., K.D., and R.K. analyzed data; D.L.C.-C., A.D.T.B., K.D., and R.K. wrote the paper.

The Journal of Neuroscience, 25 March 2015, 35(12): 4857-4868; doi: 10.1523/JNEUROSCI.4989-14.2015


In Alzheimer's disease (AD), the pathological accumulation of tau appears to be a downstream effect of amyloid β protein (Aβ). However, the relationship between these two proteins and memory loss is unclear. In this study, we evaluated the specific removal of pathological tau oligomers in aged Tg2576 mice by passive immunotherapy using tau oligomer-specific monoclonal antibody. Removal of tau oligomers reversed memory deficits and accelerated plaque deposition in the brain. Surprisingly, Aβ*56 levels decreased, suggesting a link between tau and Aβ oligomers in the promotion of cognitive decline. The results suggest that tau oligomerization is not only a consequence of Aβ pathology but also a critical mediator of the toxic effects observed afterward in AD. Overall, these findings support the potential of tau oligomers as a therapeutic target for AD.


A Drug Has Been Found That Reverses a Precursor to Alzheimer’s

Kevin McSpadden
4:11 AM ET 03/12/2015

Researchers now want to proceed to substantial clinical trials

Researchers at John Hopkins University have found that low doses of a drug more commonly used to treat epilepsy can reverse a condition that increases the risk of developing Alzheimer’s disease.

According to statements issued Wednesday, the epilepsy drug, called antiepileptic levetiracetam, calms hyperactivity in the brain ? a well-documented symptom of people with amnestic mild cognitive impairment, which is a condition that heightens the possibility of developing Alzheimer’s disease.

The team, lead by neuroscientist Michela Gallagher, now wants to pursue substantial clinical trials.

“What we want to discover now, is whether treatment over a longer time will prevent further cognitive decline and delay or stop progression to Alzheimer’s dementia,” Gallagher said.

The researchers studied 84 people with an average age of 70. Participants received various doses of the drug, as well as a placebo, and the scientists used imaging technology to map brain activity.


Alzheimer's drug trial shows promising early results

20 March 2015

Experts cautiously welcome results of trial of antibody known as aducanumab, which appears to show benefit in patients given it in very earliest stage of disease

A new drug for Alzheimer’s appears to have shown some benefit in people who were given it in the very earliest stage of the disease, say scientists.

Experts were cautious about the results of the trial of an antibody known as aducanumab, which involved just 166 patients. But the dearth of drugs to halt or even slow the progress of dementia ? of which Alzheimer’s is the most common type ? means that any positive results will be greeted with enthusiasm.

In the trial, conducted primarily to ensure the drug was safe and had no serious side-effects, brain scans showed a reduction of amyloid plaque. Accumulation of amyloid plaques is thought to be one of the major causes of Alzheimer’s.

The higher the dose of drug the patient was given, the greater the reduction. Tests also showed that those people who took the drug had a slower rate of mental decline than those who did not ? although the trial was not set up primarily to see whether there was any effect on cognition.

“These are very promising early results, which not only demonstrate the safety of this treatment but also suggest it may hold benefits in the early stages of Alzheimer’s disease,” said Dr Eric Karran, director of research at Alzheimer’s Research UK.

“While many previous anti-amyloid therapies have failed to meet their goals, these preliminary findings back up research suggesting that treatments targeting amyloid will need to be given early in the disease. Further data from this trial is yet to be reported, and it will be important to see this data as well as results from much larger trials before we can understand how effective this treatment may be.

“Alzheimer’s disease affects half a million people in the UK today, causing untold devastation, yet there are currently no treatments capable of stopping the disease in its tracks. While today’s results are promising, we must continue to invest in research and cast our net wide in the search for new ways to fight the disease.”

The trial results were presented at the International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders in Nice, France. Alfred Sandrock, group senior vice-president and chief medical officer at Biogen Idec, the company that made the drug, announced it would be moving quickly into large-scale trials which will involve hundreds, if not thousands, of people. “Based on these results, we are advancing the aducanumab clinical programme to phase three with plans to initiate enrolment later this year,” he said.

There have been positive results from drug trials before that have then turned out to be short-lived. Some drugs appeared to help people with dementia to think and reason better and even to carry out tasks in their home that they had lost the ability to perform ? but then the patient lapsed into a faster decline than before, catching up with those who had never taken the drugs.

There are 850,000 people with dementia in the UK but the numbers are expected to rise to 1 million by 2025 and 2 million by 2051. Over 60% of those diagnosed have Alzheimer’s, as did the author Terry Pratchett, who died last week.


March 11, 2015

Promising Alzheimer's treatment moves toward clinical trials

A promising new natural treatment for Alzheimer's disease is moving toward clinical trials. This will be a major step forward as there is nothing on the market that slows the progression of Alzheimer's.

Muraleedharan Nair, Michigan State University natural products chemist, has patented a botanical compound, withanamides. His spinoff company, Natural Therapeutics, will begin the trials as soon as funding is in place.

To date, none of the major pharmaceutical companies - Merck, Eli Lilly, Bristol-Myers Squibb - have been able to produce an effective treatment that passed human clinical trials, Nair said.

"This particular research has focused on Ashwagandha, an herbal remedy that's been used in Eastern medicines for centuries," he said. "Our compound withanamides may work to prevent Alzheimer's disease at the onset, and it also could prevent its progression."

While plants cannot be patented, compounds from it can. MSU holds the patent for withanamides, and earlier research revealed that the compound, found in the plants' seeds, proved to be a powerful anti-oxidant - double the strength of what's on today's market. The potent compound has shown that it can protect cells against damaging attacks by a rogue protein ?- the earliest stage of Alzheimer's.

Alzheimer's begins when a specific protein starts breaking, or cleaving, at the wrong place to produce an unwanted fragment. This bad fragment, called BAP, stresses cells' membranes, sparks plaque formation and eventually kills the cells. This attack begins in the frontal lobe, erasing memories and continuing its unrelenting assault deeper into the brain.

A complicating factor is that the majority of protein cleaving is a natural, healthy process. Pharmaceutical companies, however, have focused their efforts on blocking the tiny faction of bad cleaving of the protein producing BAP.

"Rather than trying to stop only the malevolent cleaving, our compound keeps the bad protein from entering the cell where it does its damage," he said. "Our studies have shown that withanamides effectively protect the brain cells by neutralizing the effect of BAP."

Nair, who holds nearly 90 U.S. and international patents, is using withanamides to interrupt the action of BAP, hence preventing Alzheimer's at an early stage.

Nair and his collaborators published in Phytotherapy Research that withanamides protected mouse brain cells from BAP damage. A recent study, also published in Phytotherapy Research and using mouse models, showed that withanamides passed the blood brain barrier, the filter that controls what chemicals reach the brain. The results showed that the compound reached its intended target, passing the last test before advancing to human testing.

After the clinical trials, which could be conducted as quick as six to twelve months, Nair and Natural Therapeutics will pursue FDA approval.

"Dr. Nair discovered his molecule in a food-safe plant," said Jim Richter, Natural Therapeutics President. "It's also classified as GRAS - generally regarded as safe - by the FDA. This means that we can bypass many of the hurdles that slow synthetic molecules that need testing. By compressing the timeline dramatically, we'll be able to save tens of millions of dollars, and if successful, bring an effective treatment to Alzheimer's patients."

Explore further: Beer compound could help fend off Alzheimer's and Parkinson's diseases

Provided by Michigan State University search and more info website

Short Communication

Blood?Brain Barrier Permeability of Bioactive Withanamides Present in Withania somnifera Fruit Extract

Shaiju K. Vareed1,‡,
Alison K. Bauer2,†,‡,
Kavitha M. Nair3,‡,
Yunbao Liu3,
Bolleddula Jayaprakasam3 and
Muraleedharan G. Nair3,*

Article first published online: 23 JAN 2014

DOI: 10.1002/ptr.5118

Copyright c 2014 John Wiley & Sons, Ltd.

Volume 28, Issue 8, pages 1260?1264, August 2014


The neuroprotective effect of Withania somnifera L. Dunal fruit extract, in rodent models, is known. Withanamides, the primary active constituents in W.?somnifera fruit extract exhibited neuroprotective effects against β-amyloid-induced cytotoxicity in neuronal cell culture studies. Therefore, we investigated the blood?brain barrier permeability of withanamides in W.?somnifera fruit extract in mice using HPLC coupled with high resolution quadrupole time of flight mass spectrometer (Q-TOF/MS) detection. Mice were administered with 250?mg/kg of W.?somnifera extract by intraperitoneal injection, and the blood and brain samples analyzed by Q-TOF/MS detection. Four major withanamides were detected in brain and blood of mice administered with W.?somnifera extract. The results suggested that the withanamides crossed the blood?brain barrier. These results may help to develop W.?somnifera fruit extract as a preventive or therapeutic botanical drug for stress-induced neurological disorders. Copyright c 2014 John Wiley & Sons, Ltd.

Ultrasound therapy

Ultrasound therapies target brain cancers and Alzheimer’s disease

Emily is a staff writer at Science.
By Emily Underwood
11 March 2015

From imaging babies to blasting apart kidney stones, ultrasound has proved to be a versatile tool for physicians. Now, several research teams aim to unleash the technology on some of the most feared brain diseases.

The blood-brain barrier, a tightly packed layer of cells that lines the brain's blood vessels, protects it from infections, toxins, and other threats but makes the organ frustratingly hard to treat. A strategy that combines ultrasound with microscopic blood-borne bubbles can briefly open the barrier, in theory giving drugs or the immune system access to the brain. In the clinic and the lab, that promise is being evaluated.

This month, in one of the first clinical tests, Todd Mainprize, a neurosurgeon at the University of Toronto in Canada, hopes to use ultrasound to deliver a dose of chemotherapy to a malignant brain tumor. And in some of the most dramatic evidence of the technique's potential, a research team reports this week in Science Translational Medicine that they used it to rid mice of abnormal brain clumps similar to those in Alzheimer's disease, restoring lost memory and cognitive functions. If such findings can be translated from mice to humans, “it will revolutionize the way we treat brain disease,” says biophysicist Kullervo Hynynen of the Sunnybrook Research Institute in Toronto, who originated the ultrasound method.

Some scientists stress that rodent findings can be hard to translate to humans and caution that there are safety concerns about zapping the brain with even the low-intensity ultrasound used in the new study, which is similar to that used in diagnostic scans. Opening up the blood-brain barrier just enough to get a beneficial effect without scorching tissue, triggering an excessive immune reaction, or causing hemorrhage is the “crux,” says Brian Bacskai, a neurologist at Massachusetts General Hospital in Boston who studies Alzheimer's disease and used to work with Hynynen.

Safely and temporarily opening the blood-brain barrier is a long-sought goal in medicine. About a decade ago, Hynynen began exploring a strategy combining ultrasound and microbubbles. The premise is that ultrasound causes such bubbles to expand and contract, jostling the cells forming the blood-brain barrier and making it slightly leaky.

That could help cancer physicians such as Mainprize deliver chemotherapy drugs into the brain. Hynynen also hypothesized that the brief leakage would rev up the brain's inflammatory response against β amyloid?the toxic protein that clumps outside neurons in Alzheimer's and may be responsible for killing them. Disposing of such debris is normally the role of the microglia, a type of brain cell. But previous studies have shown that when β amyloid forms clumps in the brain, it “seems to overwhelm microglia,” Bacskai says. Exposing the cells to anti bodies that leak in when the blood-brain barrier is breached could spur them to “wake up and do their jobs,” he says. Some antibodies in blood may also bind directly to the β-amyloid protein and flag the clumps for destruction.

Hynynen and others have recently tested the ultrasound strategy in a mouse model of Alzheimer's. In December 2014, for example, he and colleagues reported in Radiology that the method reduces amyloid plaques in a strain of mice engineered to develop the deposits, leading to improvements in cognition and spatial learning. Microglia consumed more β amyloid after the treatment, suggesting the cells do play a role in the effect, says neuroscientist Isabelle Aubert, who collaborates with Hynynen at Sunnybrook.

This week, neuroscientist J?rgen G?tz of the Queensland Brain Institute in St. Lucia, Australia, and his Ph.D. student Gerhard Leinenga report that they have built on Hynynen and Aubert's protocol, using a different mouse model of Alzheimer's. After injecting these animals with a solution of microscopic bubbles, they scanned an ultrasound beam in a zigzag pattern across each animal's entire skull, rather than focusing on discrete areas as others have done. After six to eight weekly treatments, the team tested the rodents on three different memory tasks. Alzheimer's mice in the control group, which received microbubble injections but no stimulation, showed no improvement. Mice whose blood-brain barriers had been made permeable, in contrast, saw “full restoration of memory in all three tasks,” G?tz says.

The team also found a two- to fivefold reduction in different types of β-amyloid plaques in the brain tissue of the treated group. The attempt to stoke microglia's appetite appeared to work; G?tz and Leinenga found much more β-amyloid protein within the trash-eating cells of treated animals. Yet rousing microglia may not be the only mechanism responsible for the rodents' memory boost, Aubert notes. She and Hynynen recently reported in Brain Stimulation that ultrasound also boosts the birth and growth of new neurons in mice.

G?tz and Leinenga next plan to test the whole-brain ultrasound scan method in larger animals with β-amyloid deposits, such as sheep. The approach, which could in theory be used for other brain diseases involving abnormal protein clumps, “is exciting,” says Gerald Grant, a neurosurgeon at the Stanford University School of Medicine in Palo Alto, California. “We've been thinking of opening up the blood-brain barrier as a way to get things into the brain, but this pays attention to getting things out.”

It's far from settled that eliminating β-amyloid deposits outside of neurons is the key to treating or stopping Alzheimer's disease, however. And Bacskai is skeptical that the mouse results say much about the technique's potential in humans. The range between a mouse that can learn and one that cannot learn “is pretty small,” so big gains in behavioral tests in mice may mean nothing in humans, he says. He adds that nonstandardized ultrasound equipment makes it hard to answer basic safety questions: “How long is the blood-brain barrier open? How big are the pores? What's the damage?”

Hynynen, who is working with a medical imaging company to commercialize the technique, notes that ultrasound application to the brains of animals including rabbits and monkeys has produced no negative side effects. And Mainprize's clinical trial may provide more safety data. He hopes to open the blood-barrier to increase chemotherapy delivery to a brain cancer patient just before he operates to remove the tumor. Using Hynynen's technology, he and colleagues will apply ultrasound and microbubbles to tissue in and around the tumor, as well as to several unaffected brain areas. Then they'll examine excised tissue for hemorrhages and to see if the treatment boosted the concentration of the drug. A similar trial is now recruiting participants in France.

If these phase I trials establish safety, “it opens the door for phase II trials looking to see if there's any benefit” to opening the blood-brain barrier, including for conditions beyond cancer, Mainprize says. Despite his doubts, Bacskai can't fully resist the dream driving this fledging field. “Imagine if your grandmother went to the clinic once per year, and it cleared amyloid β and that was all it took?no surgery, no drugs. It would be amazing.”
Posted in Biology, Brain & Behavior, Health

Sci Transl Med 11 March 2015:
Vol. 7, Issue 278, p. 278ra33
Sci. Transl. Med. DOI: 10.1126/scitranslmed.aaa2512

Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model

Gerhard Leinenga and
J?rgen G?tz*

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia Campus, Brisbane, Queensland 4072, Australia.
?*Corresponding author. E-mail: j.goetz@uq.edu.au


Amyloid-β (Aβ) peptide has been implicated in the pathogenesis of Alzheimer’s disease (AD). We present a nonpharmacological approach for removing Aβ and restoring memory function in a mouse model of AD in which Aβ is deposited in the brain. We used repeated scanning ultrasound (SUS) treatments of the mouse brain to remove Aβ, without the need for any additional therapeutic agent such as anti-Aβ antibody. Spinning disk confocal microscopy and high-resolution three-dimensional reconstruction revealed extensive internalization of Aβ into the lysosomes of activated microglia in mouse brains subjected to SUS, with no concomitant increase observed in the number of microglia. Plaque burden was reduced in SUS-treated AD mice compared to sham-treated animals, and cleared plaques were observed in 75% of SUS-treated mice. Treated AD mice also displayed improved performance on three memory tasks: the Y-maze, the novel object recognition test, and the active place avoidance task. Our findings suggest that repeated SUS is useful for removing Aβ in the mouse brain without causing overt damage, and should be explored further as a noninvasive method with therapeutic potential in AD.
Copyright ? 2015, American Association for the Advancement of Science

Nerve Growth Factor Implant

Nerve Growth Factor Implant for Alzheimer’s Shows Promise

February 14, 2015

Nerve Growth Factor Implant for Alzheimer's Shows Promise
A new Alzheimer’s therapy, which involves a nerve growth factor (NGF) implant inserted directly into the brain, is being tested by researchers at Karolinska Institutet’s Centre for Alzheimer’s Research in Sweden, and the results are are said to be very promising.

Those with Alzheimer’s disease experience an early breakdown of cholinergic nerve cells, which require a specific nerve growth factor (a group of proteins necessary for cell growth and survival) to function. As NGF levels drop, the cholinergic nerve cells begin to degrade and the patient’s condition worsens.

In an attempt to thwart the breakdown of these nerve cells, the researchers introduced NGF directly into the brains of Alzheimer’s patients. To do this, they placed NGF-producing cell capsules in the basal forebrain. These capsules, which can easily be removed, then released NGF to the surrounding cells in order to prevent their degradation.

The study is based on data from six Alzheimer’s patients. To determine whether the NGF release exerted any effect on the cholinergic nerve cells, the researchers looked for the presence of specific markers of functioning cholinergic cells.

This cell system communicates using acetylcholine, which in turn produces an enzyme called ChAT (pronounced Cat) that is found both inside and outside the cells. For the first time, the researchers developed a method that allowed them to measure ChAT in the cerebral spinal fluid.

“Our results show that when the patients received NGF, there was a significant increase in ChAT in the CSF,” said Dr. Taher Darreh-Shori, one of the researchers involved in the study.

“The patients that exhibited this increase were also those that responded best to the treatment. Our PET scans also showed an increase in cholinergic cell activity and metabolism in the brain.”

Furthermore, the researchers were able to detect a slowing of memory impairment over time compared with untreated patients. While all of this suggests that cholinergic functionality improved in the Alzheimer’s patients who had received NGF therapy, the team noted that far-reaching conclusions cannot be drawn from the results just yet.

“The results are promising, but must be treated with circumspection as only a few patients participated in the study,” said principal investigator Maria Eriksdotter, M.D., Ph.D. “So our findings will have to be substantiated in a larger controlled study using more patients.”

Their findings are published in the scientific journal Alzheimer’s & Dementia.

Source: Karolinska Institutet

Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease

Published Online: February 09, 2015
Alzheimer’s & Dementia


The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF).


Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed.


EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase.


Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-β, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures.


A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.


February 10, 2015

Protein linked to longevity and enhanced cognition protects against Alzheimer's symptoms

Scientists from the Gladstone Institutes and the University of California, San Francisco report in the Journal of Neuroscience that raising levels of the life-extending protein klotho can protect against learning and memory deficits in a mouse model of Alzheimer's disease. Remarkably, this boost in cognition occurred despite the accumulation of Alzheimer-related toxins in the brain, such as amyloid-beta and tau.

Klotho decreases naturally with aging, which also leads to a decline in cognitive ability. An earlier study from these researchers revealed that having a genetic variant that increases klotho levels is associated with better cognition in normal, healthy individuals, and experimentally elevating klotho in mice enhances learning and memory. However, klotho's influence in the face of aging-related cognitive disorders like Alzheimer's disease was unclear.

To test klotho's protective capacity, the scientists created a mouse model of Alzheimer's disease that produced higher levels of this protein throughout the body. Ordinarily, Alzheimer's-model mice have cognitive deficits, abnormal brain activity, and premature death, but raising klotho levels ameliorated these problems. The cognition-enhancing effects of the protein were powerful enough to counteract the effects of Alzheimer-related toxins, whose levels were unchanged.

"It's remarkable that we can improve cognition in a diseased brain despite the fact that it's riddled with toxins," says lead author Dena Dubal, MD, PhD, an assistant professor of neurology and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF. "In addition to making healthy mice smarter, we can make the brain resistant to Alzheimer-related toxicity. Without having to target the complex disease itself, we can provide greater resilience and boost brain functions."

Klotho's benefits may be due to its effect on a certain type of neurotransmitter receptor in the brain, called NMDA, that is crucially involved in learning and memory. While Alzheimer's impairs NMDA receptors, the mice with klotho elevation maintained normal receptor levels. In addition, these mice had more GluN2B?a subunit of NMDA?than control animals. This increase may have contributed to the protective effects of klotho, counteracting the detrimental impact of Alzheimer-related toxicity on the brain.

"The next step will be to identify and test drugs that can elevate klotho or mimic its effects on the brain," says senior author Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and the Joseph B. Martin Distinguished Professor of Neuroscience at UCSF. "We are encouraged in this regard by the strong similarities we found between klotho's effects in humans and mice in our earlier study. We think this provides good support for pursuing klotho as a potential drug target to treat cognitive disorders in humans, including Alzheimer's disease."

Explore further: Brain region vulnerable to aging is larger in those with longevity gene variant

Journal reference: Journal of Neuroscience search and more info website

Provided by Gladstone Institutes search and more info website


Promising Alzheimer's research stalled by lack of volunteers for studies

"The focus today is mainly directed on early intervention," Dr. Ralph Richter says of current Alzheimer's research.

By Brooks Hays
Feb. 10, 2015

BOSTON, Feb. 3 (UPI) -- Researchers suggest that by 2020, the number of Americans living with Alzheimer's disease will have tripled, from about 5 to 15 million people. In the meantime, research into the best ways to prevent and treat the disease will continue.
But while promising new discoveries are made each year (and will likely continue to be made in the coming decades), doctors and scientists worry the pace of Alzheimer's research is too slow. They also worry the race for a cure may be a distraction from the pressing need to develop more effective treatments -- treatments that don't just stop Alzheimer's in its tracks, but also work to reverse the damage done.

Part of the reason for both these problems, doctors say, is the dearth of Alzheimer's patients willing and ready to participate in various types of medical studies.

"It is in general a tremendous problem nationwide to recruit an adequate number of people to participate in Alzheimer's studies," says Dr. Robert Stern, clinical director at the Boston University Alzheimer's Disease Center.

Alzheimer's is a neurodegenerative disease responsible for more than 60 percent of all dementia. It's now the sixth leading cause of death in the United States. What normally begins as the slow arrival of minor memory loss issues -- often unnoticeable in its earliest stages -- soon begins to cascade, resulting in the loss of cognitive function and ultimately death.

Though the exact origins are still being debated, scientists believe the accumulation of a plaque called amyloid and a protein known as tau play key roles in slowly disrupting neurological communication--corroding synapses, severing neural pathways and eventually killing brain cells. Technically, Alzheimer's can only be confirmed after death, by testing for the presence of amyloid and tau. But new ways to test for the biomarkers are showing progress, as are drugs that halt their growth.

These select few drugs, mostly called anti-amyloid drugs, are tremendously promising.

"The compound attaches to the bad amyloid and sucks it out of the brain," Dr. Stern says of one of the new drugs, still in Phase 2 trials. They're "truly modifying the disease course, and clinically you're preventing it."

But as Stern points out, these drugs will require early detection of the plaque and protein implicated in the onset of Alzheimer's. Today, most Alzheimer's cases aren't diagnosed until neuropsychological tests reveal varying mild cognitive impairment. And many diagnoses aren't made until dementia is knocking on the door. Even if anti-amyloid treatments make it to market, these new prevention treatments, Stern says, can only do so much for the more than 5 million Americans already living with the disease -- not to mention the "umpteen million more over the coming decades that are going to develop Alzheimer's disease," he says.

Stern is leading the testing of one of the only drugs that shows promise for treating patients who are already battling Alzheimer's. The NOBLE Study, part of which is being organized and executed out of the Boston University Medical Center, features the drug T-817MA -- a compound that has (in test tubes and animal experiments) been shown to protect neurons against the toxicity induced by amyloid.

Even more importantly, Stern says, is that "it seems to also have an additional quality, which may promote the outgrowth of new connection between cells."

The T-817MA portion of the NOBLE Study is entering Phase 2, which means it has proven relatively safe and its early promise will now be tested on a larger group of patients.

But Stern says the progress is slow; and it's a problem he says isn't unique to his study. While he and other medical researchers are studying new experimental drugs, other scientists continue to search for the most effective way to recruit volunteers for Alzheimer's drug studies. Their work, too, has been slow to materialize results. Finding enough study participants remains one of the largest impediments to progress in Alzheimer's treatment research.

"In my mind, it is a tragedy that we actually have so many exciting new drugs right now that are currently in clinical trials that provide so much possible hope," Stern said. "But it takes forever to get to the point of finishing the trial."

While the benefits of drug trials for Alzheimer's can be tremendous -- including access to new drugs, regular free healthcare consultation, and an influx of human connections while dealing with what can be a lonely disease -- doctors and researchers can understand why many are reluctant to volunteer.

Fear, shame and denial are all emotions that can influence patients facing a recent Alzheimer's diagnosis and the decision of whether to participate in a drug trial.

"There is a certain fearfulness of having an MRI or other diagnostic procedures performed," said Dr. Ralph Richter of Tulsa Clinical Research. "Others are hesitant having to stop taking medications that are exclusionary by the study protocol."

But regardless of their reasoning, Richter says it's up to the research team to build confidence, trust and rapport with recruits.

"Recognizing their concerns, being available to answer their many questions and being there for them and their family for support at all times, is what counts and makes patients decide to participate in a clinical research study," Richter says.

And while more exhaustive but empathetic recruitment tactics may be a winning combination, there's still the ongoing discrepancy (funding and otherwise) between prevention and treatment research.

"The focus today is mainly directed on early intervention," Richter acknowledges. But finding a way to reverse the progression of Alzheimer's, he says, is essential.

"A large portion of the aging population has already been diagnosed with the disease."

For those and the many more who are expected to be diagnosed in the coming decades, T-817MA may be one of the few bright spots in treatment research. But its potential will only be realized if doctors like Richter and Stern can recruit enough volunteers to prove the drug's ready for Phase 3.

blocking the IL-10 anti-inflammatory response
Public Release: 5-Feb-2015
USC neurogeneticists harness immune cells to clear Alzheimer's-associated plaques
New research identifies promising therapeutic target for treating Alzheimer's disease

University of Southern California - Health Sciences

New research from scientists at the Keck School of Medicine of the University of Southern California (USC) shows that the body's immune system may be able to clear the brain of toxic plaque build-up that is the hallmark of Alzheimer's disease, reversing memory loss and brain cell damage.

The study, which appears in the Feb. 4 edition of the peer-reviewed scientific journal Neuron, identifies a promising avenue for treating a disease that the Alzheimer's Association projects will affect 16 million Americans over age 65 by 2050.

"Alzheimer's disease is the public health crisis of our time, and effective treatment does not yet exist," said Terrence Town, Ph.D., professor of physiology and biophysics at the Keck School of Medicine of USC and the study's senior author. "Our study shows that 'rebalancing' the immune response to wipe away toxic plaques from the brain may bring new hope for a safe and effective treatment for this devastating illness of the mind."

Alzheimer's disease is an irreversible, progressive brain disease that causes problems with memory, thinking and behavior. Affecting more than 5 million Americans today, Alzheimer's is the most common type of dementia, a general term for loss of memory and other mental abilities. Brains with Alzheimer's disease show build-up of a sticky plaque -- made of a protein called beta-amyloid -- that induces memory loss. When afflicted with Alzheimer's, the immune system, which typically rids the body of toxic substances, becomes imbalanced and inefficient at clearing those plaques.

In the Neuron study, Town and his team used genetically modified mice to show that blocking a substance called interleukin-10 activates an immune response to clear the brain of the beta-amyloid plaques to restore memory loss and brain cell damage. Alzheimer's-afflicted mice in which the immune cells were activated behaved more like mice without the disease in various learning and memory tests. Future studies will test the effectiveness of drugs that target interleukin-10 in rats that the scientists have genetically modified to develop Alzheimer's disease.


USC co-authors include Marie-Victoire Guillot-Sestier, Kevin R. Doty, David Gate, Javier Rodriguez, Jr., and Brian P. Leung. The study was supported in part by the National Institutes of Health (1F31NS083339-01A1, 5R00AG029726-04, 3R00AG029726-04S1, 1R01NS076794-01), American Federation of Aging Research/Ellis Medical Foundation and Zilkha Neurogenetic Institute.

Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology

DOI: http://dx.doi.org/10.1016/j.neuron.2014.12.068

?Il10 deficiency promotes Alzheimer’s β-amyloid clearance in APP/PS1 mice
?Il10 deficiency mitigates synaptic and cognitive deficits in APP/PS1 mice
?Innate immunity is “rebalanced” in Il10 deficient APP/PS1 mouse brains
?Blocking IL-10 may be therapeutically relevant for Alzheimer’s disease


The impact of inflammation suppressor pathways on Alzheimer’s disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mouse deficient in Il10 (APP/PS1+Il10?/?). Quantitative in silico 3D modeling revealed activated Aβ phagocytic microglia in APP/PS1+Il10?/? mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1+Il10?/? brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. In vitro knockdown of microglial Il10-Stat3 signaling endorsed Aβ phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aβ uptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated in AD patient brains. Our results suggest that “rebalancing” innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.


Levetiracetam Looks Promising for Pre-Dementia

February 1, 2015
Alzheimer's & Dementia Weekly

"Pre-dementia" is a common nickname for aMCI (amnestic Mild Cognitive Impairment). aMCI causes memory to decline more than what's expected from normal aging, without disrupting day-to-day life. AGB101 is a new treatment for aMCI. It is a low-dose version of FDA-Approved Levetiracetam. Learn more about the AGB101 trial.

NEW YORK /PRNewswire-USNewswire/ -- The Alzheimer's Drug Discovery Foundation (ADDF) announced a $900,000 grant to AgeneBio, a pharmaceutical company developing innovative therapies for neurologic and psychiatric diseases. The grant will support the initiation of an FDA-registered Phase 3 clinical trial of AGB101, a new therapeutic treatment for amnestic mild cognitive impairment (aMCI). aMCI is a condition in which memory is worse than to be expected for a person's age and is considered the pre-dementia stage of Alzheimer's disease. This is the second grant that the ADDF has made to AgeneBio.

AGB101 is a proprietary formulation of low-dose levetiracetam, given to patients at approximately one-fifteenth of the dose most commonly prescribed for epilepsy. This therapeutic has been commercialized for more than a decade and offers a well-characterized safety profile at fifteen times the expected dose for AGB101. AgeneBio expects to initiate the AGB101 Phase 3 clinical program in the second half of 2015.

AGB101 is the first and only treatment to target hippocampal hyperactivity, a condition characteristic of the aMCI stage of Alzheimer's disease. The Phase 3 trial will build on studies in both animal models and patients with aMCI that have demonstrated the importance of reducing hippocampal hyperactivity to restore the brain function necessary to maintain cognitive function and memory.

aMCI is believed to affect between 10 and 20 percent of individuals 65 and older. There is currently no FDA-approved therapy for patients in this pre-dementia stage of Alzheimer's disease, representing an enormous unmet clinical need.

The ADDF's Founding Executive Director and Chief Science Officer Howard Fillit, MD, said,
"The ADDF is thrilled to support AgeneBio to advance the clinical development of this drug candidate for the benefit of aMCI patients. This treatment has the potential to alter the course of Alzheimer's disease, restore normal brain function and preserve memory and cognitive abilities."
"We are extremely grateful to the ADDF for its continued support of our drug development program," said AgeneBio's CEO Jerry McLaughlin. "This additional grant is a strong endorsement of our clinical program, and we look forward to working with ADDF as our research progresses."


AgeneBio's portfolio of drug discovery work is based on the research of its founder, Michela Gallagher, PhD, Krieger-Eisenhower Professor of Psychological and Brain Sciences and Principal Investigator of the Neurogenetics and Behavior Center at Johns Hopkins University.

About AgeneBio
AgeneBio is an emerging pharmaceutical company dedicated to developing innovative therapeutics that prevent neurodegeneration and preserve and restore cognitive function for unserved patients battling amnestic mild cognitive impairment (aMCI), the symptomatic pre-dementia stage of Alzheimer's disease, and other neurological and psychiatric diseases. AgeneBio's novel pipeline of therapies is based on decades of research at Johns Hopkins University and leading research centers worldwide showing that overactivity in the hippocampus contributes to cognitive impairment and drives neurodegeneration if not controlled. This overactivity is a characteristic feature of aMCI. If approved, AgeneBio's Phase 3-ready lead candidate, AGB101, will be the first and only therapeutic targeting hippocampal overactivity and potentially the first therapeutic to slow progression to, and delay the onset of, Alzheimer's dementia. AgeneBio also has a novel GABA-A alpha 5 small molecule program in late discovery stage with potential therapeutic potential for a spectrum of untreated conditions including aMCI, autism and schizophrenia. Learn more at www.agenebio.com.


The Alzheimer's Drug Discovery Foundation (ADDF)
The mission of the Alzheimer's Drug Discovery Foundation (ADDF) is to accelerate the discovery of drugs to prevent, treat and cure Alzheimer's diseases, related dementias and cognitive aging. The ADDF has granted more than $70 million to fund over 450 Alzheimer's drug discovery programs in academic centers and biotechnology companies in 18 countries. For more information, please visit www.AlzDiscovery.org.

Anavex 2-73

Miracle hope in Victorian trial of new Alzheimer’s pill

Lucie van den Berg
Herald Sun
January 28, 2015

VICTORIANS with Alzheimer’s disease are the first in the world to receive a new drug aiming to revolutionise treatment of the most common form of dementia.

Unlike other medications, the pill is the only drug designed to relieve symptoms and slow the progression of the disease.

One Australian is diagnosed every six minutes with Alzheimer’s disease, with cases expected to balloon as the population ages.

Alfred Health was selected by the overseas drug company to lead the first trial of Anavex 2-73 on patients with the disease, giving Victorians exclusive access.

Trial leader, director of Aged Psychiatry at Caulfield Hospital, Associate Professor Steve Macfarlane said the global race to find better treatments meant the phase 2 trial would be fast-tracked and results would be known within a year.

If successful, a second trial would make the drug available to thousands of patients, and it could be on the market in three years.

“It’s a great opportunity for Victorian patients, particularly given it’s such a novel drug with the potential to modify the course of the disease and give symptomatic treatment,” Prof Macfarlane said.

So far, Alzheimer’s disease drugs have only been able to improve symptoms, but have not stopped long-term deterioration in their health.

There are a number of disease-modifying drugs in development, but they only slow the course of the disease without improving symptoms.

Prof Macfarlane said Anavex 2-73 aims to do both by protecting the brain, helping nerve cells live longer and assisting with the removal of amyloid plaque, which builds up in the brains of those with the disease.

The drug works by stimulating the sigma receptor on the cell, which triggers the body to clear up excess proteins, such as amyloid plaque.

It hopes to boost memory by making available cognitive enhancers more powerful.

Anavex 2-73 has been trialled in the lab, on animals and on healthy volunteers, but this month it was administered to the first patient with the disease. Melbourne man Malcolm Baker, 73, is part of the trial, where every patient gets the active drug, and he hopes it will improve his long-term outcome.

Alzheimer’s Australia Victoria research fellow Dr Maree Farrow said while the trial was promising, it was small and would take several years to establish the drug’s effectiveness or otherwise.

More than 30 patients with early-stage Alzheimer’s disease taking cognitive enhancer Aricept are needed for the trial.

leuprolide acetate (Lupron)

January 25, 2015
Alzheimer's & Dementia Weekly

Leuprolide Stabilizes Alzheimer's Memory Loss


Leuprolide is an FDA approved cancer drug. In a clinical trial for Alzheimer's, it stabilized memory loss for a full year. This is the first time any therapy has done that. Find out more.

Women with Alzheimer's disease showed stable cognition for a year when a drug that is more commonly used to treat advanced prostate cancer was added to their drug regimen, according to a new study from researchers at the University of Wisconsin-Madison.

"This is the first time any therapy has been shown to stabilize memory loss over a year," says Dr. Craig Atwood, co-lead author of the study and associate professor of medicine at the UW School of Medicine and Public Health.

The study was published in the Journal of Alzheimer's Disease and is available here:http://iospress.metapress.com/content/n207096671247200

Leuprolide is FDA approved for cancer and not for Alzheimer's. This means that until these clinical trials are completed, the FDA cannot be confident about the efficacy and safety of this medication for Alzheimer's. Therefore, the FDA will not "label" it for Alzheimer's. Therefore, neither the government nor the drug company that makes leuprolide have any responsibility towards an individual who takes this medicine for Alzheimer's right now. This will change after trials are complete, should the FDA approve the drug for Alzheimer's.

In the meantime, one can only use this medication "Off-Label" for Alzheimer's in the USA. "Off-label" means that an individual doctor can take responsibilty for this drug which is labeled for cancer and decide they want to use it on a patient "off-label" for Alzheimer's. Only the doctor and the patient have any responsibility for the effects of the drug.
Clinical Trial
The clinical trial, initiated by Dr. Richard Bowen at the former Voyager Pharmaceutical Corporation, followed 109 women with mild to moderate Alzheimer's disease. Some were treated with the drug leuprolide acetate (Lupron Depot), used to treat cancer in men and severe endometriosis in women, and with an acetylcholineesterase inhibitor such as Aricept, which improves mood in people with the condition but does little to slow memory loss. Others taking an acetylcholineesterase inhibitor received low-dose Lupron alone or a placebo.

It found that the women treated with both Aricept and high-dose Lupron Depot had almost no decline (0.18 points) in their scores on the ADAS-cog, a test of memory, compared with declines of 4.21 for those taking an acetylcholineesterase inhibitor and low-dose Lupron and 3.3 in those only taking an acetylcholineesterase inhibitor after one year.
How They Found It
Atwood explained that earlier epidemiological studies involving hundreds of thousands of patients had found that men who had prostate disease and were treated with Lupron had a 34 to 55 percent decreased risk of developing Alzheimer's disease compared with prostate-cancer patients who didn't receive the drug.

He explained that Lupron acts to suppress gonadotropin-releasing hormone (GnRH), which is produced in the brain and controls ovulation in women and in men. This in turn decreases the production of gonadotropins, hormones that regulate the synthesis of sex steroids like estrogen and testosterone. For these reasons, it is also used to treat estrogen-sensitive breast cancer, endometriosis, and premature puberty. Decreasing GnRH and gonadotropins with Lupron prevents some of the negative effects of elevated GnRH and gonadotropins on the brain, which occurs following menopause.

Post-menopausal women were chosen for this study because they no longer produce sex steroids; men could have been affected by the loss of testosterone caused by the Lupron.

"This promising combination therapy (acetylcholineesterase inhibitors and Lupron Depot) warrants testing in early and late stages of Alzheimer's disease," Atwood says. "However, since the company that performed this study is now out of business, it remains to be seen whether this therapy will ever be tested in further clinical trials and reach the market."

"A Clinical Study of Lupron Depot in the Treatment of Women with Alzheimer's Disease: Preservation of Cognitive Function in Patients Taking an Acetylcholinesterase Inhibitor and Treated with High Dose Lupron Over 48 Weeks," by Richard L. Bowen, George Perry, Chengjie Xiong, Mark A. Smith, Craig S. Atwood, DOI:10.3233/JAD-141626, Journal of Alzheimer's Disease, published in Volume 44, Issue 2 by IOS Press.

The Journal of Alzheimer's Disease (JAD)

The Journal of Alzheimer's Disease is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer's disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer's Disease has an Impact Factor of 3.612 according to Thomson Reuters' 2013 Journal Citation Reports. It is ranked #22 on the Index Copernicus Top 100 Journal List. The Journal is published by IOS Press.

A Clinical Study of Lupron Depot in the Treatment of Women with Alzheimer's Disease: Preservation of Cognitive Function in Patients Taking an Acetylcholinesterase Inhibitor and Treated with High Dose Lupron Over 48 Weeks
Journal Journal of Alzheimer's Disease
Publisher IOS Press
ISSN 1387-2877 (Print)
1875-8908 (Online)
Subject Medicine, Clinical Neurology and Internal Medicine
Issue Volume 44, Number 2 / 2015
Pages 549-560
DOI 10.3233/JAD-141626
Subject Group Medicine and Health
Online Date Monday, October 13, 2014
Publisher's Copyright Statement
Add to marked items
Add to shopping cart
Add to saved items
Recommend this article
PDF (429.9 KB)HTMLFirst Page PreviewFirst Page PreviewSupplemental MaterialSupplemental Material

Richard L. Bowen1, George Perry2, 3, Chengjie Xiong4, Mark A. Smith3, Craig S. Atwood5, 6, 7
1OTB Research, Charleston, SC, USA
2UTSA Neurosciences Institute and Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA
3Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
4Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
5Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
6Geriatric Research, Education and Clinical Center, Veterans Administration Hospital, Madison, WI, USA
7School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia

To test the efficacy and safety of leuprolide acetate (Lupron Depot?) in the treatment of Alzheimer's disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot? (11.25 mg leuprolide acetate), high dose Lupron Depot? (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: ?0.54, ?8.00, and ?6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD.

Email This


Share to Twitter

Share to Facebook

Click For More On: Clinical Trials , Off-Label

RNA-binding motif protein 3 (RBM3); 'Hibernation protein'

'Hibernation protein' could help repair dementia damage

Thursday January 15 2015

"Neurodegenerative diseases have been halted by harnessing the regenerative power of hibernation," BBC News reports. Researchers have identified a protein used by animals coming out of hibernation that can help rebuild damaged brain connections ? in mice.

Research found the cooling that occurs in hibernation reduces the number of nerve connections in the brain, but these regrow when an animal warms up.

A protein called RNA-binding motif protein 3 (RBM3) increases during the cooling, and it appears this protein is part of a pathway involved in the regrowth.

When the level of RBM3 was increased without cooling, researchers found the protein protected against the loss of nerve connections in mice with early-stage rodent forms of Alzheimer’s disease and a prion infection similar to Cruetzfeldt-Jakob disease (CJD). The diseases progressed more quickly when the level of RBM3 was lowered.

This same protein is increased in humans when they are given therapeutic hypothermia, where the body temperature is reduced to 34C as a protective treatment after events such as a heart attack.

The hope is that restoring neural connections (synapses) in humans could halt, or even reverse, the effects of dementia and associated neurodegenerative diseases. But this research is still very much in the early stages.

Where did the story come from?

The study was carried out by researchers from the University of Leicester and the University of Cambridge, and was funded by the Medical Research Council.

It was published in the peer-reviewed journal, Nature.

On the whole, the media reported the study accurately, but the Mail Online got carried away when they said a drug produced from this research "given in middle age … could keep the brain healthy for longer".

The experiments have only been done in mice so far, and no drug has been developed to target the pathway in humans.

What kind of research was this?

This was an animal study that looked at the effects of hibernation on the brain synapses (nerve connections) of mice.

Normally, synapses in the brain go through a process of forming, being removed, and then forming again. Various toxic processes can cause more degeneration, and in some conditions they are not reformed.

This leads to a reduction in the number of synapses, as occurs in conditions such as Alzheimer's disease, which are associated with symptoms such as memory loss and confusion.

A similar loss of synapses occurs when animals hibernate, but they are renewed when the animal warms up at the end of hibernation. Previous research found this also happens when rodents are cooled in a laboratory setting.

Researchers found the production of many proteins does not occur at these low temperatures, but some proteins called "cold-shock proteins" are stimulated ? one of these is RBM3.

Here, the researchers wanted to further investigate whether this protein plays a role in the regeneration of synapses. They hope it might be key to understanding how we could restart the process of synapse renewal in humans.

What did the research involve?

Three groups of mice were studied during hibernation induced in the laboratory setting:
?normal (wild type) mice ? controls
?mice with a rodent form of Alzheimer's disease
?mice with a prion disease, similar to Cruetzfeldt-Jakob Disease (CJD)

Some mice were cooled to 16-18C for 45 minutes and then gradually warmed back to their normal body temperature.

Their brains were studied at various stages of the cooling and rewarming process to count the number of synapses and measure the level of RBM3.

Some mice with the prion disease were not cooled so they could be used as a comparison to see if the cooling process had any effect on the course of the disease.

The other mice were also not cooled, but their levels of RBM3 were chemically increased or decreased to see what effect this had on their brains.

What were the basic results?

Normal mice and mice with the very early stages of a rodent form of Alzheimer's disease (at two months) and a prion disease (at four and five weeks after infection) lost synapses as they were cooled down, but recovered them as they warmed up.

They also all had increased levels of RBM3 during the cooling stage. These levels of RBM3 stayed elevated for up to three days afterwards.

The prion-infected mice did not succumb to the disease as quickly as mice that had been infected but not cooled.

They survived for seven days longer on average (91 days compared with 84 days). This suggests the cooling process gave some protection against the prion disease.

Mice who had rodent Alzheimer's disease for three months and a prion disease for six weeks (that is, more advanced disease) also lost synapses when they were cooled, but were not able to regrow them on warming up.

They did not have increased levels of RBM3. There was no difference in survival between these prion-infected mice and the prion-infected mice that were not cooled.

In mice where RBM3 levels were artificially reduced, both types of disease worsened more quickly and synapses were lost faster.

Reducing RBM3 levels in mice without these diseases also reduced the number of synapses, and the mice had memory problems.

When RBM3 production was stimulated in one region of the brain (the hippocampus) in mice with prion infection, this reduced the number of synapses that were lost and increased their survival.

How did the researchers interpret the results?

The researchers concluded the protein RBM3 is involved in the pathway of synapse regeneration in mice. They found stimulating the protein was protective against synapse loss in mice with a rodent form of Alzheimer's disease and a prion disease. They hope that, with further research, this might be a new avenue for drug development for humans.


The researchers have shown how cooling is protective against the loss of synapses in the early stages of rodent forms of Alzheimer's disease and a form of prion disease. Cooling also increased how long prion-infected mice survived.

But cooling was not protective in the later stages of the diseases. The researchers found this may in part be because of the protein RBM3, which is stimulated during cooling. They found levels of RBM3 increased in the early stages of the diseases when the mice were cooled, but did not in the later stages.

Stimulating this protein without cooling the mice also slowed down the loss of synapses and improved survival in mice with a prion infection.

The results also showed the disease processes sped up when RBM3 levels were reduced. The researchers say this indicates RBM3 is likely to be involved in the maintenance of synapse connections under normal conditions, not just during hibernation.

It is already known from other studies that similar increases in RBM3 occur when humans are given therapeutic hypothermia, where the body temperature is reduced to 34C as a protective treatment ? for instance, after a heart attack.

It may be the case that if this pathway is stimulated in humans, it could be a new avenue of research for the treatment of neurodegenerative disorders such as Alzheimer's disease.

This is intriguing research, but still very much in its early stages. There is much we don't know about Alzheimer's disease and other related diseases, though there is evidence that taking steps to maintain a healthy blood flow to the brain by taking regular exercise and eating a healthy diet may lower the risk (as well as help prevent heart disease).


GEN News
Jan 12, 2015

Janssen Pharmaceuticals to Help AC Immune Advance Its Alzheimer’s Disease Therapeutic Vaccines

AC Immune and Janssen Pharmaceuticals will work together to develop and commercialize therapeutic anti-Tau vaccines for the treatment of Alzheimer’s disease and potentially other tauopathies.

Janssen Research & Development, an affiliate of Janssen Pharmaceuticals, will further develop AC Immune’s lead therapeutic vaccine, ACI-35, which is currently in a Phase Ib. ACI-35 is an active therapeutic vaccine stimulating the patient's immune system to produce a polyclonal antibody response against phosphorylated Tau protein.

AC Immune will receive an upfront payment and is eligible to receive research, development, and commercialization milestone payments potentially totaling up to $509 million for Alzheimer´s disease and a potential second indication outside of Alzheimer´s disease. Additionally, the company is eligible to receive tiered royalties on net sales for any approved products resulting from the collaboration.

AC Immune and Janssen will co-develop ACI-35 through Phase Ib completion. As of Phase II and onward, Janssen will assume responsibility for the clinical development, manufacturing, and commercialization of ACI-35. Additionally, the two companies have entered a three year joint research collaboration to further characterize and develop novel vaccine therapies for the treatment of tauopathies.

Two years ago, in January 2013, AC Immune discontinued development of ACI-91, a small molecule drug in development for advanced Alzheimers disease. The drug was in-licensed and had a different mode of action than in-house therapies under development. "We are disappointed at these Phase II clinical results, particularly in view of the convincing preclinical data and ACI-91’s long-standing safety record in other indications. As a small biotechnology company we have to make judicious use of our scientific and financial resources, and so will now focus on our own home-grown molecules with different modes-of-action from ACI-91. We remain convinced that our strategy to target both the Abeta and Tau proteins will lead to a breakthrough therapy for Alzheimer’s disease,” Andrea Pfeifer, CEO of AC Immune, said in a statement at the time.


Research Article

Passive immunotherapy of tauopathy targeting pSer413-tau: a pilot study in mice

Tomohiro Umeda1,
Hiroshi Eguchi2,
Yuichi Kunori2,
Yoichi Matsumoto2,
Taizo Taniguchi3,
Hiroshi Mori1 and
Takami Tomiyama1,*

Article first published online: 9 JAN 2015

DOI: 10.1002/acn3.171

? 2015 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Cover image for Vol. 1 Issue 12
Annals of Clinical and Translational Neurology


Cellular inclusions of hyperphosphorylated tau are a hallmark of tauopathies, which are neurodegenerative disorders that include Alzheimer's disease (AD). Active and passive immunization against hyperphosphorylated tau has been shown to attenuate phenotypes in model mice. We developed new monoclonal antibodies to hyperphosphorylated tau and sought high therapeutic efficacy for future clinical use.


Using more than 20 antibodies, we investigated which sites on tau are phosphorylated early and highly in the tauopathy mouse models tau609 and tau784. These mice display tau hyperphosphorylation, synapse loss, memory impairment at 6 months, and tangle formation and neuronal loss at 15 months. We generated mouse monoclonal antibodies to selected epitopes and examined their effects on memory and tau pathology in aged tau609 and tau784 mice by the Morris water maze and by histological and biochemical analyses.


Immunohistochemical screening revealed that pSer413 is expressed early and highly. Monoclonal antibodies to pSer413 and to pSer396 (control) were generated. These antibodies specifically recognized pathological tau in AD brains but not normal tau in control brains according to Western blots. Representative anti-pSer413 and anti-pSer396 antibodies were injected intraperitoneally into 10?11- or 14-month-old mice once a week at 0.1 or 1 mg/shot 5 times. The anti-pSer413 antibody significantly improved memory, whereas the anti-pSer396 antibodies showed less effect. The cognitive improvement paralleled a reduction in the levels of tau hyperphosphorylation, tau oligomer accumulation, synapse loss, tangle formation, and neuronal loss.


These results indicate that pSer413 is a promising target in the treatment of tauopathy.


2015年1月10日 14:59

 大阪市立大学は9日、同大医学研究科 脳神経科学の富山貴美(とみやまたかみ)准教授らのグループが、アルツハイマー病の新しい治療薬となる抗体を開発したと発表した。



 この研究の成果は、日本時間の9日(金)午後3時に、米国神経学協会のオープンアクセスジャーナル Annals of Clinical and Translational Neurology にオンライン掲載された。(町田光)

acamprosate and baclofen

Multi-drug approach could be way to treat Alzheimer’s, study suggests

January 8, 2015

A French pharmaceutical company on Thursday said promising results in preliminary research using a combination of existing medications to treat Alzheimer’s could point the way toward someday combating the dementia-causing disease with a drug cocktail.

Pharnext, in interviews with company officials and a study that appears in Nature’s peer-reviewed online journal Scientific Reports, said preclinical studies suggest that combining two approved drugs can have a synergistic impact in alleviating cognitive impairment and protecting the brain’s neurons and blood vessels from Alzheimer’s-related damage.

The drugs, which are not now used to treat Alzheimer’s, include acamprosate calcium, which has been prescribed since 1989 to reduce cravings and alleviate withdrawal symptoms in alcoholics. It was combined with baclofen, a medication that has been used for decades to treat the spastic movements in people suffering from multiple sclerosis.

The findings, which were obtained in laboratory cultures and animal testing, suggest the way forward to treating Alzheimer’s disease could be the same method discovered years ago to treat HIV, a senior company official said.

“Maybe the illusion we had was that we could treat a disease such as Alzheimer’s with a single silver bullet,” Daniel Cohen, an author of the study and a founder of Pharnext, said Wednesday in a telephone interview. “When you fight a complex disease, you have to use a complex treatment.”

Using already known drugs and at lower doses than usual means the cocktail should be safe and could perhaps lead to an approved therapy in a shorter time than it takes to develop new drugs, Cohen said.

Richard Lipton, who heads the Einstein Aging Study at the Albert Einstein College of Medicine and the division of cognitive aging and dementia at Montefiore Medical Center, said after reviewing the company’s study that its data and therapeutic approach sounded promising.

“The notion of combining therapies is extremely appealing,” Lipton said.

Most pharmaceutical research focuses on developing a new drug for a disease. But Lipton also likened the focus on finding a single drug to treat a disease to trying to prevent someone from traveling from Grand Central Station to the United Nations building across town by blocking only one street. Using a multi-targeted approach would be better, but in pharmaceutical research, it’s also more costly and challenging, he said.

Lipton also cautioned that although Pharnext’s approach and data look good, the battle against Alzheimer’s has produced countless studies suggesting progress in the laboratory on animal models that has not translated into successful treatments for humans.

“If everything that worked in animals worked for humans with Alzheimer’s, I’d be a lot happier,” he said.

Instead of joining what has so far been a frustrating search for a single drug to halt or prevent Alzheimer’s disease, Pharnext has focused on what it calls “pleodrugs,” a name taken from the Greek word “pleotropic” that refers to a single gene’s ability to produce multiple effects. The privately held Paris-based company has also mined genetic and pharmacological data to identify possible combinations of approved drugs that might target specific pathologies of Alzheimer’s disease.

In this case, Pharnext targeted biochemical processes that maintain equilibrium in brain cells. Specifically, the company focused on chemical imbalances that occur between “excitatory” responses in neurotransmitters involving glutamate and “inhibitory” responses involving gamma-Aminobutryic acid (GABA) and glycine. Imbalances in those systems appear to lead to neurodegenerative effects seen in Alzheimer’s, the researchers said.

One of the approved drugs, acamprosate calcium, decreases levels of glutamate, which is also key to regulating processes that control natural cell death and survival and is generally safe even at high doses, the researchers said. Baclofen targets GABA receptors and has been used for decades to treat the spastic movements in people suffering from multiple sclerosis. Like acamprosate, it too remains safe even at high doses, the researchers said.

The drug combo was administered to cell cultures and rodents. The researchers found that the combination of the two drugs produced not just an additive effect but a synergistic effect in protecting brain cells and the circulatory network that nourishes them from damage caused by beta amyloid, Cohen said. The researchers also found evidence that systems that had been disturbed by Alzheimer’s disease were normalized.


Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy

Ilya Chumakov, Serguei Nabirotchkin, Nathalie Cholet, Aude Milet, Aur?lie Boucard, Damien Toulorge, Yannick Pereira, Esther Graudens, Sory Traor?, Julie Foucquier, Mickael Guedj, Emmanuel Vial, No?lle Callizot, R?my Steinschneider, Tangui Maurice, Viviane Bertrand, Catherine Scart-Gr?s, Rodolphe Hajj & Daniel Cohen
AffiliationsContributionsCorresponding author
Scientific Reports 5, Article number: 7608 doi:10.1038/srep07608
Received 20 October 2014 Accepted 19 November 2014 Published 08 January 2015

Alzheimer disease (AD) represents a major medical problem where mono-therapeutic interventions demonstrated only a limited efficacy so far. We explored the possibility of developing a combinational therapy that might prevent the degradation of neuronal and endothelial structures in this disease. We argued that the distorted balance between excitatory (glutamate) and inhibitory (GABA/glycine) systems constitutes a therapeutic target for such intervention. We found that a combination of two approved drugs ? acamprosate and baclofen ? synergistically protected neurons and endothelial structures in vitro against amyloid-beta (Aβ) oligomers. The neuroprotective effects of these drugs were mediated by modulation of targets in GABA/glycinergic and glutamatergic pathways. In vivo, the combination alleviated cognitive deficits in the acute Aβ25?35 peptide injection model and in the mouse mutant APP transgenic model. Several patterns altered in AD were also synergistically normalised. Our results open up the possibility for a promising therapeutic approach for AD by combining repurposed drugs.



Dec 24, 2014

Actavis-Adamas Alzheimer's Treatment Wins FDA Nod

Actavis and Adamas Pharmaceuticals said today they won FDA approval for Namzaric, in a rare favorable outcome for treatments indicated for Alzheimer’s disease.

is indicated for the treatment of moderate to severe dementia of the Alzheimer's type in patients stabilized on memantine hydrochloride and donepezil hydrochloride. Formerly known as MDX-8704, Namzaric is a once-daily oral capsule for patients currently taking memantine (10 mg twice daily or 28 mg extended-release once-daily) and donepezil 10 mg. The capsules can be opened to allow the contents to be sprinkled on food to facilitate dosing for patients who may have difficulty swallowing.

Namzaric is a fixed-dose combination (FDC) of memantine hydrochloride extended-release, a NMDA receptor antagonist; and donepezil hydrochloride, an acetylcholinesterase inhibitor (AChEI).

The two are often co-prescribed, as 70% of Namenda XR patients are also on AChEI therapy?yet in clinical trials, combination therapy with Namenda XR and an AChEI demonstrated greater improvement in cognition and global function verses an AChEI alone, according to the companies.

"Along with our partner Adamas, we are proud that this important therapy will provide a convenient and innovative treatment option for Alzheimer's patients and caregivers that reduces the number of capsules they are required to take each day for the treatment of this devastating disease," David Nicholson, Actavis svp, Global Brands R&D, said in a statement.

Gregory T. Went, Ph.D., Adamas’ chairman and CEO, added that Namzaric is the first FDA-approved FDC product to emerge from his company’s platform for modifying the pharmacokinetic profiles of approved drugs.

Memantine extended-release is the active ingredient in the currently marketed Namenda XR?, which like Namzaric is indicated for the treatment of moderate to severe dementia of the Alzheimer's type. Donepezil is the active ingredient in Aricept?, which is indicated for the treatment of mild to severe dementia of the Alzheimer's type.

Developers of Alzheimer’s treatments have long struggled to create successful new drugs. Only a handful of drug successes have ever reached the market, and even they merely slow progression of symptoms six to 12 months. In July, a Cleveland Clinic study found a 99.6% failure rate of clinical trials for Alzheimer's drug candidates between 2002 and 2012.

The FDA based its approval of Namzaric on results of a randomized, double-blind, placebo-controlled trial of 677 outpatients on a stable dose of AChEIs. The study showed statistically significant improvement in cognition and global function for patients treated with Namenda XR 28 mg plus an AChEI, compared to placebo plus an AChEI, Actavis and Adamas said.

While the clinical study was not conducted with Namazaric, the companies showed to the agency’s satisfaction the bioequivalence of Namazaric with co-administered memantine HCl extended-release and donepezil HCl. Approximately 68% of the patients randomized to receive either memantine HCl extended release 28 mg or placebo were taking donepezil as the AchEI at baseline and throughout the study.

The most commonly observed adverse reactions seen with memantine hydrochloride extended-release in patients with moderate to severe Alzheimer's disease, defined as those occurring at a frequency of at least 5% in the memantine hydrochloride extended-release group and at a higher frequency than placebo, were headache, diarrhea, and dizziness.

Actavis and Adamas collaborated on the development of the fixed-dose combination. Actavis will have exclusive U.S. commercialization rights, while Adamas will retain exclusive commercialization rights outside of the U.S.

Actavis expects to launch Namzaric in the U.S. in the second quarter of 2015, the companies said.


Pensioners in 'Viagra style' test to combat dementia


Nicola Harley

12/12/2014 | 02:30

A group of pensioners will be given a Viagra-style drug as part of an international trial to discover whether the pills could combat dementia.

The world's first clinical tests will explore whether the drug could help to prevent a common form of dementia by increasing blood flow to the brain.

Scientists led by Dr Atticus Hainsworth at St George's, University of London, will be recruiting 50 people aged over 65 in Britain who have evidence of blood vessel damage following a stroke or who are experiencing mild memory loss.

The trial will use the Viagra-style drug, Tadalafil, which works by dilating blood vessels, in a bid to help prevent the onset of vascular dementia, the second most common form of dementia, which accounts for 110,000 cases in the UK.

The Alzheimer's Society is jointly funding the initiative with the Alzheimer's Drug Discovery Foundation (ADDF) in New York.

"My colleagues and I are very enthusiastic about this transatlantic initiative, as there are too few drugs in the medicine cupboard for dementia," said Dr Hainsworth.

"We want to know whether a well-known, well-tolerated drug can be used to combat dementia, which has been called the 21st century plague.

"The drug Tadalafil is widely used to increase blood flow in penile tissue. Now we're asking whether it can do the same for another vital organ - the brain."

Vascular dementia is often caused by damage to the small blood vessels of the brain, leading to reduced blood flow to brain tissue. The blood vessel damage is seen in the brains of up to 70pc of older people.

Dr Doug Brown, the director of research and development at the Alzheimer's Society, added:

"Drug development can take decades and, sadly, the path towards developing dementia treatments over the past decade is littered with drugs that have failed in clinical trials.

"As we learn more about the causes of dementia and its links to other conditions, there is hope that treatments we routinely use for other diseases may also work for people with dementia.

"These ... studies could see existing treatments turned into drugs for the most common forms of dementia in a fraction of the time and at a fraction of the cost of developing new drugs from scratch.

"By next year 850,000 people in the UK will have dementia and we owe it to them to do everything we can to develop better treatments," he said. (? Daily Telegraph, London)

Irish Independent

7 new ways

7 new ways to fight Alzheimer’s disease

December 8, 2014

LOS ANGELES ? Alzheimer’s disease affects as many as 5 million Americans. It is the sixth leading cause of death in the United States, and there is no cure.

Yet a very small study out of UCLA is offering a glimmer of hope for those with what is often a hopeless diagnosis. Nine out of the 10 patients involved in the study, who were in various stages of dementia, say their symptoms were reversed after they participated in a rigorous program. The program included things like optimizing Vitamin D levels in the blood, using DHA supplements to bridge broken connections in the brain, optimizing gut health, and strategic fasting to normalize insulin levels.

A few months after starting the extreme program, patients in the study, aged 55 to 75, noticed their cognition had either improved or returned to normal. Only one patient, a 60 year-old female who was in the late-stages of dementia when she began the program, continued to decline.

The results, published this fall in the journal Aging, support the idea that addressing the many contributing factors of Alzheimer’s disease as a group, rather than one at a time, could potentially reverse the disease’s early progression, said study author Dr. Dale Bredesen, director of the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA.

Those factors include 36 potential deficiencies, imbalances and sources of inflammation.

“Each one of these things contributes a small piece of the puzzle,” said Bredesen. “It’s like a roof with 36 holes in it. Some people have a big hole in, say, exercise, and maybe a smaller hole in another area.”

Based on those deficiencies, the following seven suggestions are now being given to anyone interested in launching a preemptive fight against Alzheimer’s:

1. Improve your gastrointestinal health
Gastrointestinal health has been linked with brain health. Incorporating fermented foods, probiotics and prebiotics into your diet could reduce your risk of dementia. Bredesen recommends having your doctor test for a “leaky” GI tract, as that can also cause inflammation.

2. Fast strategically
Allow three hours between dinner and bedtime, and 12 hours between dinner and breakfast. The idea behind this type of fasting, says Bredesen, is that the body begins a process during the break that may help to destroy amyloid-beta, a problematic protein that builds up in the brains of Alzheimer’s patients.

3. Strengthen synapses
Supplements like DHA and citicoline may help strengthen the connections between your brain’s nerve cells, says Bredesen.

4. Reduce heavy metal toxicity
If you consume tuna frequently, check your mercury level, since exposure to heavy metals has been associated with dementia. Patients in Dr. Dale Bredesen’s pilot study, “Reversal of cognitive decline: A novel therapeutic program,” also ditched aluminum-containing deodorants ? but studies are far from conclusive about any harm conferred by anti-perspirants.

5. Cut out inflammatory Foods
Overeating grains, starchy vegetables and sugar can generate harmful inflammation in the body and brain. Patients in Bredesen’s pilot study who responded most quickly cut out simple carbohydrates.

6. Get more sleep
Seven to eight hours a night is ideal for the body to restore itself. Patients in Bredesen’s study who had trouble staying asleep got help from melatonin supplements or tryptophan, a chemical you likely know is found in turkey.

7. Balance your hormones
Scientists know the stress hormone cortisol can damage the hippocampus, a memory center in the brain. Bredesen says hormone replacement therapy may help women who have an imbalance that affects their brain function.

The 10 patients in the pilot study underwent a battery of tests, including having their blood drawn and brains scanned, and had neuropsychological evaluations. Bredesen said that most of the study participants had between 10 and 24 problems that needed correcting.

The effect of focusing on so many targets at once runs counter to what Bredesen said is a prevailing ? and flawed ? notion of identifying single targets to treat a disease caused by many factors.

“Drug companies tend to come up with a really good patch for one hole,” said Bredesen, founder and CEO of the Buck Institute. “It’s not a surprise they don’t work.”

But anecdotal studies like this one are far from generalizable, and larger studies must be done to prove whether the program will work for more than the scant number of people in this study.

These study results should be interpreted with a lot of caution, primarily because of the small study group ? and because the participants had a range of diagnoses, resulting in different interventions, James Hendrix, director of Global Science Initiatives at the Alzheimer’s Association, explained in an email statement.

“Outside of a supervised research setting, no one should adopt these specific ideas to try to improve their, or a loved one’s memory and thinking,” he said. “We simply don’t know what the effect would be.”

While this sort of life overhaul might seem dizzying, some study patients said it actually ended up simplifying their lives ? especially those who called cutting out processed and other inflammatory foods was freeing.

“Before this protocol, the notion was you were going to die with this disease,” said study patient Julie Gee, who started a website to provide support and hope for others in the same genetic situation. “There was a lack of specificity about what to do. Now we have this prevention protocol.”

Hendrix with the Alzheimer’s Association said one sound element of Bredesen’s study, given the complexity of Alzheimer’s disease, is its focus on addressing multiple risk factors. He cites as an example a two-year, 1,200-person clinical trial out of Finland, the results of which were presented earlier this year at the Alzheimer’s Association International Conference.

Among study participants engaging in nutritional changes, physical activity, brain training, social activities and management of risk factors for heart problems, cognitive performance improved.

Bredesen stresses that identifying the culprit for early Alzheimer’s symptoms must be based on a patient’s specific deficits and imbalances.

He said he will continue testing his protocol on early-stage patients ? including members of Gee’s APOE-4 online group ? to find the ideal stage of cognitive decline to introduce this program and how long improvement can be sustained.

“We are now looking at what is causing illness in order to make a big impact on it,” said Bredesen, who added that many elements of his program could be implemented in asymptomatic people as a prevention strategy.

“If you’re not deteriorating, it’s a good idea to do what our moms told us to do: Exercise, get sleep, keep stress down and don’t eat junk food.”

He hopes that normalizing early stage Alzheimer’s patients cognitively might provide a better platform on which to test future drug-based therapies.

“One ‘silver bullet’ drug doesn’t work with 36 holes in the roof,” said Bredesen. “The argument is maybe you need to patch some of those holes before trying another drug.”

Reversal of cognitive decline: A novel therapeutic program

Dale E. Bredesen1, 2
1 Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, University of California, Los Angeles, CA 90095;
2 Buck Institute for Research on Aging, Novato, CA 94945.Key
words:Alzheimer's, dementia, mild cognitive impairment, neurobehavioral disorders, neuroinflammation, neurodegeneration, systems biology
Received:9/15/14; Accepted: 9/26/14; Published: 9/27/14
Correspondence:Dale E. Bredesen, MD; E-mail: dbredesen@mednet.ucla.edu; dbredesen@buckinstitute.org


This report describes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer's disease, and which involves multiple modalities designed to achieve metabolic enhancement for neurodegeneration (MEND). The first 10 patients who have utilized this program include patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI). Nine of the 10 displayed subjective or objective improvement in cognition beginning within 3-6 months, with the one failure being a patient with very late stage AD. Six of the patients had had to discontinue working or were struggling with their jobs at the time of presentation, and all were able to return to work or continue working with improved performance. Improvements have been sustained, and at this time the longest patient follow-up is two and one-half years from initial treatment, with sustained and marked improvement. These results suggest that a larger, more extensive trial of this therapeutic program is warranted. The results also suggest that, at least early in the course, cognitive decline may be driven in large part by metabolic processes. Furthermore, given the failure of monotherapeutics in AD to date, the results raise the possibility that such a therapeutic system may be useful as a platform on which drugs that would fail as monotherapeutics may succeed as key components of a therapeutic system.


Researchers at Mainz University explore new approach for treating Alzheimer's disease

5 hours 39 minutes ago

Psoriasis medication may be effective in the treatment of Alzheimer's disease

It is estimated that about 35 million people worldwide currently suffer from dementia and it is expected that the number will increase to 135 million by the year 2050. The disease is already one of the most common health problems in the elderly, which is why experts predict that the numbers of people affected will increase over time. Researchers at the Department of Psychiatry and Psychotherapy of the University Medical Center of Johannes Gutenberg University Mainz (JGU) have recently gained new insights into how it may in future be possible to treat patients with the currently most common form of dementia, Alzheimer's disease. It seems that a drug that is actually approved for treatment of the dermal disorder psoriasis stimulates the activity of the enzyme ADAM10 in the brain of Alzheimer's patients. There is already good evidence from basic research that this enzyme should be capable of suppressing Alzheimer's disease-related effects such as impaired cerebral function and that it thus might improve learning and memory capacity in patients. The results of the related study have recently been published in the journal Neurology.

According to estimates of the German Alzheimer’s Association (DAlzG), approximately 1.5 million dementia patients currently live in Germany. Some 1 to 1.2 million of these suffer from Alzheimer's. Medicine is currently only able to treat the symptoms of the disease and delay its progress and thus also the need for increased nursing care. No curative therapy has yet been developed. This means that Alzheimer's disease remains one of the biggest challenges to modern medicine and is an important field for research.

There is still no consensus on what triggers the most common form of the disease, late-onset Alzheimer's. However, it is generally accepted that the activity of certain enzymes called secretases plays a role here. These enzymes cleave proteins on cell membranes, releasing the products of this cleavage process into the extracellular space. What happens in Alzheimer's is that there is increased cleavage of the amyloid precursor protein by beta-secretase, leading to the formation of amyloid-beta peptides. These peptides aggregate, damage nerve cells, and are the main component of the so-called Alzheimer’s plaques that accumulate in the brains of patients. The alpha-secretase ADAM10 is a competitor of beta-secretase. It cleaves the amyloid precursor protein in such a way that the synthesis of amyloid beta-peptides is prevented while the growth factor APPs-alpha, which protects nerve cells, is released.

Taking this information as their starting point, Dr. Kristina Endres and Professor Falk Fahrenholz of the Department of Psychiatry and Psychotherapy of the Mainz University Medical Center have decided to take a new approach to the treatment of Alzheimer's. Working in collaboration with Professor Klaus Lieb and Professor Andreas Fellgiebel, both also working at the Department of Psychiatry and Psychotherapy, and with the cooperation of Professor Stefan Teipel and his team at the German Center for Neurodegenerative Diseases (DZNE) in Rostock, the researchers have demonstrated that oral administration of a psoriasis medication in a group of Alzheimer's patients results in elevated levels of APPs-alpha in their spinal fluid. This is interpreted as a stimulation of the activity of the alpha-secretase ADAM10, which in turn would result in the reduced accumulation of Alzheimer's plaques. In animal models of Alzheimer's disease, it has also been shown that ADAM10 enhances learning and memory capacity. The medication was well-tolerated by the patients. In order to further investigate the effect of the test substance on cognitive performance and to establish whether it can be used as a long-term treatment for Alzheimer's patients, larger clinical trials in which the substance is administered for longer periods will need to be undertaken.

Mainz University Medical Center
Dr. Kristina Endres
Department of Psychiatry and Psychotherapy
Langenbeckstr. 1
D 55131 Mainz
Tel +49 6131 17-2133
Fax +49 6131 17-6690

Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin

Kristina Endres, PhD, Falk Fahrenholz, PhD, Johannes Lotz, MD, Christoph Hiemke, PhD, Stefan Teipel, MD, Klaus Lieb, MD, Oliver T?scher, MD* and Andreas Fellgiebel, MD*
Correspondence to Dr. Endres: Kristina.Endres@unimedizin-mainz.de
Published online before print October 24, 2014, doi: 10.1212/WNL.0000000000001017
Neurology November 18, 2014 vol. 83 no. 21 1930-1935

Objective: We investigated induction of α-secretase A disintegrin and metalloprotease 10 (ADAM10) by the synthetic retinoid acitretin (Neotigason; Actavis, M?nchen-Riem, Germany) in patients with mild to moderate Alzheimer disease (AD) via measurement of CSF content of α-secretase?derived amyloid precursor protein (APPs-α).

Methods: Twenty-one patients clinically diagnosed with mild to moderate AD received acitretin (30 mg per day) or placebo in a 4-week double-blind study. Primary endpoint was the difference of CSF APPs-α ratios calculated from the APPs-α levels after treatment and at baseline. We monitored safety and tolerability of the treatment. In addition, we assessed biomarkers such as β-amyloid 42 (Aβ42) under treatment conditions.

Results: The acitretin group showed a significant increase in CSF APPs-α levels compared with the placebo group (difference 0.38, 95% confidence interval 0.03?0.72, p = 0.035) within this rather short treatment period. The synthetic retinoid acitretin was overall safe and well tolerated.

Conclusions: Our pilot study highlights that acitretin is able to enhance the nonamyloidogenic APP processing in human patients. Clinical consequences of this regulation should be investigated in larger and longer trials in patients with AD to evaluate acitretin's potential to serve as a novel therapeutic drug.

Classification of evidence: This study provides Class III evidence that in patients with AD, oral acitretin increases CSF APPs-α levels.


Exciting News: A Game-Changing Alzheimer's Drug Could be on Its Way

December 06, 2014
Source: Flickr user Garry Knight.

According to a 2011 study, only cancer worried Americans more than being diagnosed with Alzheimer's disease, and for 22% of people responding, the risk of getting Alzheimer's disease was their No. 1 health concern. Given those numbers, it's probably not too surprising to learn that shares in Biogen Idec jumped more than 6% on Tuesday after the company reported promising early stage results for BIIB-037, a treatment for Alzheimer's disease.

Tough to treat
Alzheimer's disease accounts for between 60% and 80% of all diagnosed cases of dementia, a general catch-all term for memory loss and the loss of intellectual abilities. Across the United States, an estimated 5 million people are living with Alzheimer's disease, the vast majority of which are over 65. Since there isn't a cure, the symptoms of Alzheimer's become progressively worse over time, and as a result, Alzheimer's is sadly the sixth leading cause of death among Americans, with the average person living just eight years after their symptoms become apparent to others.

Although there aren't any approved treatments specifically designed to treat Alzheimer's disease, there are medicines commonly prescribed to help treat various symptoms of the disease. Because this care is palliative, rather than curative, spending on healthcare is considerably higher for Alzheimer's patients than it is for patients without Alzheimer's disease. Overall, Medicare and Medicaid alone spend more than $140 billion annually treating Alzheimer's patients.

On the way
Since Alzheimer's disease is so tough to treat, it's hard not to be excited about any drug that shows promise in trials, even if those trials happen to be very early stage. And it doesn't get much earlier-stage than Biogen's BIIB-037, a drug that was most recently in phase 1 trials designed to establish safety, not efficacy.

Regardless, the results of BIIB-037 in patients were nothing short of impressive. The drug, which attempts to bind to and destroy amyloid plaques that build up in the brain that are thought to be behind the disease, successfully reduced amyloid levels, with those receiving higher doses or longer treatment duration seeing the biggest benefit. Additionally, BIIB-037 improved cognition versus placebo in the study, too.

The results are solid enough that Biogen, the $77 billion company behind top selling treatments for multiple sclerosis, plans to skip straight to phase 3 trials in a bid to speed along development. Even with advancing the drug into phase 3 trials quickly, however, it's unlikely that there will be results from such a late stage trial to support approaching the FDA for approval until 2018.

Massive global need
The number of Americans living with Alzheimer's disease is expected to grow substantially over the coming years, as 10,000 baby boomers turn 65 every day. That has industry trackers estimating that more than 1 million new cases of Alzheimer's will be diagnosed every year, or roughly one new case every 33 seconds. If that proves to be true, as many as 16 million Americans may be living with the disease by 2050. But it's not just Americans who would benefit from a new treatment. According to the World Health Organization, as many as 66 million people may be living with the disease worldwide by 2030. Since so many people are likely to have the disease and require treatment, there's a lot of reason for investors to be hopeful. However, there's still a tremendous amount of work to be done before we can say that Biogen's BIIB-037 may offer life-changing hope for millions of people.

This coming blockbuster will make even Biogen jealous
The best biotech investors consistently reap gigantic profits by recognizing true potential more quickly and accurately than anyone else. There is a product in development that will change just how we treat a common chronic illness and could potentially revolutionize the entire health industry. Analysts are already licking their chops at the sales potential. To outsmart Wall Street and realize multibagger returns, you'll need The Motley Fool's new free report on the dream team responsible for this game-changing blockbuster. Click here now .

The article Exciting News: A Game-Changing Alzheimer's Drug Could be on Its Way originally appeared on Fool.com.
Todd Campbell is long Biogen. Todd owns E.B. Capital Markets, LLC. E.B. Capital's clients may or may not have positions in the companies mentioned. Todd owns Gundalow Advisors, LLC. Gundalow's clients do not have positions in the companies mentioned. The Motley Fool has no position in any of the stocks mentioned. Try any of our Foolish newsletter services free for 30 days . We Fools don't all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy .
Copyright ? 1995 - 2014 The Motley Fool, LLC. All rights reserved. The Motley Fool has a disclosure policy .

Source: Alzheimer's Association.

Smart Soup, a Traditional Chinese Medicine Formula (rhizoma acori tatarinowii, poria cum radix pini and radix polygalae)

Traditional 'smart soup' shows promise in fighting Alzheimer's

Traditional preparation of three herbs relieves and reduces symptoms of disease in mice and tests on humans are encouraging, study finds

South China Morning Post
07 December, 2014

A traditional Chinese medicine known as smart soup could help in the fight against Alzheimer's disease, scientists on the mainland believe.

The simple treatment helped relieve and even reverse Alzheimer's symptoms in mice that had been genetically modified to acquire the disease, researchers with the Chinese Academy of Sciences' Institute of Biochemistry and Cell Biology in Shanghai found.

The rodents began to show improvements after just six days of being fed the medicine, which consists of three herbs - rhizoma acori tatarinowii, poria cum radix pini and radix polygalae.

The researchers believe that chemicals in the herbs both inhibit the growth of amyloid-beta, an amino acid thought responsible for Alzheimer's, and protect neurons from its effects.

Alzheimer's disease is one of the biggest threats facing the elderly - it has been diagnosed in about 30 million people across the world and that figure is expected to double every 20 years, according to the World Health Organisation. Sufferers face increasing cognitive problems including speaking impairment and memory loss.

Mice treated with the smart soup regained the ability to find hidden platforms and their memory also showed improvement, researchers said. When faced with a new object, they would explore it for significantly longer than they did before they were treated, which researchers said was evidence of improved memory.

The findings were published in the online scientific journal PlosOne this month.

Dr Zhao Jian, associate researcher with the Shanghai institute and co-author of the paper, said the smart soup had also showed promise in early tests on humans. The team had been collaborating with hospitals in Shanghai for two years, monitoring volunteer patients taking the medicine, she said.

The goal of the research project, funded by government agencies including the National Natural Science Foundation of China, the Ministry of Science and Technology and the municipal government of Shanghai, is to develop safe, universally effective, low-cost therapies to fight and prevent Alzheimer's.

"We not only want to cure the disease, but to prevent it before the occurrence of serious symptoms. The medicine not only needs to be effective, but affordable to the mass population," Zhao said.

"The smart soup now looks like one of the most promising candidates, which comes with low cost, proven effectiveness and some likely general benefits to the brain."

Zhao said the research had been "extremely difficult" - it had taken the team more than two years to decipher some of the chemical mechanisms involved.

Alzheimer's is believed to be mainly caused by amyloid-beta, or abeta, a protein fragment molecule found in the brains of sufferers. The growth of abeta molecules can damage neurons and affect the normal functioning of the brain.

The scientists found the smart soup, or more specifically the radix polygalae, could significantly reduce the generation of abeta, with the levels in treated mice more than 18 per cent lower than in those untreated.

The other two herbs - rhizoma acori tatarinowii and poria cum radix pini - appeared to protect the neurons against the damaging effect of abeta. The findings were observed in experiments involving both mice and fruit flies, Zhao said.

Zhao said the development of Alzheimer's was a long process. Some patients acquired the disease nearly two decades before symptoms appeared.

But the experiments showed the effect of smart soup was greatest when administered before the disease fully developed.

"The earlier the treatment, the better the results. That's why we are very interested in the smart soup's potential as a preventive therapy," she said. However, she cautioned that the research was still in its early days: "The formula, though only herbs, was still a medical prescription. Until future research confirms it is safe for healthy people, we do not suggest massive use of the therapy on normal populations."

Zhong Jian, a Chinese medicine doctor in Guangdong, said smart soup had been around for hundreds of years and was commonly prescribed to patients with brain diseases such as Alzheimer's. The first official record of it appeared in Gu Jin Yi Jian, a medical book published in 1576. "Chinese medicine has many formulas with good clinical results but poor recognition by Western medical society, because we don't know how to explain it in the language of modern science," Zhong said.

Hua Zhou, associate professor of pharmacology at the Macau University of Science and Technology, said the paper was scientifically robust.

"The three herbs have been used by traditional medicine doctors for a long time. They can be found in any Chinese herbal pharmacy," he said. "But the animal tests are only the first step. How, and to what extent, the formula can be used against the disease will depend on the final results from comprehensive and rigorous clinical trials."

Armed with cutting-edge technology, mainland scientists have made numerous experiments on the effectiveness of traditional Chinese medicine.

Last month, a team at Nanjing University reported evidence showing honeysuckle could be used to treat the flu virus.

They found a gene of the herb could suppress the replication of the virus in rats' lungs and blood, significantly reducing deaths from viral strains such as H5N1, according to their paper in the scientific journal Cell Research.

Smart Soup, a Traditional Chinese Medicine Formula, Ameliorates Amyloid Pathology and Related Cognitive Deficits

November 11, 2014
DOI: 10.1371/journal.pone.0111215


Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe disease-modifying treatment and symptomatic intervention alternatives against AD. Smart Soup (SS), a Chinese medicine formula composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), is a typical prescription against memory deficits. Here, we assessed the efficacy of SS against AD. Oral administration of SS ameliorated the cognitive impairment of AD transgenic mice, with reduced Aβ levels, retarded Aβ amyloidosis and reduced Aβ-induced gliosis and neuronal loss in the brains of AD mice. Consistently, SS treatment reduced amyloid-related locomotor dysfunctions and premature death of AD transgenic Drosophila. Mechanistic studies showed that RP reduced Aβ generation, whereas AT and PRP exerted neuroprotective effects against Aβ. Taken together, our study indicates that SS could be effective against AD, providing a practical therapeutic strategy against the disease.

This article appeared in the South China Morning Post print edition as 'Smart soup' shows Alzheimer's promise


Alzheimer's & Dementia Weekly
November 23, 2014

Alzheimer's Agitation Drug AVP-923 Clears Next Hurdle

Agitation and aggression are among the most disruptive symptoms of Alzheimer's. They effect 60% of people living at home and 80% of people in care facilities. Learn about AVP-923 as it gets one step closer to availability.

ALISO VIEJO, Calif. -- Avanir Pharmaceuticals, Inc. announced that results from the Phase II study evaluating AVP-923 for the treatment of agitation in patients with Alzheimer's disease were presented at the 2014 American Neurological Association Meeting.

In this study, AVP-923 showed a clinically meaningful and statistically significant improvement in agitation on the primary endpoint and a majority of the secondary endpoints.

Why Is This Important?
"Agitation and aggression in Alzheimer's disease are among the most disruptive of dementia-related neuropsychiatric symptoms and leading causes of institutionalization," said Jeffrey Cummings, MD, director of the Cleveland Clinic Lou Ruvo Center for Brain Health, chair of the study steering committee and a paid member of Avanir Pharmaceuticals Advisory Board, Inc. "These study results are encouraging for Alzheimer's patients suffering from agitation and their caregivers."

How Big is the Breakthrough?
"We are highly encouraged by these data showing a nearly 50 percent reduction in agitation for patients treated with AVP-923. In addition, clear improvements in global measures of agitation, as assessed by both clinicians and patients/caregivers, indicate the improvement was deemed clinically meaningful," said Joao Siffert, MD, chief medical officer for Avanir. "We are committed to working with regulatory agencies in the United States and the EU with the goal to advance the program and make the treatment available as early as possible, upon approval, for patients with Alzheimer's disease who have agitation."
How was the Study Designed?
The 10-week randomized, double-blind, placebo-controlled, multicenter Phase II study evaluated the efficacy, safety and tolerability of AVP-923 for the treatment of agitation in Alzheimer's patients. A total of 220 Alzheimer's patients in the United States were enrolled. Eligible patients were initially randomized in a 3:4 ratio to receive either AVP-923 (dose escalated from DM 20mg/Q 10mg to DM 30mg/Q 10mg) or placebo.

The main efficacy measure was the agitation/aggression domain of the Neuropsychiatric Inventory (NPI). Secondary outcome measures included global assessments of disease severity, other neuropsychiatric symptoms, cognition, activities of daily living, quality of life and caregiver strain. Standard safety assessments were also conducted.
Who is Effected by Agitation in Alzheimer's Disease?
An estimated 6 million Americans have Alzheimer's, a number that has doubled since 1980 and is expected to be as high as 16 million by 2050. Alzheimer's disease is generally characterized by cognitive decline, impaired performance of daily activities, and behavioral disturbances. Behavioral and psychiatric symptoms develop in as many as 60% of community-dwelling dementia patients and in more than 80 percent of patients with dementia living in nursing homes. Dementia-related behavioral symptoms, including agitation, can be extremely distressing to the individual, the family and caregivers. These behavioral disturbances have been associated with more rapid cognitive decline, institutionalization and increased caregiver burden.
Details About the Agitation Drug AVP-923
AVP-923 is a combination of two well-characterized compounds, the active CNS ingredient dextromethorphan hydrobromide (an uncompetitive NMDA receptor antagonist, sigma-1 receptor agonist and inhibitor of the serotonin transporter [SERT] and norepinephrine transporter [NET]) plus low-dose quinidine sulfate (a CYP2D6 enzyme inhibitor), which serves to increase the bioavailability of dextromethorphan. AVP-923 is known to have certain cardiovascular risks and drug-drug interactions. Patients with history of certain cardiovascular risks and on certain drugs were excluded from the study. AVP-923 is an investigational drug not approved by the FDA for the treatment of agitation in Alzheimer's disease.
Study Details
Key highlights from the poster were:
?AVP-923 showed a statistically significant benefit on the agitation/aggression domain of the Neuropsychiatric Inventory (NPI) (primary endpoint; p=0.00008)
?The NPI agitation/aggression score was reduced by 3.3 points from baseline in AVP-923 treated patients at week five (stage 1; p=0.0002 v. placebo) and was reduced by 2.0 points in stage 2 (p=0.021)
?The change in the NPI agitation/aggression score corresponds to a mean (SD) reduction from baseline of 47 percent (43.1 percent) for AVP-923 vs. 22 percent (50.8 percent) for placebo in Stage 1, and 26 percent (67.5 percent) for AVP-923 vs. 6.7 percent (77.9 percent) for placebo in Stage 2.
?Treatment benefit with AVP-923 was evident at week one and was sustained for the duration of the 10-week study
?AVP-923 also demonstrated significant improvements versus placebo on the following outcomes: NPI total score (p=0.014), NPI4A (p=0.001), NPI4D (p<0.001), clinical global impression of change-agitation (p=0.0003), patient global impression of change (p=0.001) and measures of caregiver burden (p?0.05)
?AVP-923 was generally safe and well-tolerated and associated with a low rate of discontinuation from the study (11.8 percent)
?Treatment with AVP-923 was not associated with cognitive decline or somnolence


About Avanir Pharmaceuticals, Inc.

Avanir Pharmaceuticals, Inc. is a biopharmaceutical company focused on bringing innovative medicines to patients with central nervous system disorders of high unmet medical need. As part of our commitment, we have extensively invested in our pipeline and are dedicated to advancing medicines that can substantially improve the lives of patients and their loved ones. For more information about Avanir, please visitwww.avanir.com.

Email This


Share to Twitter

Share to Facebook


New therapies give hope to Alzheimer’s patients

By U-T San Diego
NOV. 11, 2014

Every 67 seconds, someone in the Unites States develops Alzheimer’s disease. Alzheimer’s is a disease that attacks the brain, and is the most common form of dementia, a decline in mental ability which interferes with daily life. Despite the sobering realities of Alzheimer’s, many people with the disease are finding hope in new therapies being developed.

One promising drug being studied is MK-7622. A current clinical trial at Sharp Mesa Vista Hospital is investigating the drug as a therapy for people with mild-to-moderate Alzheimer’s disease, in addition to the drug donepezil, also known as Aricept.

“This study is designed for people who have a clear history, or cognitive and functional decline for at least a year, who have already been taking donepezil,” said Dr. Michael Plopper, chief medical officer for Sharp Behavioral Health Services. “We want to establish the efficacy and safety of this medication combination, and hopefully demonstrate that it improves cognitive function for Alzheimer’s patients.”

Therapies aimed at early Alzheimer’s

The early signs of Alzheimer’s are often subtle. The person may feel they are forgetting familiar words or the location of everyday objects. As the disease progresses, family, friends and co-workers may begin to notice problems, and more severe cognitive issues become apparent.

Some new drug therapies such as Solanezumab aim to slow this progression. In another study at Sharp Mesa Vista, participants are randomly assigned to one of two groups, and take either Solanezumab or a placebo for 80 weeks. The goal is to compare the results of these two groups to determine whether Solanezumab can help slow the disease.

“With this research on early Alzheimer’s, we’re hoping to make a long-term impact for patients,” said Dr. Plopper. “It’s not a cure, but it may mean a better quality of life down the road.”

For more information on clinical trials at Sharp Mesa Vista, call 858-836-8350 or attend the Alzheimer’s Association Caregiver Conference on Nov. 1 from 1:00 -3 pm at the Sharp HealthCare System Auditorium. For information on the conference or to sign up, visit alz.org/sandiego or call (800) 272-3900.

This story was provided by the San Diego Alzheimer’s Association.

liraglutide and lixisenatide

November 9, 2014
Alzheimer's & Dementia Weekly

Lixisenatide and Liraglutide: Diabetes Drugs are Potential Alzheimer's Treatments

Impaired insulin has been long linked to diabetes as well as Alzheimer's. Learn how two approved diabetes drugs are showing exciting results in the treatment of Alzheimer's. Watch a seminar detailing the latest research in Alzheimer's & insulin.

A new study, published in Neuropharmacology and conducted by academics at Lancaster University, could bring substantial improvements in the treatment of Alzheimer's disease by using drugs currently on the market to treat type 2 diabetes.

Alzheimer's disease is the most common cause of dementia; it is predicted there will be more than 520,000 people in the UK with the disease in 2015.

This study shows the newer drug lixisenatide and the older drug liraglutide (which are both currently used in the treatment of type 2 diabetes) have neuroprotective effects (i.e. protect neurons from injury or degeneration) in a mouse model of Alzheimer's disease.

These drugs are more effective than anything currently available for the treatment of this neurodegenerative disease. Furthermore, the drug makers were unaware of the two drugs' incredibly valuable side effects; their neuroprotective qualities.

Professor Christian H?lscher from the Faculty of Health and Medicine is leading the study.

He said: "These are very exciting results. There are no drugs on the market for Alzheimer's disease that actually treat the disease, all we currently have are two types of drugs that mask the symptoms for a while. Lixisenatide and liraglutide offer a real improvement by treating the basis of the disease and, therefore, preventing degeneration."

Professor H?lscher has, with other scientists from Lancaster University, founded the charity Alzheimer's and Parkinson's Trust NorthWest in order fund this research. He adds:

"We urgently need funding to conduct the necessary clinical trials, some of which are currently ongoing. The results of which could bring about a transformation in the treatment of Alzheimer's disease in the very near future, as the drugs we are using in our studies have already been licenced for human use and are on the market."

Background to Alzheimer's disease and how the drugs work:
Impaired insulin has been linked to cerebral degenerative processes in type 2 diabetes and Alzheimer's disease. Insulin desensitisation has also been observed in the Alzheimer's disease brain. The desensitisation could play a role in the development of neurodegenerative disorders as insulin is a growth factor with neuroprotective properties.

Growth factor signalling has been shown to be impaired in the brains of Alzheimer's disease patients. The deletion of the GLP-1 (a growth factor) receptor impairs learning and signal transmission in the brain, therefore treatment with GLP-1 receptor agonists (such as lixisenatide and liraglutide) has the potential to facilitate the repair in the brain and could have beneficial effects in patients with Alzheimer's disease.

The study used APP/PS1 mice, which are transgenic mice that express human genes that cause Alzheimer's. Those genes have been found in people who have a form of Alzheimer's that can be inherited. Aged transgenic mice in the advanced stages of neurodegeneration were treated.

As part of the study, researchers observed mice as they carried out a number of memory tasks and recorded neuronal communication in the hippocampus (one of the first areas of the brain to suffer damage in Alzheimer's disease).

This study demonstrated an increase in synaptic numbers in APP/PS1 mice following chronic treatment with GLP-1 receptor agonists (such as lixisenatide or liraglutide). Synapses are of vital importance for communication between neurons and in Alzheimer's disease there is considerable synapse loss. Following chronic drug treatment, it was found that synapse numbers were not only normalised but synapses are kept functioning, ensuring that neurons were still able to communicate information. Furthermore, memory formation is normalised and protected from the detrimental effects of amyloid protein plaques in the brain, which is one of the hallmarks of Alzheimer's disease.

Interestingly, the research also demonstrated that lower doses were just as effective as the higher doses of both drugs administered, suggesting that doses to treat type 2 diabetes may be unnecessarily high to treat neurodegenerative diseases.

Clinical trials using liraglutide are currently taking place; the results of which are expected to be available for review next year. As lixisenatide has proved to be the more successful drug in this study, researchers are currently trying to raise the funds to run clinical trials investigating its effectiveness in the treatment of Alzheimer's disease.

Lancaster University

Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease

Original Research Article
Neuropharmacology, Volume 86, November 2014, Pages 241-258
Paula L. McClean, Christian H?lscher


Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). In the brains of AD patients, insulin signalling is desensitised. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and analogues such as liraglutide are on the market as treatments for type 2 diabetes. We have previously shown that liraglutide showed neuroprotective effects in the APPswe/PS1ΔE9 mouse model of AD. Here, we test the GLP-1 receptor agonist lixisenatide in the same mouse model and compare the effects to liraglutide. After ten weeks of daily i.p. injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline of APP/PS1 mice at an age when amyloid plaques had already formed, performance in an object recognition task was improved in APP/PS1 mice by both drugs at all doses tested. When analysing synaptic plasticity in the hippocampus, LTP was strongly increased in APP/PS1 mice by either drug. Lixisenatide (1 nmol/kg) was most effective. The reduction of synapse numbers seen in APP/PS1 mice was prevented by the drugs. The amyloid plaque load and dense-core Congo red positive plaque load in the cortex was reduced by both drugs at all doses. The chronic inflammation response (microglial activation) was also reduced by all treatments.

The results demonstrate that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the parameters measured

TfR bispecific antibody platform

Weekly injection could prevent Alzheimer’s disease, say scientists

Scientists have discovered how to get drugs into the brain to help prevent the build up of the sticky plaques which are thought to cause Alzheimer's disease

By Sarah Knapton, Science Editor
05 Nov 2014

A weekly injection which could prevent Alzheimer’s disease may be possible after scientists discovered how to get drugs into brain.
Treating neurological disorders like dementia has always proved difficult because the brain has a network of blood vessels ? known as the blood-brain barrier - which stop all but vital nutrients getting inside.
However for the first time, scientists have discovered how to attach antibodies to a special protein called ‘transferrin’, which exists in the body to help transport materials through the blood-brain barrier.
Once inside the brain, the antibodies block the build-up of toxic amyloid beta plaques which stop the neurons from firing and cause Alzheimer’s disease.
Tests on monkeys showed that a single injection of the antibody could prevent the build-up of the plaque without any side effects for up to a week, while an intravenous transfusion could last a month. The team now plans to move on to human trials.

“The blood-brain barrier (BBB) remains a formidable obstacle for developing therapeutics to treat neurological disease, particularly for large molecules such as antibodies,” said lead author Joy Yu of biotechnology company Genetech Inc, in San Francisco.
“If this technique proves successful in humans, patients could receive weekly subcutaneous or monthly intravenous injections to keep neurological diseases at bay.”
Alzheimer’s is the most common form of dementia, affecting half a million people in the UK, but current drugs aren’t able to affect the course of the disease
The breakthrough was welcomed by scientists and charities.
Dr Doug Brown, Director of Research at Alzheimer’s Society, said: “The blood-brain barrier acts as a protective layer by stopping some things from passing into the brain from the blood.
“However, this protection can cause problems for scientists developing drugs for the treatment of neurological diseases, including dementia.
“These researchers have investigated attaching a potential treatment to a molecule that can pass through the barrier, therefore using this as a sort of passport into the brain. Showing that this works in primates is one step closer to using this technology for treatments in people.”
Dr Eric Karran, Director of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, added: “A key challenge in Alzheimer’s drug development is ensuring that antibody treatments can be delivered to the brain in order to have an effect.
“This US study in primates highlights a method for increasing the penetration of antibody into the brain to reduce amyloid-beta production.
“Further research should investigate whether this method would be safe and effective for people.”
The research was published in the journal Science Translational Medicine.

Transl Med 5 November 2014:
Vol. 6, Issue 261, p. 261ra154
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3009835

Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates

Y. Joy Yu1,*, Jasvinder K. Atwal1,*, Yin Zhang2, Raymond K. Tong3, Kristin R. Wildsmith4, Christine Tan2, Nga Bien-Ly1, Maria Hersom1, Janice A. Maloney1, William J. Meilandt1, Daniela Bumbaca4, Kapil Gadkar4, Kwame Hoyte5, Wilman Luk5, Yanmei Lu5, James A. Ernst3, Kimberly Scearce-Levie1, Jessica A. Couch4, Mark S. Dennis2 and Ryan J. Watts1,†


Using therapeutic antibodies that need to cross the blood-brain barrier (BBB) to treat neurological disease is a difficult challenge. We have shown that bispecific antibodies with optimized binding to the transferrin receptor (TfR) that target β-secretase (BACE1) can cross the BBB and reduce brain amyloid-β (Aβ) in mice. Can TfR enhance antibody uptake in the primate brain? We describe two humanized TfR/BACE1 bispecific antibody variants. Using a human TfR knock-in mouse, we observed that anti-TfR/BACE1 antibodies could cross the BBB and reduce brain Aβ in a TfR affinity?dependent fashion. Intravenous dosing of monkeys with anti-TfR/BACE1 antibodies also reduced Aβ both in cerebral spinal fluid and in brain tissue, and the degree of reduction correlated with the brain concentration of anti-TfR/BACE1 antibody. These results demonstrate that the TfR bispecific antibody platform can robustly and safely deliver therapeutic antibody across the BBB in the primate brain.

Copyright ? 2014, American Association for the Advancement of Science


Acupuncture Stabilizes Dementia Patients
14 October 2014.

Research finds acupuncture effective for improving memory, cognition and walking for patients with dementia. First up, we take a look at acupuncture points that improve walking and movement for patients with vascular dementia. Neurologic exams often reveal gait disorders. The inability to walk properly may severely inhibit the lifestyle of patients with dementia while increasing the risk of falling. Researchers have identified several key acupuncture points that significantly improve the gait of dementia patients. In addition, acupuncture produced significantly superior patient outcomes over a control group receiving conventional pharmaceutical medications. Back electro treatment is depicted with copper wound needle.

Gait disorders associated with dementia often involve circular rotations of the hip, foot drag, reduced knee movement, stooped posture, reduced arm swing, shuffling, small steps, a broad stance, unsteadiness, or difficulty initiating movement. Researchers have discovered that the application of Huatuojiaji (EX-B2) acupuncture points from L2 to L5 combined with scalp acupuncture at Baihui (DU20) and Sishencong produced a total effective rate of 90.5%. Use of the drug Almitrine (Duxil) had a total effectiveness rate of 61.9%. As a result, the researchers conclude, “The efficacy of treating vascular dementia gait disorder with electro-acupuncture (EA) on EX-B2 along lumbar vertebra combined with scalp acupuncture was superior to orally administered Duxil.”

Acupuncture Protocol
Huatuojiaji points were needled bilaterally from L2 to L5 along with DU20 and Sishencong. Electroacupuncture was connected bilaterally to the Huatuojiaji points. Treatments were administered once per day for 30 days. A significant achievement, the research data clearly shows that this protocol significantly and positively impacts the daily lives of patients with dementia.

Memory and Thinking
Acupuncture helps to reduce dysfunction of reasoning, memory and general cognition according to research by G. Shi, et al. Vascular dementia is caused by damage to the brain from impaired blood flow. Stroke or conditions leading to damaged blood vessels or poor circulation that cause deprivation of oxygen and nutrients to the brain plus hypertension, high cholesterol, smoking and heart disease are all risk factors. Traditional Chinese Medicine (TCM) differential diagnostics revealed that patients improving the most suffered from excess syndromes, particularly Liver Yang hyperactivity and phlegm obstruction of the orifices. Patients with deficiency syndromes, including Kidney Jing-essence deficiency, demonstrated the least improvements.

Luo, et al., discovered that acupuncture successfully increases glucose metabolism in the brain areas related to cognition and memory. They also found that acupuncture improves cerebral blood flow. Objective measurements reveal that acupuncture protects against oxidative damage by improving antioxidant enzyme (SOD, GSH) activity in the brain. Acupuncture also successfully downregulates inducible nitric oxide synthase (iNOS). Acupuncture was also shown to increase the expression of GLUT1 (glucose transporter 1). GLUT1 is involved in cellular respiration, regulation of glucose levels and vitamin C uptake. Upregulation of GLUT1 promotes intercellular transport and benefits brain glucose metabolism. The laboratory results indicate that upregulation of GLUT1 by acupuncture alleviates ischemia and anoxia related cognitive impairment. As a result, the researchers conclude that acupuncture is effective in alleviating vascular dementia.

Luo, et al., investigated Professor Jingyuan Han’s approach to care for patients with vascular dementia. Han’s treatment protocols use three primary Traditional Chinese Medicine (TCM) protocols: tonify qi, regulate blood, essence nurturing. The approach is based in the three jiao vaporization protocol. This technique focuses on unblocking obstructions as the primary mode of care followed by tonification as the secondary mode of care.

Prof. Han comments that the pathogenesis of vascular dementia within the TCM (Traditional Chinese Medicine) system involves three main components: kidney deficiency, phlegm stasis and turbid toxins. He adds that many internal organs, both zang and fu, are involved. As a result, his approach focuses on stimulating invigorating and restorative functions throughout the body. Prof. Han uses a variety of acupuncture points based on differential diagnostics including Danzhong (CV17), Zhongwan (CV12), Qihai (CV6), Zusanli (ST36), Xuehai (SP10) and Waiguan (SJ5).

Other research concludes that acupuncture is successful in reducing vascular dementia disorders and notes that “that acupuncture is beneficial at least in part by preventing oxidative damage.” The researchers observed that acupuncture measurably reduced levels of 8-OHdG, a marker of oxidative damage. Another study of 184 vascular dementia patients discovered that scalp acupuncture caused significant improvements in cognition, activities of daily living, mental state and social behavior. Auricular Points

Traditional Chinese Medicine encompasses a variety of treatment modalities including acupuncture and herbal medicine. Research demonstrates that herbal medicine also benefits patients with dementia. A study published in The Journal of Brain Disease reports that the herbal formula Yi Gan San may be helpful in treating schizophrenia and neuropsychological disorders because it restores brain glutathione levels. Another study published in Progress in Neuro-Psychopharmacology and Biological Psychiatry concludes that Yi Gan San is a serotonin modulator and is a “safe and useful” formula for treating behavioural and psychological symptoms of dementia and borderline personality disorder.

Gang, F. E. N. G. "Observation on efficacy of treating vascular dementia gait disorder with electro-acupuncture (EA) on Ji?j (EX-B2) along lumbar vertebra combined with scalp acupuncture." World Journal of Acupuncture-Moxibustion 24, no. 2 (2014): 1-5.

Luo, Benhua. “Development in Study on ‘Qi Tonifying, Blood Regulating, and Essence Nurturing’ Acupuncture Technique Treating Vascular Dementia.” Chinese Journal of Gerontology. 14.139 (2014): 4091-4092.

Shi, G. X., C. Z. Liu, Wei Guan, Z. K. Wang, Lei Wang, Chuan Xiao, Z. G. Li, Q. Q. Li, and L. P. Wang. "Effects of acupuncture on Chinese medicine syndromes of vascular dementia." Chinese journal of integrative medicine (2013).

Shi GX, Liu CZ, Li QQ, Zhu H, Wang LP. Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University, Beijing, China. Journal of Traditional Chinese Medicine. 2012, 32(2):199-202.

Huang, Lin-na, An, Jun-ming, Su, Tong-sheng; Wang, Pu; Dong, Lan; Zhang, Ruo-ping; Ren, Yu-juan; Ren, Yuan-yuan. Therapeutic efficacy observation on scalp acupuncture for vascular dementia. Journal of Acupuncture and Tuina Science. 2012-02-01.

Complex therapy

Complex therapy reverses Alzheimer's memory loss
Treatment relies on a combination of therapies, not a single drug


By Mark Huffman
Mark Huffman has been a consumer news reporter for ConsumerAffairs since 2004. He covers real estate, gas prices and the economy and has reported extensively on negative-option sales. He was previously an Associated Press reporter and editor in Washington, D.C., a correspondent for Westwoood One Radio Networks and Marketwatch.

A small study of early Alzheimer's disease patients has produced stunning results. Researchers say a novel and complex treatment has restored memory function in 9 of the 10 participants.

The study, conducted jointly by the UCLA Mary S. Easton Center for Alzheimer’s Disease Research and the Buck Institute for Research on Aging, is the first to suggest that memory loss in patients may be reversed, and that improvement can be lasting.

The treatment consists of a 36-point therapeutic program involving comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific drugs and vitamins, and multiple additional steps that affect brain chemistry.

While this is very hopeful news, it comes with a rather large caveat. Dale Bredesen, author of the study, notes the very small size of the sample makes the results anecdotal. Still, it's impressive.

To prove whether or not researchers have finally unlocked the secret to turning back Alzheimer's, Bredesen says the treatment should be subjected to a large clinical trial. In the case of Alzheimer’s disease, Bredesen says there is not one drug that has been developed that stops or even slows the disease’s progression, and drugs have only had modest effects on symptoms.

“In the past decade alone, hundreds of clinical trials have been conducted for Alzheimer’s at an aggregate cost of over $1 billion, without success,” he said.

Combination of treatments
While a combination of therapies has been used to control major chronic illnesses like cancer, the combination approach has never been applied to Alzheimer's. Bredesen says a broader-based therapeutics approach, rather than a single drug that aims at a single target, may be feasible and potentially more effective for the treatment of the disease that eventually robs victims of their memory.

Though too small to be considered scientific proof, the UCLA-Buck Institute study achieved remarkable results. One patient had two years of progressive memory loss and was considering quitting her job, which involved analyzing data and writing reports. She got disoriented driving, and mixed up the names of her pets.

A second patient two kept forgetting once-familiar faces at work, forgot his gym locker combination, and had to have his assistants constantly remind him of his work schedule.

A third patient's memory was so bad she used an iPad to record everything, then forgot her password. Her children noticed she commonly lost her train of thought in mid-sentence, and often asked them if they had carried out the tasks that she mistakenly thought she had asked them to do.

Improved memory function
Following the complex therapy, all 3 patients displayed improvement in their memories beginning within 3 to 6 months after the program’s start. Six patients who had to stop working or were struggling with their jobs at the time they joined the study were able to return to work or continue working with improved performance.

The only patient in the study who did not show improvement turned out to be in late stage Alzheimer's disease, suggesting the therapy is most effective for those whose cognitive impairment is diagnosed early.

Reversal of cognitive decline: A novel therapeutic program
Dale E. Bredesen1, 2
1 Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, University of California, Los Angeles, CA 90095;
2 Buck Institute for Research on Aging, Novato, CA 94945.
Key words:
Alzheimer's, dementia, mild cognitive impairment, neurobehavioral disorders, neuroinflammation, neurodegeneration, systems biology
9/15/14; Accepted: 9/26/14; Published: 9/27/14
Dale E. Bredesen, MD; E-mail: dbredesen@mednet.ucla.edu; dbredesen@buckinstitute.org


This report describes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer's disease, and which involves multiple modalities designed to achieve metabolic enhancement for neurodegeneration (MEND). The first 10 patients who have utilized this program include patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI). Nine of the 10 displayed subjective or objective improvement in cognition beginning within 3-6 months, with the one failure being a patient with very late stage AD. Six of the patients had had to discontinue working or were struggling with their jobs at the time of presentation, and all were able to return to work or continue working with improved performance. Improvements have been sustained, and at this time the longest patient follow-up is two and one-half years from initial treatment, with sustained and marked improvement. These results suggest that a larger, more extensive trial of this therapeutic program is warranted. The results also suggest that, at least early in the course, cognitive decline may be driven in large part by metabolic processes. Furthermore, given the failure of monotherapeutics in AD to date, the results raise the possibility that such a therapeutic system may be useful as a platform on which drugs that would fail as monotherapeutics may succeed as key components of a therapeutic system.

NGP 555

FDA Approves Trials of Local Biotech’s Alzheimer’s Drug

October 1, 2014
Times of San Diego

San Diego-based NeuroGenetic Pharmaceuticals Inc. said Wednesday the Food and Drug Administration has approved clinical trials of its NGP 555 compound to treat and prevent Alzheimer’s disease.

The approval follows successful pre-clinical toxicology and safety studies of the drug under federal grants totaling $3.4 million.

“NGP 555 prevented the formation of and the deposition of amyloid plaques, thereby precluding neuronal cell death and the dementia associated with (Alzheimer’s disease),” saud Dr. William T. Comer, CEO of the privately held biopharmaceutical company.

Comer said NeuroGenetic anticipates it will begin Phase I human clinical trials by the end of 2014.

The company was founded in 2009 to develop innovative drug therapies for Alzheimer’s disease, which affects 5.5 million Americans.

PET scan of the brain of a person with Alzheimer’s disease showing a loss of function in the temporal lobe. Photo by National Institute on Aging via Wikimedia Commons


Promising drug candidate for Alzheimer's found in turmeric compound

Last updated: Today at 8am PST 59 Like353

The bright yellow spice sitting in your kitchen - that you sometimes use to make curry powder - has a compound that could be used as a drug candidate for treating neurological disorders. Researchers from the Institute of Neuroscience and Medicine in J?lich, Germany, say a turmeric compound promotes stem cell proliferation and differentiation in the brain, giving hope for patients who suffer from stroke and Alzheimer's disease.

Turmeric comes from the ginger family and, in spice form, is typically used to make curry powder.
They publish their results in the journal Stem Cell Research & Therapy.

The bioactive compound found in the spice is called aromatic (ar-) turmerone, and previous studies have shown it can block activation of microglial cells. When they are activated, these cells cause neuroinflammation, which is linked to certain neurological disorders.

Until this latest study, however, the impact of ar-turmerone's impact on the brain's self-repair ability was unknown, the researchers say.

They explain that they focused on endogenous neural stem cells (NSC) - stem cells found in adult brains. These NSCs differentiate into neurons, playing an important role in self-repair of brain function in diseases such as Alzheimer's.

To further investigate, the team tested ar-turmerone's effects on NSC in live adult rats by injecting them with ar-turmerone.

After using PET imaging and a tracer to find proliferating cells, the team observed that the subventricular zone (SVZ) was wider and the hippocampus expanded in the brains of the rats injected with the compound, compared with those that did not receive the compound.

The researchers explain that the SVZ and hippocampus are the two sites in adult mammalian brains were the growth of neurons occurs.

'One step closer to achieving major goal in regenerative medicine'
To further test the effects of ar-turmerone, the researchers also cultured and grew rat fetal NSCs in six different concentrations of the compound for 72 hours.

They found that, in certain concentrations, the compound increased NSC proliferation by up to 80% without impacting cell death whatsoever. In addition, the cell differentiation process sped up in the cells treated with the compound, compared with the untreated control cells.

Commenting on their findings, lead author Adele Rueger says:

"While several substances have been described to promote stem cell proliferation in the brain, fewer drugs additionally promote the differentiation of stem cells into neurons, which constitutes a major goal in regenerative medicine. Our findings on aromatic turmerone take us one step closer to achieving this goal."

Turmeric contains another compound called curcumin, which is known for its anti-inflammatory and neuroprotective features.

Medical News Today recently reported on a breakthrough in drug-developing techniques. Researchers from the University of Leicester in the UK said they developed a new process for creating a specific synthetic amino acid, which could provide innovative new treatments for cancer and Alzheimer's disease.

Meanwhile, researchers from the Mayo Clinic said they have identified a defect in a brain signaling pathway that could contribute to the development of Alzheimer's, potentially leading to prevention strategies or treatments.

Written by Marie Ellis

Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo

Joerg Hucklenbroich12, Rebecca Klein23, Bernd Neumaier3, Rudolf Graf3, Gereon Rudolf Fink12, Michael Schroeter123 and Maria Adele Rueger12

Stem Cell Research & Therapy 2014, 5:100

Aromatic (ar-) turmerone is a major bioactive compound of the herb Curcuma longa. It has been suggested that ar-turmerone inhibits microglia activation, a property that may be useful in treating neurodegenerative disease. Furthermore, the effects of ar-turmerone on neural stem cells (NSCs) remain to be investigated.

We exposed primary fetal rat NSCs to various concentrations of ar-turmerone. Thereafter, cell proliferation and differentiation potential were assessed. In vivo, na?ve rats were treated with a single intracerebroventricular (i.c.v.) injection of ar-turmerone. Proliferative activity of endogenous NSCs was assessed in vivo, by using noninvasive positron emission tomography (PET) imaging and the tracer [18F]-fluoro-L-thymidine ([18F]FLT), as well as ex vivo.

In vitro, ar-turmerone increased dose-dependently the number of cultured NSCs, because of an increase in NSC proliferation (P?<?0.01). Proliferation data were supported by qPCR-data for Ki-67 mRNA. In vitro as well as in vivo, ar-turmerone promoted neuronal differentiation of NSCs. In vivo, after i.c.v. injection of ar-turmerone, proliferating NSCs were mobilized from the subventricular zone (SVZ) and the hippocampus of adult rats, as demonstrated by both [18F]FLT-PET and histology (P?<?0.05).

Both in vitro and in vivo data suggest that ar-turmerone induces NSC proliferation. Ar-turmerone thus constitutes a promising candidate to support regeneration in neurologic disease.

Transcranial Magnetic Stimulation

Magnetic pulse to head could improve memory of dementia sufferers

Scientists at Northwestern University in the US, found that stimulating parts of the brain with magnetic pulses to stimulate neurons improved memory by more than 20 per cent

By Sarah Knapton, Science Correspondent6:00PM BST 28 Aug 2014

A simple magnetic pulse to the head could improve memory for Alzheimer’s disease sufferers or stroke patients, a study has found.
Scientists at Northwestern University in the US, discovered that stimulating parts of the brain improved memory by more than 20 per cent.
And the effects appear to last for several days after the treatment.
"We show for the first time that you can specifically change memory functions of the brain in adults without surgery or drugs, “said senior author Dr Joel Voss, assistant professor of medical social sciences at Northwestern University Feinberg School of Medicine
"This non-invasive stimulation improves the ability to learn new things. It has tremendous potential for treating memory disorders."

Dementia charities said the breakthrough showed potential for treating Alzheimer’s disease.
Researchers used a technique called Transcranial Magnetic Stimulation which uses a magnetic pulse to trigger electrical charges in the brain cells, forcing them to become more active.
Dr Voss said it was like giving the brain regions a more talented conductor so they play in closer synchrony.
They tested the memory of 16 volunteers between 21 and 40 who were all in good health. They then used a MRI machine to work out exactly which part of the brain was storing memories.
Memories are stored in the hippocampus, an area in the middle of the brain roughly at eye level. But the exact area can differ by up to a centimetre between individuals. Although the hippocampus is too deep for magnetic fields to penetrate, the team found an area directly above it which has direct contact.
Once they knew the exact area to target, the volunteers received brain stimulation 20 minutes a day for five consecutive days.
The researchers discovered that the volunteers performed around 20 per cent better on memory tests compared with an untreated control group, who showed no improvement during the period.
"They remembered more face-word pairings after the stimulation than before, which means their learning ability improved," Dr Voss said.
"That didn't happen for the placebo condition or in another control experiment with additional subjects.
. "The more certain brain regions worked together because of the stimulation, the more people were able to learn face-word pairings, " Voss said.
They are hopeful the technique could be used to help the early symptoms of Alzheimer’s disease; depression, schizophrenia and other mental health problems.
The current study was with people who had normal memory, who researchers did not expect to see a larger improvement because their brains are already working effectively.
"But for a person with brain damage or a memory disorder, those networks are disrupted so even a small change could translate into gains in their function," Voss added.
In an upcoming trial, he will study the electrical stimulation's effect on people with early-stage memory loss.
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, said:
“The results of this study shows some potential in the use of a non-invasive technique which may help to improve memory. This was a very small trial with only 16 people and did not look specifically at people with Alzheimer’s disease or other forms of dementia. Much more large-scale, long-term research is needed to determine whether this technique would be beneficial to people with dementia.
“There is currently no effective treatment or cure for Alzheimer’s or dementia. We urgently need an effective treatment that could stop the
The study was published in the journal Science.
In a separate study, the University of Huddersfield has discovered that a key ingredient found in pomegranates could help slow the onset of Alzheimer’s disease.
Dr Olumayokun Olajide found that punicalagin can prevent inflammation in brain cells.
This inflammation leads to the destruction of more and more brain cells, making the condition of Alzheimer's sufferers progressively worse.
The team is hopeful that a drug derived from punicalagin that could treat neuro-inflammation and slow the disease.
There are currently 800,000 people with dementia in the UK.

Targeted enhancement of cortical-hippocampal brain networks and associative memory

Science 29 August 2014:
Vol. 345 no. 6200 pp. 1054-1057
DOI: 10.1126/science.1252900

Jane X. Wang1,
Lynn M. Rogers2,
Evan Z. Gross1,
Anthony J. Ryals1,
Mehmet E. Dokucu3,
Kelly L. Brandstatt1,
Molly S. Hermiller1,
Joel L. Voss1,*

The influential notion that the hippocampus supports associative memory by interacting with functionally distinct and distributed brain regions has not been directly tested in humans. We therefore used targeted noninvasive electromagnetic stimulation to modulate human cortical-hippocampal networks and tested effects of this manipulation on memory. Multiple-session stimulation increased functional connectivity among distributed cortical-hippocampal network regions and concomitantly improved associative memory performance. These alterations involved localized long-term plasticity because increases were highly selective to the targeted brain regions, and enhancements of connectivity and associative memory persisted for ~24 hours after stimulation. Targeted cortical-hippocampal networks can thus be enhanced noninvasively, demonstrating their role in associative memory.


Alzheimer's & Dementia Weekly
August 27, 2014

Memory & Thinking Improve in Crenezumab Dementia Trial

An Alzheimer's vaccination called crenezumab just finished 2 trials. The drug showed clear, positive cognitive improvements in people with mild Alzheimer's. Learn more about the results and where crenezumab goes from here.

Roche presented data from two phase II studies investigating whether crenezumab can delay cognitive and functional decline in people with mild-to-moderate Alzheimer’s disease (AD). The larger study, known as ABBY, demonstrated initial evidence of a crenezumab treatment effect in people with mild AD. Similar effects on clinical decline were observed in BLAZE, a smaller biomarker study.

In the ABBY study, crenezumab treatment in people with mild-to-moderate AD demonstrated a trend toward slowing the decline of cognitive abilities, measured by the 12-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog12), but no effect on global functioning, measured by Clinical Dementia Rating-Sum of Boxes (CDR-SOB), the co-primary endpoints. In an exploratory analysis of people with milder disease treated with intravenous (IV) crenezumab, there was a positive trend toward increasing reduction in cognitive decline in progressively milder subsets relative to placebo.

In the BLAZE study, which enrolled people who tested positive for an amyloid imaging biomarker, the primary endpoint was a change in brain amyloid load. In a secondary endpoint analysis, treatment with IV crenezumab was associated with a trend towards slowing cognitive decline in those with mild disease (as measured by ADAS-cog12).

Biomarker results from the ABBY and BLAZE studies will be presented at an upcoming medical meeting.

“Data from these phase II studies provide valuable information about crenezumab’s potential clinical activity in people with Alzheimer’s disease, where there is a great need for treatment options,” said Richard Scheller, Ph.D., Executive Vice President and Head of Genentech Research and Early Development. “These findings support the importance of testing potential disease-modifying agents, such as beta amyloid antibodies, early in the course of the disease.”

There was no imbalance in the overall rate of adverse events (AEs); however, there was an imbalance in the rates of serious and non-serious events of pneumonia, with 3.2 percent of patients treated with crenezumab reported to develop pneumonia versus 0.6 percent of patients treated with placebo. The rate of pneumonia cases in crenezumab-treated patients is consistent with the expected rate in the elderly population (2.5-4.4 percent). In total, there were five deaths in crenezumab-treated patients across the two randomized studies; none of which were considered by the investigators to be related to crenezumab. In both studies combined, only a single case of asymptomatic amyloid-related imaging abnormalities (ARIA-E) was observed in a patient treated with crenezumab.

Despite crenezumab's successes in these trials, it did not achieve everything it set out to accomplish. Conclusions need to be drawn from the clinical trial data, adjustments need to be made, and another round of trials conducted. On the upside, since these were Phase II trials that were completed, in some ways the trials have made it past the halfway mark on the road to becoming approved medications.

The findings were presented at the Alzheimer's Association International Conference (AAIC).
About crenezumab and the ABBY and BLAZE studies
Crenezumab is an investigational, fully humanized, monoclonal antibody designed to target all forms of beta amyloid. Discovered by Swiss biotechnology company AC Immune, crenezumab is being developed by Genentech, a member of the Roche Group.

ABBY (ABE4869g, NCT01343966) is a phase II, randomised, double-blind, parallel-group, placebo-controlled study that evaluated the effects of IV or subcutaneous (an injection administered beneath the skin) crenezumab from baseline to Week 73 in patients with mild-to-moderate AD, as determined by a Mini-Mental State Examination (MMSE) score of 18-26 at baseline.
?The co-primary endpoints were to measure a reduction in cognitive decline by change in the ADAS-cog12 and global functional decline by change in the CDR-SOB. Other endpoints included change in the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scores (ADCS-ADL) and volumetric MRI (a measure of changes in brain volume associated with AD). An exploratory analysis of biomarkers was performed on data from people who provided an optional cerebrospinal fluid (CSF) sample.
?In this study, 431 patients with a baseline MMSE score of 18-26 received either 300 mg of subcutaneous crenezumab (low dose) every other week (or matching placebo) or 15 mg/kg IV crenezumab (high dose) every 4 weeks (or matching placebo) for 68 weeks.
?In patients with mild-to-moderate AD (MMSE score of 18-26) treated with high-dose IV crenezumab, there was a 16.8 percent reduction in cognitive decline (p=0.19). A 3.1 percent reduction in global functional decline was observed (p=0.85). There was no significant change in cognition in patients who received low-dose subcutaneous crenezumab.
?In the pre-specified subgroup analysis in patients with mild AD (MMSE score of 20-26), treatment with high-dose IV crenezumab led to a 23.8 percent reduction in cognitive decline (p=0.13), but not in global functional decline (-1.0 percent reduction; p=0.96).
?An exploratory analysis in patients with milder symptoms (MMSE 22-26) showed a 35.4 percent reduction in cognitive decline (p=0.036) and a 19.6 percent reduction in global functional decline (p=0.42). Effect sizes and p-values for exploratory analyses were not adjusted for multiplicity.
BLAZE (ABE4955g, NCT01397578) is a phase II, randomised, double-blind, parallel-group, placebo-controlled study that evaluated the effects of IV or subcutaneous crenezumab from baseline to Week 73 in patients with mild-to-moderate AD, as determined by a MMSE score of 18-26 at baseline.
?The primary endpoint was to measure the change in brain amyloid load using florbetapir-PET. These data will be presented at an upcoming medical meeting. Other endpoints included longitudinal changes from baseline in other biomarkers (CSF, vMRI), cognition (ADAS-cog12), global function (CDR-SOB), and activities of daily living (ADCS-ADL).
?In this study, 91 patients with a baseline MMSE score of 18-26 and a positive amyloid PET scan received either 300 mg of subcutaneous crenezumab (low dose) every other week (or matching placebo) or 15 mg/kg IV crenezumab (high dose) every 4 weeks (or matching placebo) for 68 weeks.
?In patients with mild-to-moderate AD (MMSE 18-26) treated with high-dose IV crenezumab, there was a 10.3 percent reduction in cognitive decline (p=0.84) and a 7.4 percent reduction in global functional decline (p=0.84). There was no significant cognitive change in patients who received low-dose subcutaneous crenezumab.
?In a post-hoc analysis of a group of patients with mild AD (MMSE 20-26) treated with high-dose IV crenezumab, there was a 52.0 percent reduction in cognitive decline (p=0.29) and a 41.5 percent reduction in global functional decline (p=0.44). Effect sizes and p-values were not adjusted for multiplicity.

Safety Data from ABBY and BLAZE
?There was no imbalance in the overall rate of Adverse Events (AEs); AEs were observed in 91.3 percent of patients treated with crenezumab versus 90.3 percent of patients who received placebo. AEs were generally mild-to-moderate and transient. AEs did not appear to be related to crenezumab exposure.
?A single case of asymptomatic amyloid-related imaging abnormalities (ARIA-E; sulcal effusion ? or a buildup of fluid in the grooves of the brain) was observed in a person who received high-dose IV crenezumab in the ABBY study. No case of ARIA-E was reported in the placebo arm or the BLAZE study.
?Five deaths occurred during ABBY and BLAZE, all in patients who received crenezumab during the randomized placebo-controlled period (1.4 percent of the crenezumab-treated population). The overall rate of deaths is consistent with the background rate of death in the elderly AD population. There was no consistent pattern for the cause of death and none were considered by the investigators to be related to crenezumab.
?There was an imbalance in the rate of serious and non-serious events of pneumonia, with a 3.2 percent in crenezumab-treated patients reported to develop pneumonia versus 0.6 percent in placebo-treated patients during the randomized placebo-controlled period of ABBY and BLAZE. The rate of pneumonia cases in crenezumab-treated patients is consistent with the expected rate in the elderly population (2.5-4.4 percent) and no drug-related mechanism for pneumonia was identified.

About Roche in neuroscience
With 12 investigational medicines in clinical development, neuroscience is a major focus of research and development at Roche. Our goal is to develop more effective treatment options based on the biology of the nervous system to improve the lives of people with chronic and potentially devastating diseases.

Roche has a broad AD research programme that focuses on several proteins and pathways believed to play an important role in the disease, including beta amyloid and monoamine oxidase B (MAO-B). Researchers at Roche are developing medicines designed to target these proteins in multiple ways and disease stages. Our late-stage AD pipeline includes:
?Anti-amyloid antibody crenezumab
?Anti-amyloid antibody gantenerumab
? MAO-B inhibitor RG1577.
In addition, two separate landmark AD prevention studies are evaluating crenezumab and gantenerumab in people at risk for, or with, early-onset AD.

About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and neuroscience.

1.Alzheimer's Association. 2014 Alzheimer's Disease Facts and Figures. Available at http://www.alz.org/alzheimers_disease_facts_and_figures.asp. Accessed July 2014.
2.Alzheimer's Disease International. Dementia Statistics. Available at http://www.alz.co.uk/research/statistics. Accessed July 2014.
3. Alzheimer's Association. 2012 Basics of Alzheimer's Disease. Available at https://www.alz.org/national/documents/brochure_basicsofalz_low.pdf. Accessed July 2014.

?F. Hoffmann-La Roche Ltd

Marijuana Compound  THC

Marijuana Compound May Slow, Halt Alzheimer’s


Extremely low levels of the compound in marijuana known as delta-9-tetrahydrocannabinol, or THC, may slow or halt the progression of Alzheimer’s disease, a recent study from neuroscientists at the University of South Florida shows.

Findings from the experiments, using a cellular model of Alzheimer’s disease, were reported online in the Journal of Alzheimer’s Disease.

Researchers from the USF Health Byrd Alzheimer’s Institute showed that extremely low doses of THC reduce the production of amyloid beta, found in a soluble form in most aging brains, and prevent abnormal accumulation of this protein? a process considered one of the pathological hallmarks evident early in the memory-robbing disease. These low concentrations of THC also selectively enhanced mitochondrial function, which is needed to help supply energy, transmit signals, and maintain a healthy brain.

“THC is known to be a potent antioxidant with neuroprotective properties, but this is the first report that the compound directly affects Alzheimer’s pathology by decreasing amyloid beta levels, inhibiting its aggregation, and enhancing mitochondrial function,” said study lead author Chuanhai Cao, a neuroscientist at the Byrd Alzheimer’s Institute and the USF College of Pharmacy. “Decreased levels of amyloid beta means less aggregation, which may protect against the progression of Alzheimer’s disease. Since THC is a natural and relatively safe amyloid inhibitor, THC or its analogs may help us develop an effective treatment in the future.”

The researchers point out that at the low doses studied, the therapeutic benefits of THC appear to prevail over the associated risks of THC toxicity and memory impairment.

Neel Nabar, a study co-author and MD/Ph.D. candidate, recognized the rapidly changing political climate surrounding the debate over medical marijuana.

“While we are still far from a consensus, this study indicates that THC and THC-related compounds may be of therapeutic value in Alzheimer’s disease,” Nabar said. “Are we advocating that people use illicit drugs to prevent the disease? No. It’s important to keep in mind that just because a drug may be effective doesn’t mean it can be safely used by anyone. However, these findings may lead to the development of related compounds that are safe, legal, and useful in the treatment of Alzheimer’s disease.”

The body’s own system of cannabinoid receptors interacts with naturally-occurring cannabinoid molecules, and these molecules function similarly to the THC isolated from the cannabis (marijuana) plant.

Cao’s laboratory at the Byrd Alzheimer’s Institute is currently investigating the effects of a drug cocktail that includes THC, caffeine as well as other natural compounds in a cellular model of Alzheimer’s disease, and will advance to a genetically-engineered mouse model of Alzheimer’s shortly.

“The dose and target population are critically important for any drug, so careful monitoring and control of drug levels in the blood and system are very important for therapeutic use, especially for a compound such as THC,” Cao said.

Date: August 27, 2014
Source: USF Health

Chuanhai Cao, Yaqiong Li, Hui Liu, Ge Bai, Jonathan Mayl, Xiaoyang Lin, Kyle Sutherland, Neel Nabar, Jianfeng Cai
The Potential Therapeutic Effects of THC on Alzheimer’s Disease
Abstract: The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer’s disease. N?2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin’s enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.

ischemia-tolerant mesenchymal stem cells (itMSCs)

Stemedica International Announces Pre-clinical Data of Its Alzheimer’s Study

The First Pre-clinical Mouse Study Using Ischemia-Tolerant Mesenchymal Stem Cells (itMSCs) Shows Over 30-Percent Decrease in Amyloid Beta (Abeta) Plaques

August 19, 2014
Business Wire

EPALINGES, Switzerland--(BUSINESS WIRE)--Stemedica International S.A., a Stemedica Cell Technologies Inc. subsidiary developing stem cell therapies for Alzheimer’s disease and dementia, revealed the first results of an intravenous administration of allogeneic, human, ischemia-tolerant mesenchymal stem cells (itMSCs) in a pre-clinical animal model of Alzheimer’s disease. The results demonstrated a greater than 30-percent decrease in amyloid beta (Abeta) plaques in the brain of transgenic animals treated with Stemedica itMSCs compared to the control group that were treated with lactated Ringer’s solution (LRS).

“Pre-clinical results show Stemedica International’s treatment reduces the amount of plaque as much as the best drug candidates to manage Abeta amyloidosis,” says Stemedica International’s Chief Scientist Tristan Bolmont, Ph.D. “Most importantly, our itMSC treatment did not result in side effects, such as cerebral amyloid angiopathy and micro-hemorrhages.”

These promising results were achieved during a two-year, intensive, pre-clinical research project supported by a grant from the Swiss Commission for Technology and Innovation (CTI). The research was conducted at the Laboratoire d’Optique Biomedicale and headed by Professor Theo Lasser at ?cole Polytechnique F?d?rale de Lausanne (EPFL) in Switzerland.

The results were presented at the Alzheimer’s Association International Conference in Copenhagen, Denmark, on July 14, 2014. In addition, Dr. Bolmont will share the findings during his talk at the Stem Cells Regenerative Medicine Congress 2014 in Boston, Massachusetts, on Sept. 15 at 2:30 p.m. ET.

“The combination of safety and efficacy of Stemedica’s itMSCs clears the pathway for Stemedica International to file an IND application with the FDA for clinical trials,” says Stemedica International’s General Manager Alexei Lukashev, Ph.D. “We hope our stem cell treatment can halt or slow down the progression of Alzheimer's disease and, maybe, have some reverse effect on the damage caused by Alzheimer’s disease and other forms of dementia, which the Alzheimer’s Disease Institute estimates afflicts more than 44 million people worldwide today.”

Only Stemedica International’s therapies feature itMSCs that are exclusively licensed from the parent company Stemedica Cell Technologies, Inc. Unlike other MSCs ? which are grown under normoxic conditions ? Stemedica’s bone-marrow-derived, allogeneic itMSCs are unique because they are grown under hypoxic conditions. In vitro experiments demonstrate cells that are exposed to hypoxic conditions show greater homing and engraftment than cells grown under normoxic conditions. Compared to other MSCs, itMSCs secrete higher levels of growth factors and other important proteins associated with neoangiogenesis and healing.

About Stemedica International S.A.

Founded in Epalinges, Switzerland, in 2008, Stemedica International S.A. is a global biotechnology company that develops therapeutic applications for the treatment and prevention of Alzheimer’s disease and vascular dementia. The company is a subsidiary of Stemedica Cell Technologies, Inc., a global biotechnology company that manufactures adult allogeneic stem cells. Stemedica International has an exclusive license to manufacture and distribute the parent company’s allogeneic, ischemia-tolerant mesenchymal stem cell (itMSC) and ischemia-tolerant neural stem cell (itNSC) lines and stem cell factors for Alzheimer’s disease and vascular dementia indications. The company also has Swissmedic licenses to import, export and distribute Stemedica Cell Technologies’ cell lines worldwide for human use in approved clinical trials. Manufactured in compliance with cGMP standards, the stem cell lines have a unique, proprietary technology based on the expansion of cells in constant hypoxia, which provides critical benefits in terms of safety, efficacy and scalability. For more information, visit www.stemedica-intl.com.

anti-APOE therapies

Tactic in Alzheimer’s Fight May Be Safe, Study Finds

August 11, 2014

The 40-year-old man showed up in Dr. Mary Malloy’s clinic with sadly disfiguring symptoms.

His hands, elbows, ears and feet were blemished with protruding pustules and tuber-like welts, some so painful it was hard for him to walk. He suffered from a rare genetic condition called dysbetalipoproteinemia, which caused his cholesterol levels to soar so high that pools of fatty tissue seemed to bubble up under his skin.

But there was something else about this patient. He was missing a gene that, when present in one form, greatly increases the risk of developing Alzheimer’s disease.

Dr. Malloy, who co-directs the Adult Lipid Clinic at the University of California, San Francisco, and her colleagues saw an opportunity to answer an important neurological riddle: Does the absence of the gene ? named apolipoprotein E, or APOE, after the protein it encodes ? hurt the brain?

If a person with this rare condition were found to be functioning normally, that would suggest support for a new direction in Alzheimer’s treatment.

It would mean that efforts ? already being explored by dementia experts ? to prevent Alzheimer’s by reducing, eliminating or neutralizing the effects of the most dangerous version of APOE might succeed without causing other problems in the brain.

The researchers, who reported their findings on Monday in the journal JAMA Neurology, discovered exactly that.

They ran a battery of tests, including cognitive assessments, brain imaging and cerebrospinal fluid analyses. The man’s levels of beta-amyloid and tau proteins, which are markers of Alzheimer’s, gave no indication of neurological disease. His brain size was unaffected, and the white matter was healthy. His thinking and memory skills were generally normal.

“This particular case tells us you can actually live without any APOE in the brain,” said Dr. Joachim Herz, a neuroscientist and molecular geneticist at University of Texas Southwestern Medical Center, who was not involved in the research. “So if they were to develop anti-APOE therapies for Alzheimer’s, we would not have to worry about serious neurological side effects.”

Apolipoprotein E, the protein made by the APOE gene, helps transport cholesterol. In the blood, Dr. Malloy said, it guides different proteins containing cholesterol into the liver. In the brain, it chaperones cholesterol from neurons to a storage area while they are changing, she said, and then returns the cholesterol to neurons.

The APOE gene has several forms, and one of them, the APOE4 variant, is the biggest known genetic risk factor for the most common form of Alzheimer’s. People with one copy of APOE4, about 20 percent of the population, have up to five times the risk of developing Alzheimer’s, compared to people without that variant, and they develop the disease earlier.

People with two copies, about 2 percent of the population, have up to 15 times the risk. About 90 percent of people with two copies will develop Alzheimer’s by the time they are age 80.

Another form of the APOE gene, E3, is very common but poses less risk. A third variant, E2, is rare and is the least dangerous.

Dr. Herz, who wrote an editorial about the study, said that the protein made by APOE4 slows the process of clearing beta-amyloid buildup in the brain, leading to the accumulation of the plaques associated with Alzheimer’s.

Proteins made by the other gene variants, APOE3 and APOE2, clear amyloid more quickly, and “in the absence of any APOE, the turnover is fastest,” he said.

So, it makes sense that a person with a fast-clearing form of APOE, or none at all, would have a very low risk of Alzheimer’s. Several experts are working on ways to reduce APOE4 or increase APOE2 in the brain, and the results have been promising.

Dr. Steven Paul, a professor of neuroscience at Weill Cornell Medical College, has found that by using gene therapy to implant mice with APOE2, “we reduced plaque quite effectively and quite quickly,” even in mice that also had APOE4, he said.

Dr. Paul, who is head of research and development at Voyager Therapeutics, said he is now studying the effect in monkeys. “If all goes well, in a year or so we could be thinking seriously about doing this in humans.”

Research led by Dr. David Holtzman, chairman of the neurology department at Washington University School of Medicine in St. Louis, found that when mice with amyloid plaques were given a monoclonal antibody that reduces APOE, the mice developed fewer plaques and cleared some of them from their brains.

Decades ago, before the link to Alzheimer’s was known, reports on a handful of people without APOE suggested that, aside from the physical side effects of astronomical cholesterol levels, they appeared otherwise normal.

But the 40-year-old man, a pipefitter who lives in California’s Central Valley and is married with three children, is the first documented case of an APOE-less person whose brain health has been rigorously tested. He was not further identified to protect his privacy.

“This finding is important,” Dr. Holtzman wrote in an email. It shows “that it is unlikely that APOE is key for normal brain development or function, as there are other proteins that can compensate in its absence.”

The fact that Dr. Malloy’s patient is relatively young makes the results a little less strong, because amyloid accumulation in people destined to get Alzheimer’s may not begin until later in life.

But Dr. Herz said, “based on what we know now, I would say this patient will most likely never accumulate amyloid.”

Dr. Malloy is working to treat the man’s cholesterol problem, which has barely improved despite medication and a healthy diet.

Dr. Paul and others said anti-APOE therapies would have to target broad areas of the brain without crossing the blood-brain barrier and circulating to the liver. They consider that a quite realistic goal.

“Things are developing incredibly rapidly these days,” said Dr. Herz, who is not involved in creating the new therapies. “I’m very confident that we will find approaches that address these issues.”

Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function

JAMA Neurol. Published online August 11, 2014. doi:10.1001/jamaneurol.2014.2011

Importance The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE).

Objectives To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism.

Design, Setting, and Participants Whole-exome sequencing was performed on the patient’s DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband’s mother, wife, 2 daughters, and normolipidemic control participants.

Main Outcome Measures Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.

Results The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient’s apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally.

Conclusions and Relevance Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.


Yale Study Finds Alzheimer’s Drug Reverses Memory Loss in Lab Mice

By Matthew Sturdevant
The Hartford Courant
Thursday, August 7, 2014
(Published in print: Thursday, August 7, 2014)

Hartford, Conn. ? Researching a new drug compound on mice, Yale School of Medicine researchers were able to reverse the effects of Alzheimer’s on learning and memory, the school announced this.

Yale School of Medicine psychiatry professor Paul Lombroso and others studied thousands of molecules, which could become drugs, in search of one or more that would inhibit the negative effects on the brain of a specific type of protein. In this latest study, scientists are showing for the first time that inhibiting the negative effects of a specific protein can reverse memory and learning deficits associated with Alzheimer’s in mice.

Yale researchers are duplicating the research to see if they get the same results with rats and non-human primates. The hope is that they will one day come up with a drug that could be used to help treat people with Alzheimer’s disease.

The protein, STriatal-Enriched protein tyrosine Phosphatase, or STEP, is present in the brain. Those with Alzheimer’s disease have elevated levels of STEP in their brains. Inhibiting the negative effects of STEP can reverse some cognitive effects of Alzheimer’s, according to the research published Tuesday in the Public Library of Science’s online journal PLoS Biology.

Having too much of the STEP protein can interfere with synapses, causing disorders in thought and behavior. The protein can keep synapses in the brain from strengthening, which is needed to convert short-term memories into long-term memories.

There is a benefit to STEP in the brain. A simple explanation is that it interferes with certain receptors in the brain that allow a person to re-learn something a different way. Too much STEP activity, however, can keep a person from learning or remembering, according to the research.

Lombroso and his collaborators looked at about 150,000 molecular compounds, narrowing them down to those that would inhibit STEP activity. The researchers examined eight of the most promising of the compounds for further study on mice.

The researchers had success with a molecular compound, or drug, they call TC-2153. The drug turned out to be a successful STEP inhibitor.

“This novel STEP inhibitor has given a real impetus now for pharma industries to look for additional STEP inhibitors,” Lombroso said.

The doctor said he may not have the exact drug that will end up on the market, “but the whole process of drug discovery is involved screening many, many compounds and finding ones that are optimal for higher primates (people, that is).”

Christianne Kovel, of the state chapter of the Alzheimer’s Association, said: “It is an exciting and busy time in Alzheimer’s disease research with hundreds of potential therapies being tested at various stages of the research process, and many more being developed.”

More than 5 million people in the U.S. have Alzheimer’s disease, Kovel said.

Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease

Published: August 05, 2014
?DOI: 10.1371/journal.pbio.1001923


STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepr?opionicacid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopenta?thiepin-6-aminehydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.


Drug shows promise in Alzheimer's fight
1:08 p.m. MDT July 25, 2014

KUSA - Researchers at the University of Colorado Hospital hope a drug already approved for bone marrow transplant patients could also help Alzheimer's patients.

"This is a huge problem, and we at the University of Colorado are trying to develop new treatments and diagnostics for Alzheimer's disease," said researcher Huntington Potter.

At the center of their research is a drug call Leukine. It's been approved by the FDA for 20 years but has never been tried on Alzheimer's patients.

"The way we discovered it, is people with Rheumatoid arthritis tend not to get Alzheimer's disease," said Potter. "They seem to be protected and this molecule is released during Rheumatoid arthritis. When we tried it in mice that have Alzheimer's disease, it completely cured them. Now we want to try it in humans."

In Alzheimer's patients, deposits called amyloids develop on the brain. Researchers say getting rid of those deposits is a good start, but won't solve the problem. If the deposits are removed holes are left behind that need to be filled with neurons and blood vessels in order for brain function to be restored.

Leukine has shown promise in treating all of those problems.

"One of the things that's good about Leukine is that it seems to be able to do all three, get rid of the amyloid, help the neurons regrow into those holes and help new blood vessels grow," said Potter.

Researchers hope to have clinical trials finished in several years. If they go well, the process to get Leukine on the market would be fairly quick because it's already FDA approved for other uses.

"We have to be very careful not to raise hopes to high because so many drugs in Alzheimers research have failed," said Potter. "This one has many many features that are exciting and different from what has already been tried so we're very optimistic."

(KUSA-TV ? 2014 Multimedia Holdings Corporation)


Alzheimer's & Dementia Weekly
July 18, 2014

Carmustine Cuts Alzheimer's Plaque by 75% in Mice

Label for BiCNU (Carmustine) Florida researchers noticed that people with cancer tended not to get Alzheimer's disease. So, FDA approved anti-cancer drugs were screened to see how well they reduce Alzheimer's plaque. Learn how carmustine stands out, decreasing amyloid β levels by 75%.

Long term treatment by carmustine, a chemical relative of mustard gas and already used to treat some types of brain cancer, can decrease the amount of amyloid β and number of amyloid plaques in a mouse model of Alzheimer's disease. The research is published in Biomed Central's open access journal BMC Medicine.

Alzheimer's disease progressively destroys memory, language, and judgement of affected people. While deaths due to heart disease, stroke and cancer may be decreasing, the number of deaths each year due to Alzheimer's disease is on the increase. Accumulation of amyloid β plaques can be seen in the brain from early stages, even though the exact relationship between these plaques and Alzheimer's disease has not yet been firmly established.

Noticing that people with cancer tended not to get Alzheimer's disease, and vice versa, researchers from the Florida based Torrey Pines Institute for Molecular Studies screened a library of all FDA approved anti-cancer drugs for their ability to reduce amyloid β levels in cells expressing amyloid precursor protein. From this screen they found that carmustine could decrease conversion of precursor protein to amyloid β levels by 60%.When tested in a mouse model of Alzhiemer's disease, long term treatment with carmustine was able to reduce amyloid β levels by 75%.

Discussing how this research could translate to humans, Dr. Madepalli Lakshmana, who led this study commented,
"The level of carmustine needed to achieve reduction in amyloid β is much lower than the dose already used in the treatment of some types of brain cancer. Also carmustine does not appear to act by activating microglia or by blocking secretases which reduces possible side effects seen with other anti-amyloid investigational new drugs. While more work still needs to be done, carmustine appears to be a powerful candidate drug for treatment and prevention of Alzheimer's disease."

1. Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine, Crystal D Hayes, Debleena Dey, Juan Pablo Palavicini, Hongjie Wang, Kshitij A Patkar, Dmitriy Minond, Adel Nefzi and Madepalli K Lakshmana BMC Medicine 2013, 11:81 doi:10.1186/1741-7015-11-81

Related commentary

Potential repurposing of oncology drugs for the treatment of Alzheimer's disease , Wataru Araki, BMC Medicine 2013, 11:82 doi:10.1186/1741-7015-11-82

2. BMC Medicine is the flagship medical journal of the BMC series, publishing original research, commentaries and reviews that are either of significant interest to all areas of medicine and clinical practice, or provide key translational or clinical advances in a specific field.

3. BioMed Central is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector.

MSX-3(caffeine-like effects, a water-soluble A2A antagonist)

Alzheimer’s Delayed by Caffeine?

By Jane Collingwood Associate News Editor
Reviewed by John M. Grohol, Psy.D. on July 22, 2014

Caffeine appears to have a positive effect on so-called “tau deposits” in Alzheimer’s disease, scientists have found. Tau deposits are proteins that, together with beta-amyloid plaques, are some of the characteristic features of Alzheimer’s disease.

These deposits interfere with the communication of nerve cells in the brain, and can cause nerve degeneration. No drug is currently available to prevent this process. So researchers led by Dr. Christa Muller from the University of Bonn, Germany, took a look at caffeine.

It is an “adenosine receptor antagonist,” meaning it blocks receptors in the brain that are activated by adenosine. Blocking the adenosine receptor subtype A2A may play a particularly important role.

The team created a compound with caffeine-like effects, a water-soluble A2A antagonist called MSX-3. It specifically blocks only A2A adenosine receptors. In doing so, it is significantly more effective than caffeine while having fewer side effects.

The compound was tested on mice which were altered to have a tau protein that would lead to the early development of Alzheimer’s symptoms. The Alzheimer’s-prone mice were given this A2A antagonist for several weeks, and achieved significantly better results on memory tests ? particularly spatial memory ? than those given placebo. Full results are published in the journal Neurobiology of Aging.

The team writes, “Epidemiologic evidences support that habitual caffeine intake prevents memory decline during aging and reduces the risk of developing Alzheimer’s disease.”

Commenting on their study, they explain, “We found that chronic caffeine intake [from MSX-3] prevents from the development of spatial memory deficits in tau mice. Moreover, caffeine treatment mitigated several proinflammatory and oxidative stress markers. Together, our data support that moderate caffeine intake is beneficial in a model of Alzheimer’s disease-like tau pathology, paving the way for future clinical evaluation in Alzheimer’s disease patients.”

Dr. Muller said, “We have taken a good step forward. The results of the study are truly promising, since we were able to show for the first time that A2A adenosine receptor antagonists actually have very positive effects in an animal model simulating hallmark characteristics and progression of the disease. And the adverse effects are minor.

She added, “Patience is required until A2A adenosine receptor antagonists are approved as new therapeutic agents for Alzheimer’s disease. But I am optimistic that clinical studies will be performed.”

One of the major studies of “real life” caffeine intake and cognition was carried out in 2012 by Chuanhai Cao, Ph.D., of the University of South Florida. Cao and colleagues monitored blood caffeine levels of 124 people aged 65 to 88 years for two to four years. All had mild cognitive impairment, which can progress to Alzheimer’s disease.

Those with higher blood caffeine levels scored better on tests of memory and thinking processes. No other lifestyle differences were seen.

Cao says, “These intriguing results suggest that older adults with mild memory impairment who drink moderate levels of coffee ? about three cups a day ? will not convert to Alzheimer’s disease, or at least will experience a substantial delay before converting to Alzheimer’s.”

“The results are consistent with earlier studies on mice,” he adds. Caffeinated coffee was the main source of caffeine in the study.

“We are not saying that moderate coffee consumption will completely protect people from Alzheimer’s disease,” added Cao. “However, we firmly believe that moderate coffee consumption can appreciably reduce your risk of Alzheimer’s or delay its onset.”

A very recent review of the modifiable factors linked to cognition and dementia found that 39 percent of studies on caffeine had positive results. “Acting as a stimulant of the central nervous system, caffeine causes heightened alertness and arousal,” the authors write.

“Caffeine is one type of compound known as methylxanthines whose effects are mainly to block adenosine receptors in the brain, resulting in cholinergic stimulation. It was hypothesized that such stimulation would lead to improved memory.”

Although many small studies appear to demonstrate a protective effect, “given the paucity of large cohort studies, more research is needed to establish causality,” they conclude.

In summary, caffeine has not been proven conclusively to protect against Alzheimer’s disease, but decades of research suggest that it may be effective. While caffeine is known to enhance short-term memory and cognition, there is some evidence that long-term use may protect against cognitive decline or dementia.

With the large economic and emotional impact of Alzheimer’s disease, it is vital that we identify potential triggers. Moderate consumption of caffeinated coffee is generally safe for healthy people, so would provide a simple protective strategy, if its benefit is confirmed in more reliable studies.


Laurent, C. et al. Beneficial effects of caffeine in a transgenic model of Alzheimer’s disease-like Tau pathology. Neurobiology of Aging, 31 March 2014 doi:10.1016/j.neurobiolaging.2014.03.027

Cao, C. et al. High blood caffeine levels in MCI linked to lack of progression to dementia. Journal of Alzheimers Disease. 19 March 2012 doi: 10.3233/JAD-2012-111781

Beydoun, M. A. et al. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 24 June 2014 doi: 10.1186/1471-2458-14-643


TransTech, US FDA agree on phase 3 trial of TTP488 in patients with mild Alzheimer's disease

July 12, 2014

TransTech Pharma, LLC, has reached an agreement with the US Food and Drug Administration Division of Neurology Products, under the Special Protocol Assessment (SPA) process, on the design of a single phase 3 trial of TTP488 for the treatment of patients with mild Alzheimer’s disease. A Special Protocol Assessment (SPA) from the FDA is a binding agreement that the phase 3 trial design, planned execution and statistical analyses are acceptable to support regulatory approval.

“The agreement on the SPA represents a significant milestone for the development of TTP488 and for TransTech Pharma” said Steve Holcombe, president and CFO. “We are extremely pleased to receive agreement on the SPA and to have a clear path forward for the submission and regulatory approval of TTP488 for the treatment of patients with mild Alzheimer’s disease.”

The phase 3 trial will be a randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of TTP488 for the treatment of patients with mild Alzheimer’s disease. The trial will compare TTP488 5mg daily to placebo over the course of 18 months of treatment. Approximately 800 patients with mild Alzheimer’s disease receiving standard of care (i.e. acetylcholinesterase inhibitors) will be enrolled. The primary efficacy analysis will be based on the changes in ADAS-cog (Alzheimer’s Disease Assessment Scale ? cognitive subscale) and CDR-sb (Clinical Dementia Rating ? sum of boxes). TransTech Pharma anticipates beginning enrollment of patients before the end of the year.

Substantial data suggest that RAGE, the Receptor for Advanced Glycation Endproducts, is involved in the pathogenesis of Alzheimer’s disease, and that sustained Ab interaction with RAGE at the blood-brain barrier (BBB), or in neuronal or microglial cells, is an important element of amyloid plaque formation and chronic neural dysfunction.

TTP488 is a novel, small-molecule, orally active antagonist of RAGE. In a double-blind clinical trial where data was collected over 18 months, TTP488 slowed cognitive decline in patients with mild to moderate Alzheimer’s disease. The effect, while evident in both patients with mild and moderate disease, was more prominent in patients with mild disease. TransTech Pharma discovered and developed TTP488 using its proprietary drug discovery platform TTP Translational Technology.

Alzheimer’s disease, the most common form of dementia, is a progressive neurodegenerative disorder that causes decline in cognition and functional abilities. It has been estimated to affect 5 million individuals in the United States, and represents the 6th leading cause of death. Worldwide, there are currently more than 35 million people with dementia, and the number is predicted to increase to over 115 million by 2050.

While current approved therapies for Alzheimer’s disease focus on improving the symptoms of the cognitive dysfunction, there is currently no treatment to slow disease progression.

TransTech Pharma, LLC is a privately held, clinical-stage pharmaceutical company focused on the discovery, development, and commercialization of human therapeutics to fill unmet medical needs.


New therapeutic targets release mechanisms in reactive astrocytes for treatment of Alzheimer's disease

July 9, 2014

Alzheimer's disease, which is the most common cause of dementia, is fatal and currently, there is no cure. In Alzheimer's disease, brain cells are damaged and destroyed, leading to devastating memory loss. It is reported that 1 in 8 Americans aged 65 or over have Alzheimer's disease. In 2011, 7,600 elderly people with dementia lost their way back home and became homeless in Korea. However, to date, there has been no clear understanding of the mechanisms underlying dementia in Alzheimer's disease. So far, neuronal death is the only proposed mechanism available in scientific literature.

The research team led by Dr. C. Justin Lee at Korea Institute of Science and Technology (KIST) and Dr. Daesoo Kim(KAIST) discovered that reactive astrocytes in the brains of Alzheimer's disease model mice produce the inhibitory transmitter GABA by the enzyme Monoamine oxidase B(MAO-B) and release GABA through the Bestrophin-1 channel to suppress normal information flow during synaptic transmission. Based on this discovery, the team was able to reduce the production and release of GABA by inhibiting MAO-B or Bestrophin-1, and successfully ameliorate impairments in neuronal firing, synaptic transmission and memory in Alzheimer's disease model mice.

In the behavioral test, the team used the fact that mice tend to prefer dark places. If a mouse experiences an electric shock in a dark place, it will remember this event and avoid dark places from then on. However, a mouse with modeled Alzheimer's disease cannot remember if such shock is related to dark places and keeps going back to dark places. The team demonstrated that treating these mice with a MAO-B inhibitor fully recovered the mice's memory. The selegiline is currently used in Parkinson's disease as an adjunct therapy and considered as a one of best promising medicine for MAO-B inhibitor. But it has been previously shown to be less effective in Alzheimer's disease.

The team proved that selegiline is effective for a short time, but when it is used in long term, it loses its efficacy in Alzheimer's disease model mice. When treated for 1 week, selegiline brought the neuronal firing to a normal level. But when it was treated for 2 and 4 weeks, neuronal firing came back to the levels of untreated mice. From these results, the team proposed that there is a pressing need for a new drug that has long lasting effects.

Dr. C. Justin Lee said, "From this study, we reveal the novel mechanism of how Alzheimer's patients might lose their memory. We also propose new therapeutic targets, which include GABA production and release mechanisms in reactive astrocytes for treatment of Alzheimer's disease. Furthermore, we provide a stepping stone for the development of MAO-B inhibitors with long lasting efficacy."

Source:Korea Institute of Science and Technology


Hong Kong researchers may have found way to combat Alzheimer's disease

Researchers believe they can slow disease's progress with use of molecule found in medicinal herb

07 July, 2014
South China Morning Post

Researchers believe they have found a way to slow the progress of Alzheimer's disease, one of the leading causes of death among elderly people.

A team from the University of Science and Technology has identified a protein found on the surface of brain cells that they believe causes the disease. They found that when over-activated, the protein EphA4 causes deterioration in learning and memory abilities.

The team has also identified a molecule in the Chinese medicinal herb gou teng ( uncaria rhynchophylla) that inhibits the protein's activity.

Developing a drug with the use of the molecule, rhynchophylline, could take another five to 10 years, according to Professor Nancy Ip Yuk-yu, who led the research.

"We hope our method will be able to target early abnormal changes in Alzheimer's patients and can slow the progression of the disease," she said yesterday.

In 2009, Alzheimer's disease affected about 103,000 people in Hong Kong; by 2039 it is expected to affect 332,000. Early symptoms of the disease include memory loss and a decline in thinking abilities. In its advanced stages, the disease can be fatal.

While some drugs target Alzheimer's symptoms, there are none as yet that address its cause, which is not fully understood.

The team has been studying the brain cell protein for more than 10 years. They found that its over-activation impaired the signalling between brain cells.

About three years ago, the team used rhynchophylline to improve the memory of mice.
The researchers used two groups of about 20 mice - one with Alzheimer's, one without. Each group was divided into two - one was fed with rhynchophylline for three to four months and one was not.

The mice were then put into a wading pool that contained a resting platform.

When the platform was later removed, the memory of each mouse was measured by the length of time it stayed in the section of the pool where the platform had previously been placed.

Mice which had Alzheimer's and received the treatment showed improved memory; healthy mice which received the treatment did not improve.

The study was published in Proceedings of the National Academy of Sciences of the United States of America last month.

The team is now seeking to work with drug manufacturers and medical schools, and will continue to study the brain cell protein to see whether it plays a role in other diseases.

Ip discouraged patients from eating the herb, saying the levels of rhynchophylline would be too small to have an effect.

This article appeared in the South China Morning Post print edition as New lead on Alzheimer's

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

Edited* by Mu-ming Poo, University of California, Berkeley, Berkeley, CA, and approved June 4, 2014 (received for review March 28, 2014) PNAS


Alzheimer’s disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a small-molecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.


Drug Could Halt Alzheimer's By Targeting Clotting Protein

By Rebekah Marcarelli
Jun 27, 2014

The treated mice had less inflammation and better blood flow to the brain.

Blood clots could be the "culprits" behind many of the symptoms of Alzheimer's disease; new research suggests a compound could stall the progression of the disease by interfering with the amyloid-β protein that plays a role in clot formation.

New experiments in Sidney Strickland's Laboratory of Neurobiology and Genetics at Rockefeller University has identified the compound that fights the plaque-forming protein. The work was published in the July issue of Nature Reviews Drug Discovery.

Many potential Alzheimer's drugs have attempted to target amyloid-β in the past, but have failed or cause serious side effects. This new drug interferes with the protein's ability to bind to a clotting agent in the blood.

"Our experiments in test tubes and in mouse models of Alzheimer's showed the compound, known as RU-505, helped restore normal clotting and cerebral blood flow. But the big pay-off came with behavioral tests in which the Alzheimer's mice treated with RU-505 exhibited better memories than their untreated counterparts," Strickland said. "These results suggest we have found a new strategy with which to treat Alzheimer's disease."

The researchers pinpointed RU-505 out of a pool of 93,716 candidates selected from compound libraries. The team aimed to find a compound that interfered with the interaction between fibrinogen and amyloid-β.

"We tested RU-505 in mouse models of Alzheimer's disease that over-express amyloid- β and have a relatively early onset of disease. Because Alzheimer's disease is a long-term, progressive disease, these treatments lasted for three months," Hyung Jin Ahn, a research associate in the lab, said. "Afterward, we found evidence of improvement both at the cellular and the behavioral levels."

The mice that were treated had less inflammation in the brain and the blood to their brains was closer to a normal flow than in the untreated mice.

"While the behavior and the brains of the Alzheimer's mice did not fully recover, the three-month treatment with RU-505 prevents much of the decline associated with the disease," Strickland said.

structured animal-assisted intervention (AAI) program

'Dogs for Dementia' Program Improves Social Behavior
Deborah Brauser
June 26, 2014
Medscape Medical News

LONDON ― A structured animal-assisted intervention (AAI) program may improve social behaviors in elderly patients with dementia, new research suggests.

The pilot study, conducted in Germany, showed that nursing home residents with dementia who attended weekly therapy sessions that included dog visits for 6 months had significantly longer periods of verbal communication, physical contact, and attentiveness than when they participated in a similar program with the same conditions and frequency but without the dogs.

"These positive effects were seen in all investigation points," lead author Sandra Wesenberg, research associate at the Faculty of Education at Technische Universitat Dresden in Germany, who will be graduating with a PhD degree next month, told Medscape Medical News.

"I would recommend this to other clinicians, but only if they use a good, verified program that is good for both patients and for the dogs," added Wesenberg.

The results were presented here at the International Congress of the Royal College of Psychiatrists (RCPsych) 2014.

Little Past Research

The investigators note that although AAI programs have been around for years and have become more common recently within nursing home settings, there has been very little research on their benefits.

"For a long time, research on the potentially beneficial bio-psycho-social effects of [these] interventions on people with dementia was limited to individual case reports, practical reports, and field studies with very small sample sizes," they write.

The researchers enrolled 17 nursing home residents into their small, preliminary pilot study. Of these, 77% were women; the overall mean age was 85.7 years.

All participants spent the first 6 months of the study attending 45-minute, weekly dog-assisted therapy sessions with up to 4 other people. The standardized program, known as Pet Encounters, was established in 2008 and uses dogs and owners specially trained to be around patients with dementia.

The nursing home participants then went through a similar intervention program that did not include dog visits.

"Sessions in the first, third, and sixth month were video recorded and behavior-coded," explain the investigators. Observed social behavior and durations of emotional expression were also recorded and compared between the 2 programs.

Results showed significantly longer durations between baseline and the 3-month point and between baseline and the 6-month point for the visiting dog intervention vs the no-dog intervention for verbal communication, attentiveness, physical contact, and overall positive changes (P < .05 for all).

Although there were also overall positive changes over time during the no-dog intervention, the effect was much less than during the dog visits.

"The positive effects in the AAI program occurred faster and on a broader scale than in the comparable intervention program," write the investigators.

"The findings suggest that an AAI program could have particularly beneficial effects on the well-being of people diagnosed with dementia," they add.

Wesenberg reported that they are now hoping for more funding to continue this program with these patients and to conduct a larger study.

More Research Needed

Timothy O'Grady, FRCPsych, consultant general psychiatrist in Lincoln, England, told Medscape Medical News that this was an interesting study but that he would like to know more about how the dogs affected the outcomes.

"Did verbal communication improve because the dog was a conversation piece? Or did it just help the patients to open up a little? There's not much evidence on the role of pets in mental health," said Dr. O'Grady, who was not involved with this research.

"Many people say yes to pets and that they're very nice for companionship and focus. But another perspective is that it can lead to chaos. People who can't cope very well are taking on this expense and responsibility, and it's not really that great for the animals."

Overall, he noted that this idea might be a bit romanticized and definitely needs to be researched further.

"There have been studies about using horses or different things like golf, and I think people say, 'This worked great for me and some of my patients. Let's see how it does with others.' But I'm not sure this is what these patients really need," he said.

The study authors have disclosed no relevant financial relationships.

International Congress of the Royal College of Psychiatrists (RCPsych) 2014. Poster 40. Presented June 25, 2014.


Common painkiller 'could help prevent premature ageing': Ibuprofen can help diabetes and dementia patients from growing old before their time

The popular over the counter painkiller gave ageing mice a new lease of life
Could help patients with age-related illnesses diabetes and dementia
While it's unlikely to improve illness, drug might slow its progression

By Fiona Macrae
25 June 2014

It already works wonders on pounding headaches.

But ibuprofen could also hold the secret to a long and healthy life.

In a series of remarkable experiments, the popular painkiller gave ageing mice a new lease of life.

Researchers from Newcastle University say it might help people with age-related illnesses such as diabetes and dementia from growing old before their time.

While it is unlikely to improve their illness, the inexpensive drug might slow its progression ? and help prevent them from developing other debilitating conditions.

As surprising as this might seem, researcher Thomas von Zglinicki said it is not unusual for a drug that is developed to treat one thing to have other powers.

At the heart of Professor von Zglinicki’s theory is the inflammation that causes pain, swelling and fever we experience when our body is fighting off an infection.

This inflammation is also present in a milder but longer-term form in age-related diseases such as diabetes, dementia and arthritis.

Using GM mice, the professor showed that far from being a result of ageing, this inflammation helps drive it. Mice with genes that made them particularly prone to inflammation aged twice as quickly as normal animals.

Just like people, their hair turned grey and fell out, they lost weight, became unsteady on their feet and had heart problems. They also lived half as long as usual.

Tests showed that the inflammation triggered a chain of reactions that led to cells going to sleep, rather making new copies needed to help keep the body and its organs young.

Treating the mice with ibuprofen stopped the cells from going into this sleeping state.

Plus, the animals were able to repair damage to their liver, the journal Nature Communications reports.

Professor von Zglinicki said mice were ‘basically brought back to normal’. He is now checking if the treatment also extends lifespan.

Ibuprofen is taken by up to nine million Britons a day to treat headaches, muscle pain, sprains and flu.

But it can also cause indigestion and stomach ulcers, while higher doses taken long-term for conditions such as arthritis can raise the risk of strokes and heart attacks, and even reduce a woman’s fertility.

While the professor says that regular ibuprofen might help people with age-related illnesses such as dementia and diabetes, he advises them to talk to their GP first before starting self-medication.

They should also ask their doctor to do a simple blood test to confirm they are a victim of mild but persistent inflammation.

‘The hope is not really that it will improve the illness that they have but that it might slow the progression,’ he said.

Ibuprofen is unlikely to help those who are healthy but would simply like to slow the ageing process ? in the experiments, it had no effect on mice that were ageing normally.

The professor said: ‘Long-term drug use is something one has to think about and we cannot justify it in healthy people when the data don’t give us a strong basis.’

In the meantime, he suggests that those keen to stay young try to keep a lid on inflammation by eating foods that might help combat it, such as blueberries.

Dr Lynne Cox, an ageing expert at Oxford University, called the research ‘a lovely piece of science’.

However, she said side-effects associated with long-term use of ibuprofen are so serious that people should not take it just to keep them young.

Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

Diana Jurk,
Caroline Wilson,
Jo?o F. Passos,
Fiona Oakley,
Clara Correia-Melo,
Laura Greaves,
Gabriele Saretzki,
Chris Fox,
Conor Lawless,
Rhys Anderson,
Graeme Hewitt,
Sylvia LF Pender,
Nicola Fullard,
Glyn Nelson,
Jelena Mann,
Bart van de Sluis,
Derek A. Mann
& Thomas von Zglinicki

Corresponding author
Nature Communications 2, Article number: 4172 doi:10.1038/ncomms5172 Received 20 November 2013 Accepted 20 May 2014 Published 24 June 2014

Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1?/? fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1?/? tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.


June 22, 2014
Alzheimer's & Dementia Weekly

"AD04 is the 1st Drug Ever to Show Disease Modifying Properties in Alzheimer's"


The Alzheimer's drugs on the market today help compensate for the problems caused by Alzheimer's. However, they do not stop the disease or change its course. AD04 by AFFiRiS promises to change all that. In clinical trials, it was able to modify the course of Alzheimer's, potentially changing the face of Alzheimer's treatment.

AFFiRiS announced the results of a phase II study in Alzheimer's patients. AFFiRiS' proprietary compound AD04 is the first drug ever to demonstrate clinical and biomarker effects consistent with disease modification in Alzheimer's patients. Upon treatment with AD04, effects consistent with disease modification were achieved for at least 18 months in 47 % of treated patients. This beneficial effect was dose dependent and more effective in early disease patients. Furthermore, prevention of hippocampal decline was correlated with the beneficial impact on clinical progression and was statistically significant. Therefore, these results for the very first time meet all of the criteria for disease modification as defined by US and European Regulatory Agencies FDA (Food and Drug administration) and EMA (European Medicines Agency).

The remarkable results of AFFiRiS' clinical phase II study in Alzheimer's patients of AD04 demonstrate the impressive therapeutic effect of AD04. The results also make it the first ever compound demonstrating clinical and biomarker evidence consistent with disease modification of Alzheimer's disease. A statistically significant correlation was demonstrated between the cognitive/functional outcome and the volume of the hippocampus, the region of the brain locating the cognitive/memory functions, both of which demonstrated positive impact on disease progression over 18 months. Similar stabilization was also seen across behavioral and quality of life outcomes.

There was also a stabilization of the cognitive/functional endpoint found in those patients of this study who were treated with AD02, so far the company's lead compound in AD. Dependent on dosage and formulation of AD02 in three different study arms, 24 ? 31 % of the patients showed cognitive/functional stabilization or improvement. However, statistically significant correlation with biomarker Hippocampus volume could not be demonstrated within the observation period of 18 months. Altogether 332 patients were treated in an international multi-centric clinical trial into five different study arms, and over 85 % completed the study.

Significant Impact
Commenting on these results Dr. Walter Schmidt, CEO and Co-founder of AFFiRiS AG, states:
"Our results demonstrate that AD04 is the first drug ever to show disease modifying properties in Alzheimer's patients. This success is owed to our strategy of clinical maturation, which in the case of Alzheimer's has so far moved forward four different product candidates namely AD01 ? AD04 into clinical development."
Dr. Frank Mattner, CSO and Co-founder, adds:
"Both compounds applied in this trail, AD02 and AD04, showed excellent safety profiles. Top compound AD02 performed very well in stabilization of cognitive functions in a dose dependent manner. 24 ? 31 % of treated patients showed stabilization of clinical progression. However, AD04 turned out to be superior to AD02 as 47 % of the patients stabilized regarding their cognitive/ functional status. On top of this, this effect was statistically significantly correlated with the rescue of the hippocampus, the region of the human brain, where cognitive and memory functions are located (p=0.0016). This correlation of significant clinical and biomarker effects meets EMA's and FDA's definition of disease modification in the context of a compound with a consistent mode of action. Therefore, we decided to have a strong focus on AD04 for further clinical development. Our strategy of clinical maturation allows for an efficient progress during clinical development. By doing so, it reduces financial risks associated with any clinical trial."
In fact, the clinical maturation strategy has been established by AFFiRiS and is based on parallel clinical testing of several drug candidates against a certain disease to ensure that the best therapy for humans will be developed.

Prof. Achim Schneeberger, Chief Medical Officer at AFFiRiS, extends:
"From the beginning we were running our Alzheimer's therapy program with several drug candidates. AD04 now shows the most convincing therapeutic benefits including an effect on NPI and quality of life, which are relevant to patients and their caregivers. Because the current results are so extremely positive and consistent across clinical outcomes and brain volumes we expect to verify them in further clinical investigations."

Additional Programs
In addition to its Alzheimer's therapy program AFFiRiS' pipeline contains product candidates against Parkinson, Atherosclerosis, Diabetes and several other conditions. Dr. Mattner comments: "AFFiRiS focuses on the development of drugs against conditions with urgent requirement for new treatments and attractive market volumes. Our Alzheimer's and our Parkinson developments are successful examples for this. Indeed AFFiRiS was the first company world-wide that started clinical testing of Parkinson drug with the potential for disease modification. Eagerly awaited results of this clinical trial will be released within the next two months."

About AFFiRiS AG
Based on its proprietary IP positions AFFiRiS develops tailor-made drugs mainly as Peptide-based vaccines. Target diseases include Alzheimer's, Parkinson, Diabetes and other indications with attractive markets and unmet medical need. Alzheimer's is the lead indication.

AFFiRiS is located at the campus of the Vienna Biocenter, Vienna Austria and employs 95 highly qualified employees.


Press releases

Breakthrough in Alzheimer's disease:

AFFiRiS halted clinical progression in Alzheimer patients upon treatment with AD04 in a phase II clinical study

Vienna, 4 June 2014 ? AFFiRiS announced today the results of a phase II study in Alzheimer patients. AFFiRiS' proprietary compound AD04 is the first drug ever to demonstrate clinical and biomarker effects consistent with disease modification in Alzheimer patients. Upon treatment with AD04, effects consistent with disease modification were achieved for at least 18 months in 47 % of treated patients. This beneficial effect was dose dependent and more effective in early disease patients. Furthermore, prevention of hippocampal decline was correlated with the beneficial impact on clinical progression and was statistically significant. Therefore, these results for the very first time meet all of the criteria for disease modification as defined by US and European Regulatory Agencies FDA (Food and Drug administration) and EMA (European Medicines Agency).

AFFiRiS AG of Vienna, Austria, today released for the first time results of a clinical phase II study in Alzheimer patients of its proprietary compound AD04, a therapeutic drug against Alzheimer's disease. The results show an impressive therapeutic effect of AD04 and make it the first ever compound demonstrating clinical and biomarker evidence consistent with disease modification of Alzheimer's disease. A statistically significant correlation was demonstrated between the cognitive/functional outcome and the volume of the hippocampus, the region of the brain locating the cognitive/memory functions, both of which demonstrated positive impact on disease progression over 18 months. Similar stabilization was also seen across behavioral and quality of life outcomes.

There was also a stabilization of the cognitive/functional endpoint found in those patients of this study who were treated with AD02, so far the company's lead compound in AD. Dependent on dosage and formulation of AD02 in three different study arms, 24 ? 31 % of the patients showed cognitive/functional stabilization or improvement. However, statistically significant correlation with biomarker Hippocampus volume could not be demonstrated within the observation period of 18 months. Altogether 332 patients were treated in an international multi-centric clinical trial into five different study arms, and over 85 % completed the study.

Significant Impact
Commenting on these results Dr. Walter Schmidt, CEO and Co-founder of AFFiRiS AG, states: "Our results demonstrate that AD04 is the first drug ever to show disease modifying properties in Alzheimer's patients. This success is owed to our strategy of clinical maturation, which in the case of Alzheimer has so far moved forward four different product candidates namely AD01 ? AD04 into clinical development."

Dr. Frank Mattner, CSO and Co-founder, adds: "Both compounds applied in this trail, AD02 and AD04, showed excellent safety profiles. Top compound AD02 performed very well in stabilization of cognitive functions in a dose dependent manner. 24 ? 31 % of treated patients showed stabilization of clinical progression. However, AD04 turned out to be superior to AD02 as 47 % of the patients stabilized regarding their cognitive/ functional status. On top of this, this effect was statistically significantly correlated with the rescue of the hippocampus, the region of the human brain, where cognitive and memory functions are located (p=0.0016). This correlation of significant clinical and biomarker effects meets EMA's and FDA's definition of disease modification in the context of a compound with a consistent mode of action. Therefore, we decided to have a strong focus on AD04 for further clinical development. Our strategy of clinical maturation allows for an efficient progress during clinical development. By doing so, it reduces financial risks associated with any clinical trial." In fact, the clinical maturation strategy has been established by AFFiRiS and is based on parallel clinical testing of several drug candidates against a certain disease to ensure that the best therapy for humans will be developed.

Prof. Achim Schneeberger, Chief Medical Officer at AFFiRiS, extends: "From the beginning we were running our Alzheimer's therapy program with several drug candidates. AD04 now shows the most convincing therapeutic benefits including an effect on NPI and quality of life, which are relevant to patients and their caregivers. Because the current results are so extremely positive and consistent across clinical outcomes and brain volumes we expect to verify them in further clinical investigations."

Profitable Programs
In addition to its Alzheimer's therapy program AFFiRiS' pipeline contains product candidates against Parkinson, Atherosclerosis, Diabetes and several other conditions. Dr. Mattner comments: "AFFiRiS focuses on the development of drugs against conditions with urgent requirement for new treatments and attractive market volumes. Our Alzheimer's and our Parkinson developments are successful examples for this. Indeed AFFiRiS was the first company world-wide that started clinical testing of Parkinson drug with the potential for disease modification. Eagerly awaited results of this clinical trial will be released within the next two months."

Photographic material of the press conference is available for download immediately after the event at:

A recording of the press conference will be made available at:

Further pictures available at:

This press release contains forward-looking statements and should not be used for investment decisions.

About AFFiRiS AG (By: May 2014)
Based on its proprietary IP positions AFFiRiS develops tailor-made drugs mainly as Peptide-based vaccines. Target diseases include Alzheimer, Parkinson, Diabetes and other indications with attractive markets and unmet medical need. Alzheimer is the lead indication.

Current investors are: MIG-Fonds and Athos Service GmbH, both Munich, Germany.

AFFiRiS is located at the campus of the Vienna Biocenter, Vienna Austria and employs 95 highly qualified employees.

In Surprise, Placebo, not Aβ Vaccine, Said to Slow Alzheimer’s

06 Jun 2014

On June 4, AFFiRiS AG offered a smattering of results from its Phase 2 clinical trial of AD02, an active vaccine for Alzheimer’s disease derived from the company’s proprietary method of making synthetic antigens based on the Aβ peptide. At a press conference in Vienna, company scientists reported that among older people with early Alzheimer’s, a placebo group fared better than any other. Patients in this group reportedly had less cognitive decline over the course of 18 months, correlating with less hippocampal shrinkage. This group had been injected not with any Aβ-based antigen, but only with what the company calls an immunomodulator that was part of the AD02 formulation. Company scientists then renamed this placebo formulation AD04, and said they planned to explore options for clinical development. The therapeutic that was the object of the trial, AD02, did not work.

“We believe what we are reporting is nothing less than a breakthrough in Alzheimer’s disease therapy,” CEO and company co-founder Walter Schmidt told reporters. Several AD clinical trial researchers contacted by Alzforum were unsure what to make of this announcement. They questioned the strength of the data disclosed thus far, and urged caution unless a clear rationale for AD04 emerges.

Schmidt declined to disclose the immunomodulator’s identity but said it has been used before in different indications. “This result came as a surprise,” he said at the press conference. “We assume the immune system is being activated, but we don’t know how.”

For the Phase 2 trial of AD02, AFFiRiS enrolled 332 men and women aged 50 to 80 from 40 centers around Europe. All had early AD. In the double-blind study, three groups of patients, about 70 in each, received four monthly injections of a low or a high dose of AD02 peptide antigen, delivered in two different formulations, followed by two booster shots at nine and 15 months. Two more groups of about 50 patients each received the same number of injections of two different forms of placebo, both containing a version of the undisclosed immunomodulator that was part of the AD02 formulations. (Vaccines are typically administered with adjuvants to boost the immune response to the antigen.) Schmidt said that the two placebo formulations, which are opaque, were necessary to keep the trial blinded.

Unexpectedly, nearly half the patients in the second placebo group appeared to be protected from cognitive decline and hippocampal atrophy, the company scientists said. According to Schmidt, this outcome constituted evidence of disease modification. Researchers contacted by Alzforum noted that the correlations between hippocampal atrophy and cognition in this trial occur in the absence of treatment, and that the data hence imply no treatment effect, per se.

For the primary endpoint shown at the press conference, the researchers combined the Alzheimer's Disease Assessment Scale?Cognitive Subscale (ADAS?Cog) and Alzheimer's Disease Cooperative Study?Activities of Daily Living Inventory (ADCS-ADL) into a composite score. Typically in AD clinical trials, these batteries are analyzed and reported separately. In addition, AFFiRiS reported that some patients in this placebo group showed stable neurobehavioral patterns as determined by the Neuropsychiatric Inventory, and that caregiver quality of life was better than in the four other groups.

Outside experts were perplexed by the findings. Some pointed out that the company presented little actual data, such as sample sizes, standard errors, or dropout/completion numbers. "There is no reason why companies can't fully present their study design and protocol-specified outcomes in press conferences like this, so that outcomes can be fairly assessed,” Lon Schneider, University of Southern California, Los Angeles, wrote to Alzforum in an email. Most commentators declined to speak on the record.

Other researchers noted that if AD04 is indeed a therapeutic, then the AD02 groups should have performed as well, if not better, because AD02 contained AD04 plus the Aβ-based antigen. Could it be that AD02 counters AD04’s beneficial effects? Schmidt told Alzforum his group wondered the same thing but is unsure.

Some scientists suggested that the smaller patient numbers in the placebo groups versus the treatment groups could skew the results. Researchers commonly find that a significant number of AD patients do not progress during the time of trial observation, especially in early stages of the disease. In part because each trial features some non-progressors, the percent not progressing is not a commonly used way to show study results. It is more typical to show numeric decline on each outcome.

What about AD02 itself? This vaccine comprises a six-amino-acid affitope of Aβ’s N-terminus, meaning it mimics the primary amino acid structure of Aβ. According to AFFiRiS, the peptide fragment encourages B-cell recognition of Aβ while leaving the amyloid precursor protein alone and avoiding a pro-inflammatory T-cell response. Phase 1 data hinted that patients in the earliest stages of AD who took AD02 mounted a mild immune response and stopped declining on the Mini Mental State Examination (see Jun 2012 conference story). In the Phase 2 trial, patients on AD02 showed no statistically significant improvement over those in either placebo arm, though the safety monitoring board found all interventions to be safe and tolerable.

Patients from this study have been invited to participate in an open-label follow-up Phase 2 trial, though at the press conference, Schmidt said that the company was still deciding whether to continue that follow-up study. AFFiRiS plans to develop AD04 further, and perhaps AD02, but Schmidt said he and colleagues were still discussing how to move forward. In the future, the company would need to test AD04 against its own placebo and explore the optimum dose and injection frequency, he said.

A prior licensing agreement for AD02 has been terminated, Schmidt disclosed during the question period of the press conference. In 2008, GlaxoSmithKline had acquired rights to two AFFiRiS vaccines, according to Reuters. Click here to view the June 4 press conference. ?Gwyneth Dickey Zakaib


Kyodo News PR Wire

AsiaNet 57118

Neurim Pharmaceuticals、アルツハイマー病のアドオン薬Circadin(R)がもたらす有効性について研究成果を発表

テルアビブ(イスラエル)、 2014年5月27日/PRNewswire/ ?
Neurim Pharmaceuticalsは本日、アルツハイマー病(AD)の標準治療に用いられるアドオン薬Circadin(R)(メラトニン2mg、徐放性)の安全性と有効性を評価する、探索的第II相プラセボ対照無作為化臨床試験の結果を発表しました。「Clinical Interventions in Aging(エイジングに対する臨床的措置)」誌に掲載された本研究では、AD患者の認知能力および睡眠の質の維持について、同薬の有効性が示されています。

「内因性メラトニンレベルは、前臨床期アルツハイマー病(プレクリニカルAD)で既に減少しています。メラトニンは質の良い睡眠にとって重要であり、最近になって睡眠の質がADに関連していることが明らかになってきたので、不足しているホルモンを補完することがAD治療において有効か、そしてその補完が睡眠の改善につながるか、といった研究の意義は大きいのです。」と、Neurim Pharmaceuticalsの臨床試験担当主任Tali Nir博士は言いました。

本研究では、軽度から中等度のアルツハイマー病と診断された80人の患者(不眠症との共存ありまたはなし)が標準的な治療(メマンチンありまたはなしのアセチルコリンエステラーゼ阻害剤)を受けている状態で、24週間にわたり毎晩、無作為にCircadin(R)を2 mgまたはプラセボを二重盲検法で投与されました。それによるとCircadin(R)を6ヶ月間投与された患者は、手段的日常生活動作(IADL)とミニメンタルステート検査(MMSE)において、プラセボよりも臨床的に意義のある、より優れた認識能力を発揮したことが報告されています。なお、認知機能を評価する平均ADAS-Cog(アルツハイマー病評価尺度)ではグループ差は認められませんでした。またCircadin (R)の投与では、ピッツバーグ睡眠の質指数(PSQI)のコンポーネント4により測定される睡眠効率も改善しました。共存症として不眠症を患っている患者のサブグループでは、平均IADL(p = 0.032)、MMSE(+1.5対-3ポイント、 p=0.0177)の睡眠効率(p = 0.04)、およびADAS- Cogの中央値(-3.5対+3ポイント、p = 0.045)における対プラセボで、有意かつ臨床的に有効でした。なお、忍容性は良好でした。

「アドオン薬のCircadin (R)を6ヶ月間、軽度から中等度のAD患者に対して投与した場合の認知機能と睡眠機能に関する今回の有望なデータは、同薬の有効性と安全性を証明しており、その結果について大きな喜びを感じています。今回の研究発表は、睡眠障害と、AD発症に関係がある脳内におけるβアミロイドの蓄積との因果関係が発見されたエキサイティングな時期と重なっています。」と、Neurim Pharmaceuticals のCSO であるZisapel教授は述べ、次のように続けています。「この研究は、アルツハイマー患者の認知機能と睡眠機能の両方を治療する上で、良質な睡眠とメラトニン動作のメカニズムがいかに重要であるか、そしてAD治療におけるこのメカニズムをさらに追究すべきであるという方向性を示しています。」


Neurim Pharmaceuticalsについて:
Neurim Pharmaceuticalsは、神経科学分野の創薬・開発事業を展開し、脳の修復・補完目的の薬品を製造する製薬会社です。Circadin(R)は同社初の承認薬であり、40カ国以上で販売されています。同社の末期疾患治療向けのパイプライン製品には、小児不眠症治療薬の徐放性メラトニンのミニタブ、睡眠障害やアルツハイマー病治療薬のPiromelatineがあります。

Eran Schenker博士
電話: +972-3-768-4914

情報元: Neurim Pharmaceuticals

Neurim Pharmaceuticals Announces Publication of Positive Effects of Add-on Circadin(R) in Alzheimer’s Disease Patients


TEL-AVIV, Israel, June 19, 2014 /PRN=KYODO JBN/ ?

Neurim Pharmaceuticals announced today publication of the results from an
exploratory Phase 2 randomized placebo-controlled clinical trial evaluating the
safety and efficacy of add-on Circadin(R) (Prolonged Release melatonin 2mg) to
standard therapy in Alzheimer’s disease (AD) patients. The study, published in
the Clinical Interventions in Aging Journal, demonstrates positive effects of
the drug on cognitive performance and sleep maintenance in the AD patients.

"Endogenous melatonin levels are reduced already at preclinical AD stages.
Because melatonin is important for good sleep quality and because poor sleep
quality has recently been linked to AD, it was important to investigate whether
replenishing the missing hormone would be beneficial in AD patients and whether
such effects would be related to the improvement in sleep" said Dr Tali Nir,
head of clinical trials at Neurim Pharmaceuticals.

In this study, 80 patients diagnosed with mild-to-moderate Alzheimer’s
disease, with and without insomnia co-morbidity, receiving standard therapy
(acetylcholinesterase inhibitors with or without memantine) were randomly
assigned in a double-blind manner to 2 mg of Circadin(R) or placebo treatment
nightly for 24-weeks. The paper reports that patients treated with Circadin(R)
for 6 months had significantly better cognitive performance than those with
placebo as measured by Instrumental Activities of Daily Living (IADL) and Mini
Mental State Examination (MMSE). Mean Alzheimer’s Disease Assessment Scale
- cognition (ADAS-Cog) did not differ between groups. Sleep efficiency as
measured by Pittsburgh Sleep Quality Index (PSQI) Component 4 also improved
with Circadin(R). In a subgroup of patients suffering from comorbid insomnia,
Circadin(R) treatment resulted in significant and clinically meaningful effects
vs. placebo in mean IADL (p=0.032), MMSE (+1.5 vs. -3 points, p=0.0177) sleep
efficiency (p=0.04), and median ADAS-Cog values (-3.5 vs. +3 points, p=0.045) .
The treatment was well tolerated.

"We are very pleased with the encouraging data demonstrating efficacy and
safety of add-on Circadin(R) for 6 months on cognitive functioning and sleep in
patients with mild-moderate AD. This publication comes at an exciting time when
the causal relationship between sleep disturbance and the AD-relevant
accumulation of beta amyloid in brain was discovered," said Prof. Zisapel, CSO
of Neurim Pharmaceuticals. "This study demonstrates the significance of good
sleep quality and melatoninergic mechanisms in improving both cognition and
sleep problems in Alzheimer patients and calls for further focus of this
mechanism in AD treatment."

About Circadin:

Circadin(R) is a novel sleep medication approved by regulatory agencies
around the world for the treatment of primary insomnia in patients aged 55 and
over. Approval was based on positive effects of Circadin on sleep quality,
sleep induction, and daytime functioning without impairing cognitive

About Neurim Pharmaceuticals:

Neurim Pharmaceuticals Ltd. is a neuroscience drug discovery and
development pharma company creating drugs for brain restoration &
reinforcement. Circadin(R)-Neurim’s first approved drug, is commercially
available in over 40 countries. Neurim’s advanced-stage pipeline products
include prolonged-release melatonin minitabs for pediatric insomnia and
Piromelatine for sleep disorders and Alzheimer’s Disease.

Contact Details:
Dr. Eran Schenker

SOURCE: Neurim Pharmaceuticals


June 12, 2014
Alzheimer's & Dementia Weekly

Amlodipine is Racing to be the 1st Vascular Dementia Treatment

Amlodipine, an inexpensive drug approved for high blood pressure, could become the first ever treatment for vascular dementia. Vascular dementia is one of the most common forms of dementia. Find out how amlodipine can help.

The widely prescribed drug amlodipine has shown promising effects in people with vascular dementia, the most common type of dementia after Alzheimer's disease. The Alzheimer's Society and the British Heart Foundation (BHF) are running a major ?2.25m (U.S. $ 3.8 million) clinical trial to test the drug's effectiveness in people with the condition.

Experts based at the School of Medicine, Dentistry and Biomedical Sciences at Queen's University Belfast are testing nearly 600 people with vascular dementia in a groundbreaking two year trial into the drug's potential as a dementia treatment. The researchers, led by Professor Peter Passmore, hope to show that 10mg a day of the drug can significantly improve memory and cognitive health. As amlodipine is already licensed and known to be safe, the treatment ? which costs the NHS just ?1.07 (U.S. $ 1.80) a month ? could be in use as a treatment within five to ten years.

Vascular dementia is caused by problems with the blood supply to the brain and affects about 150,000 people in the UK. Those with heart conditions, high cholesterol and diabetes are especially at risk, and it can be triggered by a stroke. There are currently no available treatments for vascular dementia yet there are fewer ongoing clinical trials for the condition than there are for hay fever.

Amlodipine is used to treat high blood pressure, a major risk factor for vascular dementia. It is known to enter the brain and researchers think it might work by protecting brain cells from damage when blood supply to the brain is poor.
Professor Peter Passmore at the School of Medicine, Dentistry and Biomedical Sciences, and lead investigator, said:

'Vascular dementia is a very common disease and to date no major trial has been successful in developing an effective treatment for this disease. We hope, using evidence from previous research, and by trialling the drug amlodipine we may get a step closer to improving the outcomes of patients with vascular dementia in the next decade.'
Jeremy Hughes, Chief Executive at Alzheimer’s Society said:

'It is scandalous that despite affecting 150,000 people there are no effective treatments for vascular dementia and very few new treatments under investigation. This groundbreaking trial could be the best hope we have to get an effective treatment in use in the next decade.

'Developing new drugs from scratch can costs hundreds of millions and take up to twenty years but our flagship Drug Discovery programme aims to test existing drugs in people with dementia, fast-tracking the process and bringing new treatments to market faster and more cheaply.
Professor Peter Weissberg, Medical Director at the BHF said:

'The 2.3 million people living with coronary heart disease in the UK are at increased risk of developing vascular dementia. Unfortunately, as yet, there are no effective treatments for this devastating condition.

'Amlodipine is a widely prescribed, blood pressure lowering treatment that has shown some promising effects in vascular dementia. The BHF and Alzheimer's Society have joined forces to fund this definitive study. If positive, it would pave the way for an affordable treatment for vascular dementia in the near future.'

Further information
?Find out more about the clinical trial to test amlodipine as a new treatment for vascular dementia.

The Alzheimer's Society

Reprogramming of Reactive Glial Cells

June 9, 2014
Alzheimer's & Dementia Weekly

Breakthrough in Brain Repair

Penn State's Professor Chen has developed an innovative model of regenerating neurons in Alzheimer's. Learn how Dr. Chen hopes to develop this further in the years ahead. Find out how this may ultimately offer Alzheimer's patients the ability to have fresh memories after regenerating new neurons.

Researchers at Penn State University have developed an innovative technology to regenerate functional neurons after brain injury, and also in model systems used for research on Alzheimer's disease. The scientists have used supporting cells of the central nervous system, glial cells, to regenerate healthy, functional neurons, which are critical for transmitting signals in the brain.

Gong Chen, a professor of biology, the Verne M. Willaman Chair in Life Sciences at Penn State, and the leader of the research team, calls the method a breakthrough in the long journey toward brain repair. "This technology may be developed into a new therapeutic treatment for traumatic brain and spinal cord injuries, stroke, Alzheimer's disease, Parkinson's disease, and other neurological disorders," Chen said. The research is posted online in the journal Cell Stem Cell.

When the brain is harmed by injury or disease, neurons often die or degenerate, but glial cells become more branched and numerous. These "reactive glial cells" initially build a defense system to prevent bacteria and toxins from invading healthy tissues, but this process eventually forms glial scars that limit the growth of healthy neurons. "A brain-injury site is like a car-crash site," Chen explained. "Reactive glial cells are like police vehicles, ambulances, and fire trucks immediately rushing in to help -- but these rescue vehicles can cause problems if too many of them get stuck at the scene. The problem with reactive glial cells is that they often stay at the injury site, forming a glial scar and preventing neurons from growing back into the injured areas," he explained.

So several years ago, Chen's lab tested new ways to transform glial scar tissue back to normal neural tissue. "There are more reactive glial cells and fewer functional neurons in the injury site," Chen said, "so we hypothesized that we might be able to convert glial cells in the scar into functional neurons at the site of injury in the brain. This research was inspired by the Nobel prize-winning technology of induced pluripotent stem cells (iPSCs) developed in Shinya Yamanaka's group, which showed how to reprogram skin cells into stem cells," Chen recalled.

Chen and his team began by studying how reactive glial cells respond to a specific protein, NeuroD1, which is known to be important in the formation of nerve cells in the hippocampus area of adult brains. They hypothesized that expressing NeuroD1 protein into the reactive glial cells at the injury site might help to generate new neurons -- just as it does in the hippocampus. To test this hypothesis, his team infected reactive glial cells with a retrovirus that specifies the genetic code for the NeuroD1 protein. "The retrovirus we used is replication-deficient and thus cannot kill infected cells like other viruses found in the wild," Chen said. "More importantly, a retrovirus can infect only dividing cells such as reactive glial cells, but it does not affect neurons, which makes it ideal for therapeutic use with minimal side effect on normal brain functions."

In a first test, Chen and his team investigated whether reactive glial cells can be converted into functional neurons after injecting NeuroD1 retrovirus into the cortex area of adult mice. The scientists found that two types of reactive glial cells -- star-shaped astroglial cells and NG2 glial cells -- were reprogrammed into neurons within one week after being infected with the NeuroD1 retrovirus. "Interestingly, the reactive astroglial cells were reprogrammed into excitatory neurons, whereas the NG2 cells were reprogrammed into both excitatory and inhibitory neurons, making it possible to achieve an excitation-inhibition balance in the brain after reprogramming," Chen said. His lab also performed electrophysiological tests, which demonstrated that the new neurons converted by the NeuroD1 retrovirus could receive neurotransmitter signals from other nerve cells, suggesting that the newly converted neurons had successfully integrated into local neural circuits.

In a second test, Chen and his team used a transgenic-mouse model for Alzheimer's disease, and demonstrated that reactive glial cells in the mouse's diseased brain also can be converted into functional neurons. Furthermore, the team demonstrated that even in 14-month-old mice with Alzheimer's disease -- an age roughly equivalent to 60 years old for humans -- injection of the NeuroD1 retrovirus into a mouse cortex can still induce a large number of newborn neurons reprogrammed from reactive glial cells. "Therefore, the conversion technology that we have demonstrated in the brains of mice potentially may be used to regenerate functional neurons in people with Alzheimer's disease," Chen said.

To ensure that the glial cell-to-neuron conversion method is not limited to rodent animals, Chen and his team further tested the method on cultured human glial cells. "Within 3 weeks after expression of the NeuroD1 protein, we saw in the microscope that human glial cells were reinventing themselves: they changed their shape from flat sheet-like glial cells into normal-looking neurons with axon and dendritic branches," Chen said. The scientists further tested the function of these newly converted human neurons and found that, indeed, they were capable of both releasing and responding to neurotransmitters.

"Our dream is to develop this in vivo conversion method into a useful therapy to treat people suffering from neural injury or neurological disorders," Chen said. "Our passionate motivation for this research is the idea that an Alzheimer's patient, who for a long time was not able to remember things, could start to have new memories after regenerating new neurons as a result of our in vivo conversion method, and that a stroke victim who could not even move his legs might start to walk again."

Source: Penn State.

Journal Reference:
1.Ziyuan Guo, Lei Zhang, Zheng Wu, Yuchen Chen, Fan Wang, Gong Chen.

In Vivo Direct Reprogramming of Reactive Glial Cells into Functional Neurons after Brain Injury and in an Alzheimer’s Disease Model.

Cell Stem Cell, 2013; DOI: 10.1016/j.stem.2013.12.001


Conversion of reactive glial cells into functional neurons in vivo using NeuroD1
NeuroD1 induces glia-neuron conversion in an Alzheimer’s disease mouse model
NeuroD1 also reprograms NG2 cells into glutamatergic and GABAergic neurons
Human astrocytes can also be converted into glutamatergic neurons with NeuroD1


Loss of neurons after brain injury and in neurodegenerative disease is often accompanied by reactive gliosis and scarring, which are difficult to reverse with existing treatment approaches. Here, we show that reactive glial cells in the cortex of stab-injured or Alzheimer’s disease (AD) model mice can be directly reprogrammed into functional neurons in vivo using retroviral expression of a single neural transcription factor, NeuroD1. Following expression of NeuroD1, astrocytes were reprogrammed into glutamatergic neurons, while NG2 cells were reprogrammed into glutamatergic and GABAergic neurons. Cortical slice recordings revealed both spontaneous and evoked synaptic responses in NeuroD1-converted neurons, suggesting that they integrated into local neural circuits. NeuroD1 expression was also able to reprogram cultured human cortical astrocytes into functional neurons. Our studies therefore suggest that direct reprogramming of reactive glial cells into functional neurons in vivo could provide an alternative approach for repair of injured or diseased brain.

hybrid compounds of curcumin and melatonin

Chemists Blend Two Molecules Into One To Combat Alzheimer’s


Medicinal Chemistry: A hybrid of curry’s curcumin and the sleep hormone melatonin is more potent in a cellular Alzheimer’s model than each molecule alone

By Louisa Dalton
Department: Science & Technology
News Channels: Biological SCENE, Organic SCENE
Keywords: Alzheimer’s disease, curcumin, melatonin, molecular hybridization, amyloid, neuroinflammation

Chemists merged parts of curcumin and melatonin into a novel hybrid (bottom).
Credit: Shijun Zhang

Some researchers think that because many things go wrong in the neurons of patients with Alzheimer’s disease, treatments that try to fix just one are unlikely to change the course of the disease. To battle Alzheimer’s on multiple fronts, chemists propose hybridizing two compounds that show promise alone: the natural products curcumin and melatonin. The crossbred molecule shows greater potency in preventing cell death in one model of Alzheimer’s than either parent compound (ACS Chem. Neurosci. 2014, DOI: 10.1021/cn500081s).

There are several problems in the brain that researchers think lead to the development of Alzheimer’s disease, including neuroinflammation, oxidative stress in neurons, formation of amyloid-β plaques, and accumulation of tangles of tau proteins inside cells. Shijun Zhang of Virginia Commonwealth University and his group turned to molecular hybridization to find compounds that targeted as many of these problems as possible.
They started with two natural products shown to be neuroprotective in previous studies. Curcumin, one of the compounds responsible for the yellow color of the spice turmeric, lowers amyloid-β levels in the brain, decreases neuroinflammation, and quenches free radicals. The sleep hormone melatonin regulates circadian rhythms and has some anti-inflammatory and antioxidant properties. Some studies have reported that melatonin improves sleep and lowers the evening irritability often seen in patients with Alzheimer’s.

When Zhang examined the structures of curcumin and melatonin, he instantly saw that he could hybridize them using a carbonyl found in both compounds. His group synthesized a hybrid molecule that sports a novel β-ketone amide that replaces the β-diketone in curcumin and the acetamide in melatonin.
The researchers tested the hybrid on human neuroblastoma cells genetically tweaked to produce high levels of amyloid-β peptides and eventually die. They found that their compound prevented cell death at concentrations that were 1% of those needed for curcumin or melatonin alone or together.

The mechanism behind the hybrid’s effectiveness is unknown, Zhang says, but early tests suggest it scavenges free radicals in the cells’ mitochondria. The group’s latest version of the hybrid can cross the blood-brain barrier in mice. Now they are testing the compound in mouse models for Alzheimer’s.
Creating a molecule that targets different aspects of the disease is an intriguing alternative to drug cocktails, says Sally A. Frautschy of the University of California, Los Angeles. Yet the hybrid will require rigorous testing in other cellular and animal models of Alzheimer’s disease, she says. Gregory M. Cole, also at UCLA, agrees more testing is needed, in particular to determine if beneficial properties of the two parent molecules were lost in the hybrid.

Chemical & Engineering News
ISSN 0009-2347
Copyright ? 2014 American Chemical Society

Discovery of 5-(4-Hydroxyphenyl)-3-oxo-pentanoic Acid [2-(5-Methoxy-1H-indol-3-yl)-ethyl]-amide as a Neuroprotectant for Alzheimer’s Disease by Hybridization of Curcumin and Melatonin

In our effort to develop effective neuroprotectants as potential treatments for Alzheimer’s disease (AD), hybrid compounds of curcumin and melatonin, two natural products that have been extensively studied in various AD models, were designed, synthesized, and biologically characterized. A lead hybrid compound (7) was discovered to show significant neuroprotection with nanomolar potency (EC50 = 27.60 ± 9.4 nM) in MC65 cells, a cellular AD model. Multiple in vitro assay results established that 7 exhibited moderate inhibitory effects on the production of amyloid-β oligomers (AβOs) in MC65 cells, but not on the aggregation of Aβ species. It also exhibited significant antioxidative properties. Further mechanistic studies demonstrated that 7’s antioxidant effects correlate well with its neuroprotective potency for MC65 cells, and these effects might be due to its interference with the interactions of AβOs within the mitochondria of MC65 cells. Furthermore, 7 was confirmed to cross the blood-brain barrier (BBB) and deliver a sufficient amount to brain tissue after oral administration. Collectively, these results strongly support the hybridization approach as an efficient strategy to help identify novel scaffolds with a desired pharmacology, and strongly encourage further optimization of 7 to develop more potent neuroprotectants for AD.


Researchers Find Compound that can Slow Down Alzheimer's Disease Progression

By Staff Reporter

Jun 03, 2014 02:46 AM EDT
Researchers have found that a compound, 2-PMAP, halves the level of amyloid protein, which are associated with Alzheimer's disease. The study was conducted on animal models, but scientists are hopeful that the compound could be used to slow down or delay Alzheimer's disease progression in humans too.

Alzheimer's disease is a common form of dementia, affecting older people. People with AD have problems performing everyday tasks. Around five million people in the U.S. have AD

The study was conducted by researchers at the NYU Langone Medical Center. According to scientists, 2-PMAP is non-toxic in mice and lowers the levels of amyloid protein.

Previous research has shown that amyloid beta protein forms plaques in the brain, causing thinking and memory problems.

"What we want in an Alzheimer's preventive is a drug that modestly lowers amyloid beta and is also safe for long term use," said lead author of the study Martin J. Sadowski, MD, PhD., associate professor of neurology, psychiatry, and biochemistry and molecular pharmacology.

"Statin drugs that lower cholesterol appear to have those properties and have made a big impact in preventing coronary artery disease. That's essentially what many of us envision for the future of Alzheimer's medicine," Sadowski added, according to a press release.

Some people, such as a group in Iceland, carry a mutation that slows down the accumulation of amyloid beta protein in the brain. These people have a lower risk of developing Alzheimer's disease later in life.

Dr Sadowski and colleagues sifted through various compounds to find one that could lower the level of the protein in the brain. The new compound reduces the levels of amyloid precursor protein (APP) in the brain.

Researchers conducted test on cell lines as well as mice models. They found that even at low concentrations, the compound lowered APP levels. The mice used in the study were genetically engineered and had a mutation that gave them the hereditary form of the Alzheimer's disease.

According to the researchers, the compound easily crosses from the bloodstream into the brain, meaning that it doesn't require complex medication that might lower its effects.

Additionally, the compound is highly selective and so acts only on amyloid proteins and doesn't interfere with other brain chemicals.

The study is published in the journal Annals of Neurology.

Modulation of amyloid precursor protein expression reduces β-amyloid deposition in a mouse model

Ayodeji A. Asuni PhD1,
Maitea Guridi MSc1,
Joanna E. Pankiewicz MD, PhD1,2,
Sandrine Sanchez PhD1 and
Martin J. Sadowski MD, PhD1,2,3,*

Article first published online: 28 APR 2014

DOI: 10.1002/ana.24149


Proteolytic cleavage of the amyloid precursor protein (APP) generates β-amyloid (Aβ) peptides. Prolonged accumulation of Aβ in the brain underlies the pathogenesis of Alzheimer disease (AD) and is regarded as a principal target for development of disease-modifying therapeutics.


Using Chinese hamster ovary (CHO) APP751SW cells, we identified and characterized effects of 2-([pyridine-2-ylmethyl]-amino)-phenol (2-PMAP) on APP steady-state level and Aβ production. Outcomes of 2-PMAP treatment on Aβ accumulation and associated memory deficit were studied in APPSW/PS1dE9 AD transgenic model mice.


In CHO APP751SW cells, 2-PMAP lowered the steady-state APP level and inhibited Aβx-40 and Aβx-42 production in a dose?response manner with a minimum effective concentration???0.5μM. The inhibitory effect of 2-PMAP on translational efficiency of APP mRNA into protein was directly confirmed using a 35S-methionine/cysteine metabolic labeling technique, whereas APP mRNA level remained unaltered. Administration of 2-PMAP to APPSW/PS1dE9 mice reduced brain levels of full-length APP and its C-terminal fragments and lowered levels of soluble Aβx-40 and Aβx-42. Four-month chronic treatment of APPSW/PS1dE9 mice revealed no observable toxicity and improved animals' memory performance. 2-PMAP treatment also caused significant reduction in brain Aβ deposition determined by both unbiased quantification of Aβ plaque load and biochemical analysis of formic acid?extracted Aβx-40 and Aβx-42 levels and the level of oligomeric Aβ.


We demonstrate the potential of modulating APP steady-state expression level as a safe and effective approach for reducing Aβ deposition in AD transgenic model mice. Ann Neurol 2014

transthyretin (TTR)

Liver protein could protect against Alzheimer’s

24 May 2014

A PROTEIN found in the liver may protect against Alzheimer’s disease by stopping the build-up of plaque, a new study found.

The protein, which tends to form harmful aggregates when it is produced in the liver, appears to protect against Alzheimer’s disease when it is produced in the brain.

Groups, or aggregates, of amyloid beta proteins develop in the brains of people with Alzheimer’s disease. These form “amyloid plaques” which are thought to contribute to the nerve cell death that causes Alzheimer’s symptoms.

Professor Joel Buxbaum of The Scripps Research Institute in Florida said: “This result was completely unexpected when we started this research.

“But now we realise that it could indicate a new approach for Alzheimer’s prevention and therapy.”

The finding published in the Journal of Neuroscience focused on transthyretin (TTR), a protein known to function as a transporter, carrying the thyroid hormone thyroxine and vitamin A through the bloodstream and cerebrospinal fluid.

To do this it must come together in a four sub-unit structure called a tetramer.

Certain factors such as old age and TTR gene mutations can make these tetramers prone to fall apart and misfold into tough aggregates called amyloids.

TTR amyloids accumulate in the heart, kidneys, peripheral nerves and other tissues and cause life-shortening diseases including familial amyloid polyneuropathy and senile systemic (cardiac) amyloidosis.

Dr Buxbaum built on previous research that hinted that TTR in the brain might protect against other amyloids ? particularly the Alzheimer’s associated protein amyloid beta.

Lab experiments showed TTR seemed able to grab hold of amyloid beta and prevent it from aggregating. Mice overproduced amyloid beta and TTR expression was increased in affected brain tissue providing a protective affect.

Scientists analysed a segment of DNA near the TTR gene called the promoter region, where special DNA-binding proteins called transcription factors could increase TTR gene activity.

The analysis suggested that Heat Shock Factor 1 (HSF1), known as a master switch for a broad protective response against certain types of cellular stress, could bind to the TTR gene’s promoter.

Researchers found that in liver cells the HSF1 response somehow brought about a modest decrease in TTR production.

In liver cells TTR activity rose when HSF1 was blocked, suggesting that HSF1 helps keep a lid on liver TTR production.

Dr Buxbaum added: “It’s becoming evident that the same molecule can do very different things in different contexts.”

The next stage is to develop a small molecule compound, suitable for delivery in a pill, that at least modestly boosts HSF1 activity and/or TTR production in neurons ? and thus might prevent or delay Alzheimer’s dementia

The Systemic Amyloid Precursor Transthyretin (TTR) Behaves as a Neuronal Stress Protein Regulated by HSF1 in SH-SY5Y Human Neuroblastoma Cells and APP23 Alzheimer's Disease Model Mice

Xin Wang1,
Francesca Cattaneo1,2,
Lisa Ryno1,
John Hulleman1,
Nat?lia Reixach1, and
Joel N. Buxbaum1

The Journal of Neuroscience, 21 May 2014, 34(21): 7253-7265; doi: 10.1523/JNEUROSCI.4936-13.2014


Increased neuronal synthesis of transthyretin (TTR) may favorably impact on Alzheimer's disease (AD) because TTR has been shown to inhibit Aβ aggregation and detoxify cell-damaging conformers. The mechanism whereby hippocampal and cortical neurons from AD patients and APP23 AD model mice produce more TTR is unknown. We now show that TTR expression in SH-SY5Y human neuroblastoma cells, primary hippocampal neurons and the hippocampus of APP23 mice, is significantly enhanced by heat shock factor 1 (HSF1). Chromatin immunoprecipitation (ChIP) assays demonstrated occupation of TTR promoter heat shock elements by HSF1 in APP23 hippocampi, primary murine hippocampal neurons, and SH-SY5Y cells, but not in mouse liver, cultured human hepatoma (HepG2) cells, or AC16 cultured human cardiomyocytes. Treating SH-SY5Y human neuroblastoma cells with heat shock or the HSF1 stimulator celastrol increased TTR transcription in parallel with that of HSP40, HSP70, and HSP90. With both treatments, ChIP showed increased occupancy of heat shock elements in the TTR promoter by HSF1. In vivo celastrol increased the HSF1 ChIP signal in hippocampus but not in liver. Transfection of a human HSF1 construct into SH-SY5Y cells increased TTR transcription and protein production, which could be blocked by shHSF1 antisense. The effect is neuron specific. In cultured HepG2 cells, HSF1 was either suppressive or had no effect on TTR expression confirming the differential effects of HSF1 on TTR transcription in different cell types.


FDA Clears Kick Off of Phase 3 Alzheimer's Disease Study

Fri, 05/23/2014

Get today's drug discovery & development headlines and news - Sign up now!

AZTherapies Inc., a company developing novel treatments for Alzheimer's disease based on technology licensed from Massachusetts General Hospital, announced that it has received notice from FDA that it may proceed with the Phase 3 clinical study submitted in its IND application. This study is for its lead program, ALZT-OP1, a novel combination therapy for the prevention and treatment of early Alzheimer's disease.

ALZT-OP1 is a multifunctional drug therapy consisting of the administration of two previously approved drugs that act on important mechanisms relevant to Alzheimer's disease, with a new formulation and targeted delivery to ensure blood and brain concentrations necessary to achieve their actions. Drug A inhibits beta-amyloid peptide polymerization, and drug B inhibits the neuro-inflammatory response in patients with amnestic mild cognitive impairment (aMCI) due to suspected Alzheimer's disease (AD). These two drugs, which have excellent safety and tolerability profiles, are being repurposed using novel technology licensed from MGH and further developed in the company, to slow cognitive loss or prevent the onset of dementia due to AD.

"Confronting two triggering causes associated with Alzheimer's disease progression simultaneously provides a new multifunctional treatment approach for modifying disease progression. Very early intervention, in subjects with the earliest clinical signs of dementia due to AD, will be key in preventing and/or delaying the onset of dementia," said company founder, Dr. David Elmaleh, "The in-vitro and in-vivo data support the potential for halting disease onset and progression."
"Alzheimer's disease modifying treatments should affect the underlying pathophysiology of the disease and add additional value to the benefits of the presently approved drugs. I am optimistic about AZTherapies' multi-functional treatment approach which, if successful, could have a long-term beneficial effect on the course of AD progression," commented Dr. Rachelle Doody, Cain Professor of Neurology, Baylor College of Medicine and a recognized key opinion leader (KOL) in the field of Alzheimer's research. Doody was a principal investigator in studies that led to the approval of Aricept and Namenda, two currently FDA-approved drug treatments for improving Alzheimer's disease symptoms.

"The company technology includes intellectual property protecting the drug combination, dosing, formulation and drug properties that will deliver the drug to both blood and brain through inhalation," said Dr. Peter Conti, a professor of radiology, Biomedical Engineering and Pharmaceutical Sciences at the University of Southern California and a member of the Board of Directors at AZTherapies. Conti is an expert in the field of neuroimaging and positron emission tomography, and has been involved in the early use of Alzheimer's diagnostics, such as F-18 Florbetapir, the amyloid-imaging tracer developed by Avid.

"AZTherapies intends to request a Special Protocol Assessment (SPA) from FDA and expects to reach an agreement on the design and size of a clinical trial in support of a 505(b)(2) NDA for the treatment of early Alzheimer's disease (AD)," said Brenda Fielding, vice president of Regulatory Affairs, Clinipace Worldwide.

The company reported that preparations are currently underway to initiate the study, "A Phase 3 Safety and Efficacy Study of ALZT-OP1 in Subjects with Evidence of Amnestic Mild Cognitive Impairment due to Suspected Alzheimer's Disease" by the fourth quarter of this year (Q4-2014). This Phase 3 study is expected to be conducted in upwards of 10 countries around the world, including the US.

Alzheimer's Disease is an irreversible neurodegenerative disease, its onset and progression are associated with cognitive and functional decline causing a gradual daily life activity impairment, psychotic disturbances, and becomes fatal at its advanced stages. It currently ranks as the 6th leading cause of death in the United States and remains an unmet medical need. Despite numerous recent advances, Alzheimer's disease continues to pose a challenge for both diagnostic and treatment strategies. An estimated 5.2 million Americans have Alzheimer's disease in 2014, including 200,000 individuals younger than age 65 who have younger-onset Alzheimer's. It is estimated that by 2050, Alzheimer's disease will triple and yearly escalation cost to top one trillion dollars.

Date: May 23, 2014
Source: AZTherapies

antisense oligonucleotide (OL-1)

May 20, 2014

Compound reverses symptoms of Alzheimer's disease in mice, research shows

A molecular compound developed by Saint Louis University scientists restored learning, memory and appropriate behavior in a mouse model of Alzheimer's disease, according to findings in the May issue of the Journal of Alzheimer's Disease. The molecule also reduced inflammation in the part of the brain responsible for learning and memory.

The paper, authored by a team of scientists led by Susan Farr, Ph.D., research professor of geriatrics at Saint Louis University, is the second mouse study that supports the potential therapeutic value of an antisense compound in treating Alzheimer's disease in humans.

"It reversed learning and memory deficits and brain inflammation in mice that are genetically engineered to model Alzheimer's disease," Farr said.

"Our current findings suggest that the compound, which is called antisense oligonucleotide (OL-1), is a potential treatment for Alzheimer's disease."

Farr cautioned that the experiment was conducted in a mouse model. Like any drug, before an antisense compound could be tested in human clinical trials, toxicity tests need to be completed.

Antisense is a strand of molecules that bind to messenger RNA, launching a cascade of cellular events that turns off a certain gene.

In this case, OL-1 blocks the translation of RNA, which triggers a process that keeps excess amyloid beta protein from being produced. The specific antisense significantly decreased the overexpression of a substance called amyloid beta protein precursor, which normalized the amount of amyloid beta protein in the body. Excess amyloid beta protein is believed to be partially responsible for the formation of plaque in the brain of patients who have Alzheimer's disease.

Scientists tested OL-1 in a type of mouse that overexpresses a mutant form of the human amyloid beta precursor gene. Previously they had tested the substance in a mouse model that has a natural mutation causing it to overproduce mouse amyloid beta. Like people who have Alzheimer's disease, both types of mice have age-related impairments in learning and memory, elevated levels of amyloid beta protein that stay in the brain and increased inflammation and oxidative damage to the hippocampus ? the part of the brain responsible for learning and memory.

"To be effective in humans, OL-1 would need to be effective at suppressing production of human amyloid beta protein," Farr said.

Scientists compared the mice that were genetically engineered to overproduce human amyloid beta protein with a wild strain, which served as the control. All of the wild strain received random antisense, while about half of the genetically engineered mice received random antisense and half received OL-1.

The mice were given a series of tests designed to measure memory, learning and appropriate behavior, such as going through a maze, exploring an unfamiliar location and recognizing an object.

Scientists found that learning and memory improved in the genetically engineered mice that received OL-1 compared to the genetically engineered mice that received random antisense. Learning and memory were the same among genetically engineered mice that received OL-1 and wild mice that received random antisense.

They also tested the effect of administering the drug through the central nervous system, so it crossed the blood brain barrier to enter the brain directly, and of giving it through a vein in the tail, so it circulated through the bloodstream in the body.

They found where the drug was injected had little effect on learning and memory.

"Our findings reinforced the importance of amyloid beta protein in the Alzheimer's disease process. They suggest that an antisense that targets the precursor to amyloid beta protein is a potential therapy to explore to reversing symptoms of Alzheimer's disease," Farr said.

Explore further: Modified stem cells offer potential pathway to treat Alzheimer's disease

More information: Central and Peripheral Administration of Antisense Oligonucleotide Targeting Amyloid-β Protein Precursor Improves Learning and Memory and Reduces Neuroinflammatory Cytokines in Tg2576 (AβPPswe) Mice, Susan A. Farr, Michelle A. Erickson, Michael L. Niehoff, William A. Banks, John E. Morley. Journal of Alzheimer's Disease 40(4). DOI: 10.3233/JAD-131883

Journal reference: Journal of Alzheimer's Disease search and more info website

Provided by Saint Louis University search and more info website

Pages 1005-1016
Susan A. Farr, Michelle A. Erickson, Michael L. Niehoff, William A. Banks, John E. Morley
Central and Peripheral Administration of Antisense Oligonucleotide Targeting Amyloid-β Protein Precursor Improves Learning and Memory and Reduces Neuroinflammatory Cytokines in Tg2576 (AβPPswe) Mice
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Currently, there are no therapies to stop or reverse the symptoms of AD. We have developed an antisense oligonucleotide (OL-1) against the amyloid-β protein precursor (AβPP) that can decrease AβPP expression and amyloid-β protein (Aβ) production. This antisense rapidly crosses the blood-brain barrier, reverses learning and memory impairments, reduces oxidative stress, and restores brain-to-blood efflux of Aβ in SAMP8 mice. Here, we examined the effects of this AβPP antisense in the Tg2576 mouse model of AD. We administered the OL-1 antisense into the lateral ventricle 3 times at 2week intervals. Seventy-two hours after the third injection, we tested learning and memory in T-maze foot shock avoidance. In the second study, we injected the mice with OL-1 antisense 3 times at 2-week intervals via the tail vein. Seventy-two hours later, we tested learning and memory T-maze, novel object recognition, and elevated plus maze. At the end of behavioral testing, brain tissue was collected. OL-1 antisense administered centrally improved acquisition and retention of T-maze foot shock avoidance. OL-1 antisense administered via tail vein improved learning and memory in both T-maze foot shock avoidance and novel object-place recognition. In the elevated plus maze, the mice which received OL-1 antisense spent less time in the open arms and had fewer entries into the open arms indicating reduced disinhibitation. Biochemical analyses reveal significant reduction of AβPP signal and a reduction of measures of neuroinflammation. The current findings support the therapeutic potential of OL-1 AβPP antisense.

Holistic exercise

May 19, 2014

Study shows dementia patients benefit from holistic exercise program

While dementia patients can often suffer from depression and declining physical and mental ability, exercise has been shown to help improve both their physical and psychological wellbeing. Researchers at Teesside University in the U.K. investigated how combining cognitive activities and elements of yoga, tai chi, qigong and meditation with routine physical exercise affected dementia patients. They found that a holistic exercise program focusing on both mind and body can help improve quality of life for dementia patients. Their findings are published in the Journal of Bodywork and Movement Therapies.

For this study, conducted in association with the Alzheimer's Society (UK), researchers developed the Happy Antics program, a holistic exercise plan that integrates physical movements with activities designed to take the emotional, intellectual, social, and spiritual health of patients into consideration. Each Happy Antics session started with a short cognitive exercise during which participants were shown a picture of an object while the instructor spoke briefly about it. Then patients were encouraged to discuss the object and ask questions. This activity was followed by warm-up exercises and then physical exercise incorporating principals of tai chi, yoga, qigong, and dance movements. Each session ended with a short, guided meditation activity that focused on breathing and mindful awareness.

Fifteen participants ranging from 52 to 86 years old attended the program: eight dementia patients, five care-givers, and two volunteers. The overall attendance rate for six sessions was 70%, and all participants reported having enjoyed taking part in the holistic exercise sessions, looked forward to attending them, and felt like the sessions helped them socially. Some patients also said they felt more relaxed after the sessions and experienced some degree of pain relief. Other patients found learning to do the new exercises "empowering," even though sometimes they faced physical difficulty performing the tasks.

"When the wellness approach is applied to exercise, holistic exercise strives to encourage individuals not only to take part in the physical activities, but also to become aware of their own physical and psychological states, and to perform exercise that is purposeful and meaningful to them," explained lead investigator Yvonne J-Lyn Khoo, BSc (Hons), MSc, PhD, of the Health and Social Care Institute, Teesside University.

The holistic mind-and-body approach proved to be both enjoyable and helpful for patients suffering from dementia. Not only did they like the sessions, but also showed improvement in memory recall in their anticipation of the physical movements associated with the music.

"Observations at the sixth session showed that even though people with dementia could not remember what had occurred during previous sessions, six people with dementia who participated in the holistic exercise sessions could anticipate the physical movements associated with specific music and three people with dementia were able to remember the sequence of the physical movements," said Dr. Khoo. "This showed potential in maintained procedural memory among people with dementia who attended the holistic exercise sessions."

The Happy Antics program included participation by care-givers. While the program helped dementia patients, it also had positive effects on the other participants, with one care-giver reporting less pain after attending the sessions. This particular finding of pain relief after participating in holistic exercise is an important one given the unique complexity of chronic pain. "This suggests that participating in holistic exercise may offer some relief in burden for care-givers as they face many challenges in providing care for patients with dementia, including physical and psychological distress," added Dr. Khoo.

Dementia is a complex and debilitating condition, but with holistic exercise programs like Happy Antics, patients experienced some relief, joy, and lasting positive effects. "The Happy Antics program was able to stimulate and engage people with dementia in exercise as well as provide a social learning environment and offer potential psychological benefits," concluded Dr. Khoo.

Explore further: Study: Intensive exercise training program for dementia patients improves care in clinical setting

More information: "The Happy Antics Programme: Holistic Exercise for People with Dementia," by Yvonne J-Lyn Khoo, BSc (Hons), MSc, PhD; Paul van Schaik, UCAPD, BSc, MSc, PhD; Jackie McKenna, DOI: dx.doi.org/10.1016/j.jbmt.2014.02.008 . It appears online ahead of the Journal of Bodywork and Movement Therapies, Volume 18, Issue 3 (July 2014)

Provided by Elsevier search and more info

The Happy Antics programme: Holistic exercise for people with dementia

Yvonne J-Lyn Khoo, BSc (Hons), MSc, PhD

Corresponding Author Information
email address
, Paul van Schaik, UCAPD, BSc, MSc, PhD

, Jackie McKenna

Received 23 January 2014; received in revised form 8 February 2014; accepted 19 February 2014. published online 25 April 2014.
Corrected Proof


Holistic exercise for people with dementia could have psychological and physical benefits, but there is a lack of research on the experience of this type of exercise. Therefore, the objective of this study was to determine the feasibility and acceptance of holistic exercise among people with dementia.
A holistic exercise programme for people with dementia was designed and implemented. Semi-structured interviews were undertaken to explore participants' experience of holistic exercise, transcribed verbatim and analyzed.
Seven themes were generated from the data. They were enjoyment, relaxation, keeping active, social interaction, pain relief, learning something new and intention to continue, respectively.
The results of the current small-scale study provide evidence for the feasibility and acceptance of holistic exercise for people with dementia. In addition, participants appeared to benefit in terms of psychological and physical wellbeing.

tubulin treatment

Israeli discovery could reverse Alzheimer’s damage

TAU professor has uncovered a protein that may protect brain cells from harm by dementia-based diseases

By David Shamah May 18, 2014, 3:29 pm 19
The Times of Israel

Research by a Tel Aviv University team may point the way to protecting cells from the damage wrought by Alzheimer’s disease, and even reverse damage that the disease caused before treatment. The method involves a protein similar to one which protects the brain from damage, but which is lacking in Alzheimer’s patients.

What causes Alzheimer’s is still a mystery, but the direct physical conditions leading to the dementia associated with the disease are very clear to scientists. Plaque accumulations and tangles in neurons kill brain cells in Alzheimer’s sufferers, leading to the degeneration of cognitive function and the loss of memory associated with the disease.

One of the most important objectives of Alzheimer’s research has been to figure out ways to protect brain cells from these senile plaques and neurofibrillary tangles. In a study published in the May edition of the Journal of Alzheimer’s Disease, Tel Aviv University Prof. Illana Gozes describes how NAP, a snippet of a protein essential for brain formation, has been proven in previous studies to protect cognitive functioning. Loss of NAP exposes cells to physical damage that eventually destroys them, but applying proteins with NAP-like properties makes them healthy again.

It’s just such a protein that Gozes and her team have discovered. The research, she said, could eventually lead to development of drugs to treat Alzheimer’s.

Gozes holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and is director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of Tel Aviv University’s Sagol School of Neuroscience. “Several years ago we discovered that NAP showed efficacy in Phase 2 clinical trials in mild cognitive impairment patients, a precursor to Alzheimer’s,” she said. “Now, we’re investigating whether there are other novel NAP-like sequences in other proteins.”

NAP, also known as davunetide, is an eight-amino acid peptide that has been shown to provide potent neuroprotection in several human trials. NAP is derived from activity-dependent neuroprotective protein (ADNP), a molecule that is essential for brain formation.

“NAP operates through the stabilization of microtubules ? tubes within the cell which maintain cellular shape. They serve as ‘train tracks’ for movement of biological material,” said Gozes. “In Alzheimer’s disease, these microtubules break down. The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell.”

In the study, Gozes and her team examined the tubulin (a subunit of the microtubule) and the protein TAU (tubulin-associated unit), important for assembly and maintenance of the microtubule. Abnormal TAU proteins form the tangles that contribute to Alzheimer’s. The larger the tangles, the more cognitive function is damaged.

In tests on mice suffering from dementia-like characteristics which found the abnormal TAU proteins, a tubulin fragment with NAP-like sequences was applied to cells with very promising results, Gozes said. As NAP “evaporated,” the brain cells were less protected and deteriorated. The tubulin treatment reversed the damage. “We looked at the mouse ‘dementia’-afflicted brain and saw there was a reduction in the NAP parent protein, but upon treatment with the tubulin fragment, the protein was restored to normal levels,” she said. In addition, the treatment restored the size of mice brains, which had shrunk due to the disease.

Further tests are set to be conducted on more animal cohorts. Eventually, an effective treatment for Alzheimer’s and other dementia-related diseases could come of this research, Gozes believes. “We clearly see here the protective effect of the treatment,” she said. “We witnessed the restorative and protective effects of totally new protein fragments, derived from proteins critical to cell function, in tissue cultures and on animal models.” Further work is needed, she said, but the team’s research could one day turn into a treatment to alleviate, or even reverse, Alzheimer’s disease.

Illana Gozes, Tal Iram, Evgenia Maryanovsky, Carmit Arviv, Liora Rozenberg, Yulie Schirer, Eliezer Giladi, Sharon Furman-Assaf

Novel Tubulin and Tau Neuroprotective Fragments Sharing Structural Similarities with the Drug Candidate NAP (Davuentide)

Abstract: NAP (NAPVSIPQ, davunetide) is a microtubule stabilizing peptide drug candidate. Here, we set out to identify NAP-like peptides that provide neuroprotection and reduce tau pathology. NAP-like peptides were derived using publically available search engines, which identified sequence homologies in the microtubule subunit tubulin and in the microtubule associated protein, tau. NATLSIHQ (NAT) and STPTAIPQ were derived from tubulin, and TAPVPMPD (TAP) was derived from tau. All peptides provided neuroprotection against the Alzheimer’s disease (AD) toxin, the amyloid-β 1-42 peptide, although NAT and TAP were much more potent than STPTAIPQ. NAT also protected astrocytes, while STPTAIPQ was active only at micromolar concentrations. Because NAT and TAP were much more potent than STPTAIPQ in neuroprotection, those peptides were also tested for inhibition of tau-like aggregation (the second protein hallmark pathology of AD). Both NAT and TAP inhibited tau-like aggregation, with NAT being active over a very broad concentration range. NAT also protected in vivo in a frontotemporal dementia transgenic mouse model (Tau-Tg), when tested at the age of ~10 months. Results showed significantly decreased levels of the NAP parent protein, activity-dependent neuroprotective protein in the cerebral cortex of the Tau-Tg which was increased back to normal levels by NAT treatment. This was coupled to protection of Brain-Body weight ratio in the compromised Tau-Tg. With AD being the major tauopathy and with tau taking part in frontotemporal dementia, novel NAP derivatives that reduce tauopathy and provide neuroprotection are of basic and clinical interest.


Antidepressant May Cut Alzheimer's Protein

May 15th 2014

Research shows a common antidepressant may cut production of one of the chief suspects behind Alzheimer's, a new avenue in the hunt for drugs to prevent the devastating brain disease.

It's far too early for anyone worried about dementia to try the drug citalopram, which sells as the brand Celexa ? and comes with side effects.

"This is not the great new hope. This is a small step," cautioned Dr. Yvette Sheline of the University of Pennsylvania, who is leading the research with Dr. John Cirrito of Washington University in St. Louis.

Alzheimer's is characterized by sticky plaques that form in patients' brains 10 to 15 years before the first memory symptoms are noticed. Scientists have tried treatments to clear away those plaques, made of a protein named beta-amyloid that somehow goes awry and starts clumping together, but with no success yet.

Wednesday's study is a somewhat different approach, beginning to explore if it's possible to slow the plaque from building up by altering the body's production of amyloid.

First, researchers gave citalopram to older mice with Alzheimer's-like brain damage. The animals' existing plaques didn't go away but they quit growing ? and dramatically fewer new plaques formed compared to mice given sugar water, the research team reported in the journal Science Translational Medicine.

Next, researchers gave a single dose of citalopram or a placebo to 23 healthy young adults, people who neither were depressed nor old enough to have brain plaques. Tests of the volunteers' spinal fluid over the next day and a half showed their normal amyloid production dropped by 37 percent, the researchers reported.

It will take years of additional research to tell if that translates into any protective effect. Citalopram and similar drugs called SSRIs alleviate depression by affecting levels of the brain chemical serotonin; Sheline said citalopram probably alters amyloid production in a completely different way.

In fact, the next question is whether it's even possible to tamp amyloid production down for long periods or if the body would just get used to the drug and adjust. Sheline has begun enrolling healthy older adults into a study to see if using citalopram for two weeks has the same effect.

-The Associated Press

Sci Transl Med 14 May 2014:
Vol. 6, Issue 236, p. 236re4
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3008169


An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

Yvette I. Sheline1,*,
Tim West2,
Kevin Yarasheski3,
Robert Swarm4,
Mateusz S. Jasielec5,
Jonathan R. Fisher6,
Whitney D. Ficker6,
Ping Yan6,
Chengjie Xiong5,7,
Christine Frederiksen8,
Monica V. Grzelak6,
Robert Chott3,
Randall J. Bateman6,7,9,
John C. Morris6,7,
Mark A. Mintun10,
Jin-Moo Lee6,7,9 and
John R. Cirrito6,7,9

Author Affiliations
1Departments of Psychiatry, Radiology, and Neurology, University of Pennsylvania, Philadelphia , PA 19104, USA.
2C2N Diagnostics LLC, St. Louis, MO 63110, USA.
3Department of Medicine, Washington University, St. Louis, MO 63110, USA.
4Department of Anesthesiology, Washington University, St. Louis, MO 63110, USA.
5Department of Biostatistics, Washington University, St. Louis, MO 63110, USA.
6Department of Neurology, Washington University, St. Louis, MO 63110, USA.
7Knight Alzheimer’s Disease Research Center, Washington University Medical Center, St. Louis, MO 63110, USA.
8Department of Surgery, Washington University, St. Louis, MO 63110, USA.
9Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.
10Avid Radiopharmaceuticals and Eli Lilly Inc., Philadelphia, PA 19104, USA.
?*Corresponding author. E-mail: sheline@mail.med.upenn.edu


Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased Aβ in brain interstitial fluid in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of preexisting plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.
Copyright ? 2014, American Association for the Advancement of Science

Citation: Y. I. Sheline, T. West, K. Yarasheski, R. Swarm, M. S. Jasielec, J. R. Fisher, W. D. Ficker, P. Yan, C. Xiong, C. Frederiksen, M. V. Grzelak, R. Chott, R. J. Bateman, J. C. Morris, M. A. Mintun, J-M. Lee, J. R. Cirrito, An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice. Sci. Transl. Med. 6, 236re4 (2014).

Young blood

Young blood: Stanford researchers hope plasma injections from the young rejuvenate Alzheimer's patients

Ron LeutyReporter-
San Francisco Business Times
May 4, 2014, 10:00am PDT

What if a few shots of a young person's plasma could halt Alzheimer’s disease in an older person?

How beautifully simple. After all, hospitals and clinics for decades have infused hemophiliacs, patients with immune system disorders or those with traumatic injuries with the yellowish liquid spun out of fresh blood and made up of water, hundreds of proteins, hormones, clotting factors and the like.

The Stanford University lab of Tony Wyss-Coray, a professor of neurology and neurological sciences, is pursuing fresh evidence that the plasma of young people may carry factors that disappear as we age and make us susceptible to Alzheimer’s and other conditions. Giving that "young" plasma to older patients may transport those factors, Wyss-Coray said, and rejuvenate the brains of Alzheimer's patients.

Results of a study of mice by Wyss-Coray’s lab were published online Sunday in the journal Nature Medicine. It is important because most previous research has focused on the impact that these plasma infusions have had on the regeneration of muscle and other tissue; Wyss-Coray’s lab not only looked at the physical changes in the brains of old mice given blood from young mice but how their behavior changed.

The study was funded by the U.S. Department of Veteran Affairs, the National Institute of Aging and California’s stem cell research funding agency, the California Institute for Regenerative Medicine.

It’s just this sort of research that surely pointed Google Inc. last year toward forming Calico, its aging research venture headed by former Genentech CEO Art Levinson.

Nature Medicine | Letter

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice

Saul A Villeda,
Kristopher E Plambeck,
Jinte Middeldorp,
Joseph M Castellano,
Kira I Mosher,
Jian Luo,
Lucas K Smith,
Gregor Bieri,
Karin Lin,
Daniela Berdnik,
Rafael Wabl,
Joe Udeochu,
Elizabeth G Wheatley,
Bende Zou,
Danielle A Simmons,
Xinmin S Xie,
Frank M Longo
& Tony Wyss-Coray

Nature Medicine (2014) doi:10.1038/nm.3569
Published online 04 May 2014

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging1, 2. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts?in which circulatory systems of young and aged animals are connected?identified synaptic plasticity?related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.