CAD106 and CNP520
antisense oligonucleotides (ASOs)
transcranial magnetic stimulation (TMS) neuroAD Therapy System
M1 muscarinic allosteric modulators
Crenezumab and gantenerumab
selective induction of PGC-1α
Fe2+ chelating agents and resveratrol
interventions to indirectly support food and drink intake
interleukin 33 (IL-33)
17 drugs on pace to launch in the next five years
selective rescue of spine density in engram cells
transcranial magnetic stimulation (TMS) and cognitive training
PD-1 immune checkpoint blockade
colony-stimulating factor 1 receptor (CSF1R) inhibition
Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy
Satoshi SaitoEmail author, Yumi Yamamoto, Takakuni Maki, Yorito Hattori, Hideki Ito, Katsuhiko Mizuno, Mariko Harada-Shiba, Raj N. Kalaria, Masanori Fukushima, Ryosuke Takahashi and Masafumi IharaEmail author
Acta Neuropathologica CommunicationsNeuroscience of Disease20175:26
DOI: 10.1186/s40478-017-0429-5? The Author(s). 2017
Received: 13 February 2017Accepted: 22 March 2017Published: 4 April 2017
Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-β accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-β protein likely impairs cerebrovascular integrity as well as cognitive function in early stage Alzheimer’s disease. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, has been reported to disassemble amyloid-β in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-β assembly may facilitate its clearance through several elimination pathways. Vehicle- or taxifolin-treated Tg-SwDI mice (commonly used to model CAA) were used in this investigation. Cognitive and cerebrovascular function, as well as the solubility and oligomerization of brain amyloid-β proteins, were investigated. Spatial reference memory was assessed by water maze test. Cerebral blood flow was measured with laser speckle flowmetry and cerebrovascular reactivity evaluated by monitoring cerebral blood flow changes in response to hypercapnia. Significantly reduced cerebrovascular pan-amyloid-β and amyloid-β1-40 accumulation was found in taxifolin-treated Tg-SwDI mice compared to vehicle-treated counterparts (n?=?5). Spatial reference memory was severely impaired in vehicle-treated Tg-SwDI mice but normalized after taxifolin treatment, with scoring similar to wild type mice (n?=?10?17). Furthermore, taxifolin completely restored decreased cerebral blood flow and cerebrovascular reactivity in Tg-SwDI mice (n?=?4?6). An in vitro thioflavin-T assay showed taxifolin treatment resulted in efficient inhibition of amyloid-β1-40 assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-β oligomers in vivo after taxifolin treatment (n?=?4?5), suggesting the effects of taxifolin on CAA are attributable to the inhibition of amyloid-β oligomer formation. In conclusion, taxifolin prevents amyloid-β oligomer assembly and fully sustains cognitive and cerebrovascular function in a CAA model mice. Taxifolin thus appears a promising therapeutic approach for CAA.
CAD106 and CNP520
Arizona drug studies target Alzheimer's earlier
Feb. 17, 2017
Two recent studies cast a cloud over the effectiveness of new drugs to combat Alzheimer's disease, but ongoing drug trials continue as researchers hope that an effective treatment can be found.
Despite great hope and hundreds of millions of dollars spent to develop an experimental drug viewed as a candidate to slow Alzheimer's disease, a late-stage medical study revealed the scientific hard facts late last year.
The drug, solanezumab, worked no better than a placebo.
Alzheimer's researchers got another dose of bad news Tuesday when drugmaker Merck announced it would halt a late-stage study of another drug, verubecestat, due to lack of effectiveness.
"Any time a drug trial doesn't pan out, especially ones that reach Phase 3, people feel understandably disappointed," said Dan Lawler, executive director of the Alzheimer's Association's Desert Southwest Chapter.
What they're testing
Some scientists have long theorized that a type of protein, beta-amyloid, accumulates in the brain and leads to memory and thinking problems, but other scientists have questioned the "amyloid hypothesis." And so far, no drugs developed to attack beta-amyloid have proven successful at combating cognitive decline in patients with the mind-robbing disease.
Phoenix-based Banner Alzheimer’s Institute, which launched a decade ago, has become a leading proponent of the idea that giving at-risk patients drugs earlier ? before memory and thinking problems surface ? could be a possible way to attack the disease.
Several studies are testing that very idea, including two clinical trials spearheaded by Banner that are testing anti-amyloid drugs on people who face high genetic risk but no symptoms. Those studies ? one involving an extended family in Colombia and a second involving healthy older adults who carry a high genetic risk of developing Alzheimer’s disease ? are testing anti-amyloid drugs on patients before memory and thinking problems occur.
Dr. Eric Reiman, executive director of Banner Alzheimer’s Institute, acknowledged that Alzheimer’s drug trials “are not for the faint-hearted.”
“There is no guarantee that any of these will work,” Reiman said. “I believe we have at least a 50 percent chance that one of them works,” by 2025.
The 2,100-person study of Eli Lilly’s experimental drug solanezumab, designed to bind to and clear beta-amyloid, failed to benefit patients who had mild dementia. Merck's verubecestat, designed to target an enzyme that produces beta-amyloid, did not prove effective in a study of about 2,000 people with mild to moderate Alzheimer's.
In a recent article in the journal Nature, Reiman argued that there are possible explanations for solanezumab's failure, such as doses that were too low or administered too late, after the disease had marched on the brain.
He said research of anti-amyloid treatments must continue, both in people with memory and thinking problems and in symptom-free individuals with a genetic risk of Alzheimer's.
“Although the possibility remains that critical elements of the amyloid hypothesis are simply wrong, it would be premature to draw that conclusion until different (anti-amyloid) treatments have failed to work, even in unimpaired people at increased risk when the disease is less extensive,” Reiman wrote in the Nature article.
Two studies underway
Banner Alzheimer’s Institute is studying an anti-amyloid drug, crenezumab, in an extended family of Colombia residents. These family members carry a rare genetic mutation that guarantees they will get Alzheimer’s disease, usually beginning in their mid-40s.
The study seeks to recruit about 300 family members, including 200 who carry the Alzheimer's mutation and 100 without the mutation. Family members who carry a mutated version of the gene that guarantees early-onset Alzheimer's will be given either crenezumab or a placebo. The other 100 non-mutation carriers will also get a placebo.
Reiman said he expects enrollment in the Colombia trial will be completed by this spring.
Banner also is also recruiting for a second study of people who carry two copies of an Alzheimer's risk gene, APOE4. The Generation study will recruit older adults who carry two copies of the risk gene but have not shown signs of dementia.
The study is funded with a $33.2 million grant from the National Institute on Aging and $15 million from Banner Alzheimer's Foundation and the Alzheimer's Association. Drugmakers Novartis and Amgen will contribute two experimental drugs, called CAD106 and CNP520.
"Enrollment has been slow but methodical," said Reiman, adding that Banner and Amgen expect to add more clinical trial sites to the study. "We think enrollment will accelerate through the end of this year."
A third Alzheimer's prevention study led by Harvard University researchers also is recruiting local patients. The study, called anti-amyloid treatment in asymptomatic Alzheimer's, or A4, also will study solanezumab on older adults without symptoms.
Dr. Reisa Sperling of Massachusetts General Hospital and Harvard Medical School admits that last November's failure of Eli Lilly's solanezumab study was disappointing. She said her team is still assessing the data from the study and believes the key still remains earlier treatment ? before memory and thinking problems occur.
"We know amyloid is building in the brain for more than a decade," Sperling said.
Aging Boomers at risk?
Reiman said several other prevention trials are underway at Banner and at universities across the nation. In many ways, it's a race to provide an effective treatments for an aging population.
About 5 million Americans live with Alzheimer's disease or other dementia, and projections suggest that number could triple by 2050 as Baby Boomers age. However, a University of Michigan-led research team last November reported some good news: The percentage of adults age 65 and older with dementia declined from 11.6 percent in 2000 to 8.8 percent in 2012.
Lawler, of the Alzheimer's Association, said Arizona families afflicted with Alzheimer's disease are intrigued by these prevention trials ? testing experimental drugs on people who carry no symptoms.
Lawler said his organization has pushed for more research involving both people with dementia and their healthy family members.
Even unsuccessful drugs trials like solanezumab provide scientists new clues about the disease, Lawler said.
"There is a lot of excitement with the state of research today and what is to come in the next five to 10 years," Lawler said. "We are an epicenter of research here and knowledge of what drugs are being developed. There is a lot of excitement on what could be coming."
Iran displays world’s 1st herbal medicine for Alzheimer’s treatment
Jan 28, 2017
Iranian researchers and scientist unveil the world's first herbal medicine to treat Alzheimer’s called Melitropic.
Iranian researchers and scientist unveil the world's first herbal medicine to treat Alzheimer’s called Melitropic.
Iranian researchers and scientists have put on display the world’s first ever herbal medicine to cure Alzheimer’s or stop it from progressing through alleviating its symptoms such as memory loss and confusion.
The medicine, named Melitropic, was unveiled during a ceremony in Iran’s Institute of Medicinal Plants at Jihad University on Saturday morning.
Iranian Health Minister Hassan Qazizadeh Hashemi, President of Jihad University Seyyed Hamidreza Tayyebi and a number of researchers were in attendance.
The Iranian researchers reportedly drew on the country’s historically extensive expertise in treatment of brain disorders, and utilized latest related studies in the world to produce the herbal medicine.
Chairman of the Institute of Medicinal Plants at Jihad University, Dr. Shamsali Rezazadeh, said a series of clinical experiments were carried out on 42 patients with mild to moderate Alzheimer’s symptoms to determine the effectiveness of Melitropic.
He added that the patients were aged 65-80. While dracocephalum extract was administered to those in the experiment group, the patients in the control group received placebos.
Rezazadeh said forgetfulness and recognition indices plus potential side effects were analyzed after four months of studies; and the results recorded an obvious and noticeable improvement in the mental status of patients, who had been given dracocephalum extract. The anxiety disorder and irritability symptoms had considerably dropped among subjects in the experiment group.
The chairman of the Institute of Medicinal Plants at Jihad University emphasized that certain measures have been taken into consideration in order to introduce Melitropic to world markets.
New drug sak3 may offer hope to Alzheimer's disease patients
Date: January 26, 2017
Source: Tohoku University
Summary: Acetylcholine is a neurotransmitter in the brain that plays an important role in controlling attention and cognition. Acetylcholine system dysfunction is believed to be one of the causes of Alzheimer's disease (AD) and vascular dementia.
Acetylcholine is a neurotransmitter in the brain that plays an important role in controlling attention and cognition. Acetylcholine system dysfunction is believed to be one of the causes of Alzheimer's disease (AD) and vascular dementia.
Now, a new drug that could treat Alzheimer's disease, SAK3, has been developed by a Japanese research group led by Tohoku University Professor Kohji Fukunaga.
In their study, the researchers found that the T-type calcium channel enhancer, SAK3, stimulates the release of acetylcholine in the brain and improves cognition by activating the memory molecule CaMKII. According to Professor Fukunaga, SAK3 also reduces the production of amyloid beta protein in the study's model mice. This, he says, could lead to the development of the first disease-modifying drug to prevent mild to severe Alzheimer disease.
SAK3 is now in the preclinical stage of drug development, and has so far proven to be safe and well-tolerated in animal experiments. Clinical trials are expected to begin in the next few years.
16 January 2017
Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer
Yasushi Yabukia, Kazuya Matsuoa, Hisanao Izumia, Hidaka Hagaa, Takashi Yoshidab, Minoru Wakamorib, Akira Kakehic, Kenji Sakimurad, Takaichi Fukudae, Kohji Fukunagaa, ,
T-type voltage-gated Ca2+ channels (T-VGCCs) function in the pathophysiology of epilepsy, pain and sleep. However, their role in cognitive function remains unclear. We previously reported that the cognitive enhancer ST101, which stimulates T-VGCCs in rat cortical slices, was a potential Alzheimer's disease therapeutic. Here, we introduce a more potent T-VGCC enhancer, SAK3 (ethyl 8'-methyl-2′,4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1,3'-imidazo [1,2-a]pyridin]-2-ene-3-carboxylate), and characterize its pharmacological properties in brain. Based on whole cell patch-clamp analysis, SAK3 (0.01?10 nM) significantly enhanced Cav3.1 currents in neuro2A cells ectopically expressing Cav3.1. SAK3 (0.1?10 nM nM) also enhanced Cav3.3 but not Cav3.2 currents in the transfected cells. Notably, Cav3.1 and Cav3.3 T-VGCCs were localized in cholinergic neurve systems in hippocampus and in the medial septum. Indeed, acute oral administration of SAK3 (0.5 mg/kg, p.o.), but not ST101 (0.5 mg/kg, p.o.) significantly enhanced acetylcholine (ACh) release in the hippocampal CA1 region of na?ve mice. Moreover, acute SAK3 (0.5 mg/kg, p.o.) administration significantly enhanced hippocampal ACh levels in olfactory-bulbectomized (OBX) mice, rescuing impaired memory-related behaviors. Treatment of OBX mice with the T-VGCC-specific blocker NNC 55-0396 (12.5 mg/kg, i.p.) antagonized both enhanced ACh release and memory improvements elicited by SAK3 administration. We also observed that SAK3-induced ACh releases were significantly blocked in the hippocampus from Cav3.1 knockout (KO) mice. These findings suggest overall that T-VGCCs play a key role in cognition by enhancing hippocampal ACh release and that the cognitive enhancer SAK3 could be a candidate therapeutic in Alzheimer's disease.
antisense oligonucleotides (ASOs)
New Alzheimer's drug compound 'worth investigating'
January 25, 2017
A new approach to slowing the ravages of Alzheimer's disease has shown promise in early studies on mice and monkeys, and is "worth investigating" in humans, U.S. scientists said Wednesday.
The method involves injecting a synthetic compound in the brain that reduces the amount of a protein called tau which can accumulate, damage cells and lead to failures of memory.
"We've shown that this molecule lowers levels of the tau protein, preventing and, in some cases, reversing the neurological damage," said senior author Timothy Miller, professor of neurology at Washington University School of Medicine.
The molecule, known as an antisense oligonucleotide, works by targeting genetic instructions for tau before it is ever made, said the report in the journal Science Translational Medicine.
"This compound is the first that has been shown to reverse tau-related damage to the brain that also has the potential to be used as a therapeutic in people," added Miller.
Much more work is needed to test whether it is safe in humans, and whether it works the same in people as in animals.
"But everything we've seen so far says that this is worth investigating as a potential treatment for people," said Miller.
Researchers are cautious because mouse models of Alzheimer's are not exactly the same as the disease that affects humans.
Past research has failed to find an effective treatment for Alzheimer's, the most common form of dementia.
According to the World Health Organization, 47.5 million people have dementia worldwide.
- What it did -
In mice, the treatment "significantly reduced" tau compared to mice given a placebo, said the report.
The compound appeared not only to stop but reverse some of the tau buildup. In 12-month-old mice, levels of total tau and tau tangles in the brains were lower than in untreated nine-month-old mice.
"The treated mice lived an average of 36 days longer than untreated mice, and they were better at building nests, which reflects a combination of social behavior, cognitive performance and motor capabilities," said the report.
In monkeys, researchers injected two doses of placebo or oligonucleotide, one week apart, directly into the cerebrospinal fluid that surrounds the spinal cord and brain.
Two weeks later, tau protein in the monkeys' brains and cerebrospinal fluid was reduced.
Other treatments using oligonucleotide have been approved by the U.S. Food and Drug Administration for Duchenne's muscular dystrophy and spinal muscular atrophy.
California-based Ionis Pharmaceuticals discovered the oligonucleotide for spinal muscular atrophy, and partnered with Miller to develop the oligonucleotide treatment for reducing tau.
Human trials are already under way, using oligonucleotides against Huntington's disease and amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease.
Gordon Wilcock, Emeritus professor of geratology at the University of Oxford, described the tau work as "important."
"However, results in animal models are a long way from treating humans," said Wilcock, who was not involved in the study.
"Not only will the treatment's safety have to be established before clinical trials can take place, but also an alternative and more practical way of delivering this treatment to the brain is needed."
Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy
Science Translational Medicine 25 Jan 2017:
Vol. 9, Issue 374,
Accumulation of hyperphosphorylated tau directly correlates with cognitive decline in Alzheimer’s disease and other primary tauopathies. One therapeutic strategy may be to reduce total tau expression. We identified antisense oligonucleotides (ASOs) that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and preexisting phosphorylated tau and Thioflavin S pathology were reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In addition, mouse survival was extended, and pathological tau seeding was reversed. In nonhuman primates, tau ASOs distributed throughout the brain and spinal cord and reduced tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid. These data support investigation of a tau-lowering therapy in human patients who have tau-positive inclusions even after pathological tau deposition has begun.
transcranial magnetic stimulation (TMS) neuroAD Therapy System
Positive Results for neuroAD Device in Mild Alzheimer's
Medscape Medical News
December 30, 2016
Researchers are reporting more positive data from the phase 3 randomized clinical trial of the neuroAD Therapy System (Neuronix Ltd) for patients with mild to moderate Alzheimer's disease (AD).
The novel system uses transcranial magnetic stimulation (TMS), along with cognitive training exercises "aimed to match the same brain regions being stimulated by TMS," the investigators say. In the 131-patient multicenter trial, participants received 6 weeks of treatment with this system or a placebo/sham device and sham cognitive exercises.
Building on top-line results announced earlier by the manufacturer, co-principal investigator Marwan N. Sabbagh, MD, Barrow Neurological Institute in Phoenix, Arizona, reported that improvements on the AD Assessment Scale-Cognitive Subscale (ADAS-COG) were significantly better 6 weeks after treatment for patients in he neuroAD group who had mild AD compared with the patients in the placebo group with mild AD. However, neither endpoint reached significance for the patients with moderate AD.
In addition, no treatment-related serious adverse events (AEs) or seizure events were reported.
"We're seeing an increasing interest in device-based treatments rather than pharmacologically based treatments. And with this system, we saw cognitive benefits within 12 weeks, which is pretty fast," Dr Sabbagh told Medscape Medical News.
The data were released during a presentation at the recent Clinical Trials on AD (CTAD) meeting in San Diego, California.
Based on the positive results, the company will be seeking regulatory clearance from the US Food and Drug Administration (FDA), which would make it the first device approved by the agency for treating AD.
According to company CEO Eyal Baror, if the device is approved, "very early" pricing estimates are between $6000 and $10,000 per patient for 30 sessions of a full course of treatment, depending on factors such as location.
After the presentation, session moderator Diana R. Kerwin, MD, Texas Alzheimer's and Memory Disorders, Dallas, noted that she was pleased to see no serious device-related AEs reported, "which is one thing I was concerned about."
"There also seemed to be some improvement in cognition. What was presented today shows it might potentially be a good add-on therapy," Dr Kerwin said to Medscape Medical News.
"It would be considered symptomatic therapy since there wasn't any data showing that there was any underlying disease modifying. And coming in 5 days a week would be a bit burdensome for patients. But it did show some beneficial data," she added.
Effective in Mild AD
The trial was conducted between October 2013 and March 2016 at 10 centers in the United States and in Israel, which is where Neuronix is headquartered.
All patients were aged 60 to 90 years and had baseline scores of 18 to 26 on the Mini-Mental State Examination and scores higher than 17 on the ADAS-Cog. They underwent in-clinic sessions five time a week for 6 weeks, with each session lasting approximately 1 hour.
The novel treatment delivered "brain MRI neuro-navigated, focal TMS concurrently with tailor made cognitive training exercises," report the investigators. The exercises "are designed to engage the cognitive functions of the brain networks targeted by a preceding train of TMS."
The ADAS-Cog and Clinical Global Impression of Change (CGI-C) were both administered at baseline, at week 7 (1 week after treatment ended), and at week 12 (6 weeks after treatment ended).
Score changes on the ADAS-Cog were 0.7 points at week 7 and ?2.1 points at week 12 for the neuroAD group who had baseline ADAS-Cog scores of 30 or less vs ?1.1 and ?0.3 points, respectively, for the sham treatment group (P < .05).
However, differences in changes on the secondary measure of CGI-C just missed significance. For the treatment group, the scores were 3.98 at week 7 and 3.69 at week 12 vs 4.05 and 4.14, respectively, for the sham group (P = .07).
Neither outcome was significant in the patients who had moderate AD at baseline. And when the patients with mild and moderate AD were combined, "it kind of washed out the effect," said Dr Sabbagh.
"This followed the trend from multiple studies showing that mild patients respond but moderate patients don't," he added.
As for treatment-related AEs, he reported that they were "mild and transient" and included headache, scalp discomfort, neck pain, or fatigue.
"TMS has already been approved for other indications, such as clinical depression, so technologically, we know that the device is safe," Dr Sabbagh said to Medscape Medical News. And although the process is laborious and time consuming, "generally speaking, most people tolerated it very well."
He noted that they aren't claiming that the device has a disease-modifying effect. "But we know it has an acute cognitive effect in these patients. And we'll determine over time if it's a prolonged, sustained effect."
In fact, the company is planning on further studies on maintenance and assessing the treatment over longer periods of time, he said. "We don't yet know the timelines on those [studies], but they are planning on it."
The intervention has already been approved for use in Europe. And it's available either commercially or in clinical trials running in Israel, Hong Kong, and Korea.
When asked for comment, Maria Carrillo, PhD, chief science officer of the Alzheimer's Association, said that the neuroAD system "is an interesting concept."
However, "when you're trying to look for efficacy for memory, even for a potentially symptomatic treatment, I think you need a more robust study," Dr Carrillo told Medscape Medical News.
"It was intriguing to see some effects on cognition, but they were short-lived and washed out a little bit after 12 weeks."
She noted that one session attendee even pointed out that TMS has a transient benefit. "It's a little like if a chiropractor gives an adjustment that gives short-lived benefit but doesn't address the underlying issue that needs to be modified," she said.
"So the question becomes: is this worth 6 weeks of almost-daily therapy for that benefit that will last you another 6 to 12 weeks? We just don't know."
The study was funded by Neuronix. Dr Sabbagh, Dr Kerwin, and Dr Carrillo have disclosed no relevant financial relationships.
9th Annual Clinical Trials on Alzheimer's Disease 2016. Presented December 9, 2016. Abstract OC31.
Investigation into new molecules that could potentially treat Alzheimer's
MOSCOW INSTITUTE OF PHYSICS AND TECHNOLOGY
PUBLIC RELEASE: 28-DEC-2016
This year, results have been published of two significant research studies about molecules that could potentially treat Alzheimer's disease. The chief researcher in both studies was the head of the Laboratory of Medical Chemistry and Bioinformatics at MIPT Yan Ivanenkov. Papers on the two new molecules were published in Molecular Pharmaceutics and Current Alzheimer Research. Mark Veselov, another MIPT employee, also participated in the second study.
Both papers cover the study of neuroprotectors - antagonists to the 5-HT6R receptor. The latest research confirms that this target has a high therapeutic potential in the treatment of Alzheimer's disease. Preclinical studies on lab animals have shown that the compounds have a high selectivity.
Alzheimer's is one of the most widespread diseases in elderly people. People over the age of 60 are at the greatest risk of developing the disease, but it can also occur at a younger age. Patients suffer from loss of memory and cognitive functions; they become socially detached and lose their independence, and the body can no longer function properly, which inevitably leads to death. According to medical statistics, Alzheimer's is the cause of two out of every three cases of dementia in the elderly and it is a huge economic problem in developed countries - the financial impact in the US, for example, is higher than for cancer or cardiovascular diseases.
Scientists have not yet succeeded in finding an effective cure for Alzheimer's. Despite the fact that we know how the disease develops, we cannot say that we are even close to a solution. Pharmaceutical studies are still being conducted in order to be able to reduce the symptoms of the disease.
In the first paper, specialists Alexander Ivashenko and Yan Lavrovsky from Alla Chem LLC, Avineuro Pharmaceuticals Inc. and R-Pharm Overseas Inc. (all US companies), in collaboration with MIPT's Yan Ivanenkov, worked on a 5-HT6R activity blocking compound. A similar task was investigated in Yan and Alexander's second study with another MIPT employee, Mark Veselov. 5-HT6R receptors were chosen because they are integrated into nerve cell membranes and are capable of reacting to certain external signals, which is why scientists consider them as targets for AD treatment. The antagonists to the receptor are able to ease the symptoms of the disease in a clinical environment.
Scientists studied the pharmacokinetic features, activity, efficiency, and also the toxicity profile of AVN-211. First, a screening test was performed using recombinant human cells containing 5-HT6R to make sure that AVN-211 really is an antagonist. Another series of experiments with cell cultures demonstrated its ability to spread in a tissue and provided preliminary data about its state in the human body - metabolism, biochemical interactions, etc.
Tests were then performed on lab animals - mice, rats and monkeys to obtain the pharmacokinetic profile of a drug candidate in a real body. Observing concentration changes in the animals' blood after intake provided information about the compound's pharmacodynamics.
Memory disorder stress tests have shown that AVN-211 might be able to improve memory function. Rats and mice were taught to find an exit from a maze, while their cognition was imaired by drugs provoking memory loss. Animals who were given the drug demonstrated better results. In addition, healthy animals who received the new drug were better learners and could be trained more efficiently.
These results led the researchers to believe that AVN-211 will be able to combat cognitive dysfunction caused by AD.
Scientists also think that this compound can be used to treat certain mental disorders. Tests with chemicals that produce the same symptoms as psychosis have shown a possible antipsychotic and anxiolytic (reducing anxiety) effect. Such effects are used in treating schizophrenia and depression. It was also noticed that AVN has a comparable effect to haloperidol - a common antipsychotic drug.
In vitro studies revealed that this compound affects the 5-HT6R receptor more effectively and selectively compared to all other drugs, including those currently in clinical trials. Studies on lab animals showed that AVN-211 has low toxicity.
The same tests were performed for AVN-322. Screening with the 5-HT6R receptor on human cell culture proved that the molecule is a highly effective antagonist. In vivo tests were performed on mice: the animals were taught how to get out of a maze and had to remember that a section of the floor was electrified. The results showed that mice that received low levels of AVN-322 performed better than after any existing neuroleptic drugs.
The pharmacokinetics of AVN-322 were analyzed in mice, rats, dogs and monkeys. During a 30-day intake monkeys did not have any toxic after-effects. A possible danger was noticed after a 180-day intake in rats - the substance can cause brachycardia and hypotension. However the exact after-effects are less serious than all other existing drugs. Pre-clinical data proves that AVN-322 also has a good pharmacokinetic profile - it is very digestible and passes well through the blood-brain barrier.
In conclusion, we can say that both compounds have a high pharmaceutical potential and low toxicity. The positive results of the studies mean that researchers can move on to clinical trials in order to verify the safety and effectiveness of a drug that could potentially treat one of the most serious diseases of our time.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
AVN-211, Novel and Highly Selective 5-HT6 Receptor Small Molecule Antagonist, for the Treatment of Alzheimer’s Disease
Alexandre V. Ivachtchenko†‡, Yan Lavrovsky§, and Yan A. Ivanenkov*∥⊥
† Alla Chem LLC, 1835 East Hallandale Beach Boulevard, #442, Hallandale Beach, Florida 33009, United States
‡ Avineuro Pharmaceuticals, Inc., 1835 East Hallandale Beach Boulevard, #442, Hallandale Beach, Florida 33009, United States
∥ Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russian Federation
§ R-Pharm Overseas, Inc., 12526 High Bluff Drive, Suite #300, San Diego, California 92130, United States
⊥ Chemistry Department, Moscow State University, Leninskie Gory, Building 1/3, GSP-1, 119991, Moscow, Russia
Mol. Pharmaceutics, 2016, 13 (3), pp 945?963
Within the past decade several novel targets have been indicated as key players in Alzheimer-type dementia and associated conditions, including a “frightening” memory loss as well as severe cognitive impairments. These proteins are deeply implicated in crucial cell processes, e.g., autophagy, growth and progression, apoptosis, and metabolic equilibrium. Since recently, 5-HT6R has been considered as one of the most prominent biological targets in AD drug therapy. Therefore, we investigated the potential procognitive and neuroprotective effects of our novel selective 5-HT6R antagonist, AVN-211. During an extensive preclinical evaluation the lead compound demonstrated a relatively high therapeutic potential and improved selectivity toward 5-HT6R as compared to reference drug candidates. It was thoroughly examined in different in vivo behavioral models directly related to AD and showed evident improvements in cognition and learning. In many cases, the observed effect was considerably greater than that determined for the reported drugs and drug candidates, including memantine, SB-742457, and Lu AE58054, evaluated under the same conditions. In addition, AVN-211 showed a similar or better anxiolytic efficacy than fenobam, rufinamide, lorazepam, and buspirone in an elevated plus-maze model, elevated platform, and open field tests. The compound demonstrated low toxicity and no side effects in vivo, an appropriate pharmacokinetic profile, and stability. In conclusion, AVN-211 significantly delayed or partially halted the progressive decline in memory function associated with AD, which makes it an interesting drug candidate for the treatment of neurodegenerative and psychiatric disorders. Advanced clinical trials are currently under active discussion and in high priority.
AVN-322 is a Safe Orally Bio-Available Potent and Highly Selective Antagonist of 5-HT6R with Demonstrated Ability to Improve Impaired Memory in Animal Models
Current Alzheimer Research, Volume 13 (E-pub ahead of print)
Author(s): Alexandre V. Ivachtchenko, Yan A. Ivanenkov, Mark S. Veselov and IM Okun.
Affiliation: 5924 Seacrest View Rd., San Diego, CA 92121, USA
Background: In recent years, 5-hydroxytryptamine subtype 6 receptor (5-HT6 receptor, 5- HT6R) has emerged as a promising therapeutic target for the treatment of neuropathological disorders, including Alzheimer’s disease (AD) and schizophrenia. 5-HT6 receptors were hypothesized to be implicated in the processes of learning, memory, and cognition with 5-HT6R antagonists being effective in animal models of cognition and memory impairment. Several selective 5-HT6R ligands are currently undergoing clinical trials for treatment of AD.
Methods: We describe results of preclinical development of a novel and highly selective and potent 5- HT6R antagonist, AVN-322, as a clinical candidate for the treatment of AD to improve concurrent debilitation of memory and cognition in the AD patients, and schizophrenia as a substance with antipsychotic effect. In the manuscript, we present its in vitro and vivo efficacy, ADME, pharmacokinetics in animals and in humans, and toxicity.
Results: While having high binding affinity in medium picomolar range, the lead compound demonstrates substantially better selectivity index then the reference drug candidates currently being tested in clinical studies. AVN-322 showed high oral bioavailability and favorable blood-brain barrier (BBB) penetration. In vivo testing revealed its clear cognition enhancing effect. AVN-322 significantly restored both scopolamine- and MK-801-induced cognitive dysfunction and demonstrated antipsychotic potential.
Conclusion: Taking into account its good safety profile and favorable pharmacokinetics, AVN-322 can be reasonably considered as a novel drug candidate for the treatment of neurological disorders such as AD and/or schizophrenia.
Occupational therapy holds potential to provide clinical benefits to dementia patients
December 22, 2016
A French observational study in real life showed that dementia patients benefiting from occupational therapy sessions report relevant clinical benefits over the intervention period, according to a research study published in the Journal of Alzheimer's Disease this month. The research suggested the influence of occupational therapy on reducing behavioral troubles, caregivers' burden and amount of informal care over the intervention period and a stabilization over the 3-months period thereafter.
France put a massive effort for improving dementia care through a national Alzheimer plan in 2008 and this effort was confirmed by the next government (Neurodegenerative Diseases Plan 2014-2019). Some new care models and interventions have been implemented such as integrated care, case management or occupational therapy. Occupational therapy has been spread nationwide through specialized Alzheimer team intervening at home with medical prescription. Even if efficacy of occupational therapy has been demonstrated in some clinical trials, its efficacy under routine care conditions was unknown and deserved to be investigated.
The research was conducted on a network of 16 specialized Alzheimer team in Aquitaine, South West of France and was supported by the regional agency of Health (Agence R?gionale de la Sant? d'Aquitaine). Titled "Benefits of Occupational Therapy in Dementia Patients: Findings from a Real-World Observational Study," the study included 421 dementia patient who had been referred to occupational therapy by their general practionner or memory clinics and who had been followed up to 6 months. Research studied the clinical evolution of patients between inclusion and 3 month follow-up (end of the 15 home sessions) and between 3 and 6-month follow-up (no session planned over this timeframe)
The study's results indicate that behavioral troubles, caregivers' burden, amount of informal care provided by caregivers and patients' quality of life were significantly reduced over the 3-month intervention period and remained stable thereafter. Cognitive performances remained stable over the 6-month study period and functional performances remained stable over the 3-month intervention period but were significantly reduced thereafter. Moreover, patients who had been diagnosed more recently and those with milder cognitive deficits may gain more benefits from occupational therapy in terms of functional decline or caregivers' burden decline. These findings suggest that occupational therapy should target early dementia stages in order to optimize its potential clinical benefits.
In many Western countries, recent national guidelines have aimed at improving home dementia care. This study highlights the potential occupational therapy in terms of patients' and their caregivers' well-being. The findings also opens a new field of research on occupational therapy. Indeed, occupational therapy has been conceptualized as a short-term home intervention, but long-term benefits and consequences of disruption are unknown. "Future studies should explore more in detail which sub-groups of patients could gain more benefits from OT as well as its long-term clinical effects notably on global care quality and users' satisfaction" stated Cl?ment Pimouguet.
Moreover, strategies aiming to improve initial benefits of occupational therapy should be promoted. The French research team will conduct a randomized trial that aim to compare the maintenance of occupational therapy over an additional 4-month period and usual occupation therapy as recommended.
Benefits of Occupational Therapy in Dementia Patients: Findings from a Real-World Observational Study
Article type: Research Article
Authors: Pimouguet, Cl?menta; b; * | Le Goff, Ml?aniea; b | Wittwer, J?r?mea; b | Dartigues, Jean-Fran?oisa; b; c | Helmer, Catherinea; b; d
Affiliations: [a] INSERM, ISPED, Centre INSERM U1219-Epidemiologie-Biostatistique, Bordeaux, France | [b] University Bordeaux, Bordeaux, France | [c] Service de Neurologie, Department of Clinical Neurosciences, CHU Pellegrin, Bordeaux, France | [d] INSERM, Clinical Investigation Center ? Clinical Epidemiology 1401, Bordeaux, France
Correspondence: [*] Correspondence to: Cl?ment Pimouguet, Institut de Sant? Publique, d’Epid?miologie et de D?veloppement, Universit? de Bordeaux, 146 rue L?o Saignat, 33076 Bordeaux Cedex, France. Tel.: +33 05 57 57 56 44; Fax: +33 05 56 24 00 81; E-mail: email@example.com.
Abstract: Background: There is a growing interest in developing non-pharmacological approaches in dementia. Clinical efficacy occupational therapy (OT) under routine care conditions has not been investigated yet. Objective: To analyze the short-term effects of OT in patients with dementia; and to identify factors related to greater benefit. Methods: Patients referred to OT were evaluated before starting a 3-month intervention and at 3 and 6 months later. Measures included: Mini-Mental State Examination (MMSE), Disability Assessment in Dementia, Neuropsychiatric Inventory Questionnaire, patients’ quality of life (EQ 5D-VAS), caregivers’ burden (Zarit scale), and amount of informal care. Linear mixed models were used to analyze trajectories of outcomes. Logistic regressions with stepwise descending selection were used to study factors associated with benefits. Results: 421 dementia patients benefited from OT (mean MMSE?=?17.3). Patients remained cognitively stable over time. Functional performances also remained stable at 3 months and significantly decreased at 6 months (crude reduction of 2.8 points, p?<?0.01). Behavioral troubles were significantly reduced over the intervention period and remained stable after (p?<?0.01). Patients’ quality of life increased over the 3-month intervention (p?=?0.16) and significantly decreased thereafter. Caregivers’ burden and informal care significantly decreased over the 3-month intervention and remained stable thereafter. Patients who benefited from OT with regard to function were less educated and had higher cognitive levels. Conclusion: OT may be an effective intervention to maintain cognition and functionality and to reduce psychiatric symptoms in dementia patients. Mild stages of dementia could gain more benefits from OT with regard to functional decline.
Keywords: Behavioral troubles, cognition, dementia, function, non-pharmacological intervention, observation study, occupational therapy
Journal: Journal of Alzheimer's Disease, vol. Preprint, no. Preprint, pp. 1-9, 2016
Accepted 28 October 2016 | Published: 9 December 2016
M1 muscarinic allosteric modulators
M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss
Sophie J. Bradley,1 Julie-Myrtille Bourgognon,2 Helen E. Sanger,3 Nicholas Verity,2 Adrian J. Mogg,3 David J. White,4 Adrian J. Butcher,2 Julie A. Moreno,2 Colin Molloy,1 Timothy Macedo-Hatch,2 Jennifer M. Edwards,2 Jurgen Wess,5 Robert Pawlak,6 David J. Read,2 Patrick M. Sexton,7 Lisa M. Broad,3 Joern R. Steinert,2 Giovanna R. Mallucci,2,8 Arthur Christopoulos,7 Christian C. Felder,9 and Andrew B. Tobin1
First published December 19, 2016 - More info
Journal of Clinical Investigation
Research Article Neuroscience
The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR?selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.
AC Immune SA (ACIU) Partner Genentech Announces Crenezumab Trial Data
AC Immune SA (NASDAQ: ACIU) announced that its partner Genentech, member of Roche group, has presented important data to support the unique binding and increased dosing of its Alzheimer's therapy on crenezumab, an anti-Abeta antibody. These data were presented at the 9th Clinical Trials on Alzheimer's disease Conference (CTAD) in San Diego, USA: they were from a Phase 1b safety study and an exposure-response model to evaluate the best dose of crenezumab for the treatment of people with Alzheimer's disease. The model predicts, relative to the Phase 2 trials, an improved outcome of the CREAD Phase 3 clinical trial in patients with prodromal-to-mild Alzheimer by using the higher dose of 60mg/kg of crenezumab.
Prof. Andrea Pfeifer, CEO of AC Immune, commented: "We are impressed by the drug-disease model, as well as the safety data of the Phase 1b study which further support the higher dose of crenezumab in the Phase III trial targeting prodromal-to-mild Alzheimer patients."
About the crenezumab drug-disease progression modelGenentech has developed a comprehensive drug-disease progression model to simulate the Phase 3 clinical trial and estimate the likelihood of achieving relative reduction in disease progression in patients treated with different doses of crenezumab, in different patient populations. The drug-disease model adequately described the historical longitudinal decline in ADAS-Cog 12 and CDR-SB in mild to moderate AD patients of crenezumab in Phase 2 studies (ABBY/BLAZE).
The clinical trial simulations using the drug-disease model predict a meaningful response of crenezumab in patients with mild AD at a dose of 60mg/kg IV every 4 weeks, as measured by CDR-SB and ADAS-Cog 12. This dose of 60mg/kg IV was selected by Genentech for the Phase 3 CREAD trial, which started recruitment of patients in Q1 2016.
About the Phase 1b study resultsGenentech presented the results of the first two cohorts of the Phase 1b crenezumab dose escalation study (NCT02353598) in 52 patients with mild-to-moderate Alzheimer's disease. No dose-limiting toxicities were observed at 30, 45 and 60mg/kg doses of crenezumab. No events of Amyloid Related Imaging Abnormality-Edema (ARIA-E) were observed in the Phase 1b study and only a few patients (6 of 52) showed asymptomatic Amyloid Related Imaging Abnormality-Hemsiderin(ARIA-H) which did not result in treatment discontinuation. The pharmacokinetic profile of crenezumab is dose proportional up to the 60mg/kg dose and is consistent with historical data. The serum concentrations at this dose are four fold higher than in the 15mg/kg IV every four weeks dose used in the Phase 2 trials. These safety and pharmacokinetic data of the Phase 1b dose escalation study support the continued treatment of patients with crenezumab at a higher dose of 60mg/kg.
About CrenezumabCrenezumab was discovered by AC Immune using its SupraAntigen technology platform and out-licensed to Genentech in 2006 as a potential therapy for Alzheimer's disease. Crenezumab is a fully humanized IgG4 monoclonal antibody that binds all forms of misfolded Abeta proteins, but especially to Abeta oligomers, to prevent and break up Abeta aggregation and promote Abeta disaggregation. The IgG4 subclass has reduced the effector function, allowing microglia to clear Abeta from the brain while minimizing an inflammatory response.
Genentech is currently evaluating the clinical efficacy and safety of crenezumab in a Phase 3 clinical trial, CREAD, in 750 participants with prodromal or mild Alzheimer's disease, which started in Q1 2016 and is expected to read out in 2020. In addition crenezumab was chosen by an international panel of experts, including the US National Institutes of Health, for use in a first-ever prevention trial in Alzheimer's disease in a large extended family in Colombia (API ADAD) in 2012.
Crenezumab and gantenerumab
Roche confident in Alzheimer's programmes, despite Lilly flop
Nov 23, 2016
Nov 23 Roche said on Wednesday it still believed drugs targeting a protein called beta amyloid had potential to help fight Alzheimer's disease, despite the high-profile failure of such a product from Eli Lilly.
As the setback sent shares in Lilly skidding, Roche pointed out there were significant differences between two experimental Alzheimer's drugs it was developing and the U.S. drugmaker's failed solanezumab.
"We remain confident in our clinical development programmes and continue evaluating two late-stage antibodies that target beta amyloid, crenezumab and gantenerumab," a Roche spokesman said in a statement.
"Crenezumab and gantenerumab are distinct from each other, as well as from other investigational medicines."
Roche added its clinical trials programmes incorporated lessons from ongoing research in the field, noting it was investigating high drug doses and also targeting early-stage patients, who might benefit more from drug interventions.
The failure of Lilly's amyloid-based drug has cast doubt on this approach to fighting the memory-robbing disease, although a number of experts believe other therapies tackling the problem protein in slightly different ways might still work. (Reporting by John Miller and Ben Hirschler; Editing by Mark Potter)
Using herpes drugs to slow down Alzheimer's disease could become reality
Date: December 13, 2016
Source: Ume? universitet
Summary: The first clinical study to investigate if herpes virus drugs can have an effect on fundamental Alzheimer’s disease processes has been launched. The research group has previously demonstrated a correlation between herpes virus infection and an increased risk of Alzheimer’s disease.
The first clinical study to investigate if herpes virus drugs can have an effect on fundamental Alzheimer's disease processes has been launched at Ume? University in Sweden. The research group has previously demonstrated a correlation between herpes virus infection and an increased risk of Alzheimer's disease.
Ume? University researchers, led by Hugo L?vheim at the Department of Community Medicine and Rehabilitation and the Unit of Geriatric Medicine, have launched a clinical study investigating the effect of herpes drugs on Alzheimer's disease. For four weeks, 36 people with Alzheimer's disease will be receiving treatment with Valaciklovir, a drug which specifically targets active herpes virus. Several investigations will be made before and after the treatment to measure the effects on fundamental Alzheimer's disease processes. Moreover, the participants will be examined with brain imaging, which together with a tracer substance accumulating in cells with active herpes virus infection could potentially detect herpes virus infection in brain cells in people with Alzheimer's disease.
"I'm very excited about this study. In earlier population-based studies, we have seen that herpes virus infection increases the risk of Alzheimer's disease. It is very interesting to see if we can influence the neurodegenerative processes of Alzheimer's disease by using a well-established treatment of herpes," says Hugo L?vheim, lead researcher of the study and physician at the Geriatric Centre at the University Hospital of Ume?.
The study, named VALZ-Pilot, has been approved by the Medical Products Agency Sweden and the Regional Ethical Review Board in Ume?. The recruitment of study participants will be initiated in December 2016.
Materials provided by Ume? universitet. Note: Content may be edited for style and length.
Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial
Dr Petr Novak, PhDcorrespondencePress enter key for correspondence informationemailPress enter key to Email the author, Prof Reinhold Schmidt, MD, Prof Eva Kontsekova, DrSc, Norbert Zilka, PhD, Branislav Kovacech, PhD, Rostislav Skrabana, PhD, Zuzana Vince-Kazmerova, PhD, Stanislav Katina, PhD, Lubica Fialova, PhD, Michal Prcina, PhD, Vojtech Parrak, MD, Peter Dal-Bianco, MD, Martin Brunner, MD, Wolfgang Staffen, MD, Michael Rainer, MD, Matej Ondrus, MD, Stefan Ropele, Ing, Miroslav Smisek, MD, Roman Sivak, Ing, Prof Bengt Winblad, PhD, Prof Michal Novak, DrSc
Published: 09 December 2016
Article has an altmetric score of 315
DOI: http://dx.doi.org/10.1016/S1474-4422(16)30331-3 |
Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau proteins is therefore a promising strategy for disease-modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial.
We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50?85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov, number NCT01850238; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov, number NCT02031198.
This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 [53%] vaccinated patients [92 individual events]). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres.
AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1.
AXON Neuroscience SE.
CLINICAL BENEFITS OF TRAMIPROSATE IN ALZHEIMER’S DISEASE ARE ASSOCIATED WITH HIGHER NUMBER OF APOE4 ALLELES: THE “APOE4 GENE-DOSE EFFECT”
S. Abushakra1, A. Porsteinsson2, B. Vellas3, J. Cummings4, S. Gauthier5, J.A. Hey1, A. Power1, S. Hendrix6, P. Wang7, L. Shen7, J. Sampalis8, M. Tolar1
Corresponding Author: Susan Abushakra, MD, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA 01701, USA, Phone: 508.508.7709, Fax: 508.861.1500, firstname.lastname@example.org
J Prev Alz Dis 2016;3(4):219-228
Published online October 24, 2016, http://dx.doi.org/10.14283/jpad.2016.115
Background: Tramiprosate is an oral amyloid anti-aggregation agent that reduces amyloid oligomer toxicity in preclinical studies and was evaluated in two 78-week trials in North America and Western Europe that enrolled 2,025 patients with Mild to Moderate Alzheimer’s Disease. The completed North American study did not achieve its efficacy objectives, but a pre-specified subgroup analysis suggested potential efficacy in apolipoprotein E4 (APOE4) carriers. To further explore this observation, we analyzed tramiprosate Phase 3 clinical data based on the number of APOE4 alleles.
Objectives: To analyze tramiprosate efficacy, safety, and occurrence of vasogenic edema in the three APOE4 subgroups: homozygous, heterozygous and non-carriers.
Design: Randomized, double-blind, placebo-controlled parallel-arm multi-center studies.
Setting: Academic Alzheimer’s disease & dementia centers, community-based dementia and memory clinics, and neuropsychiatric clinical research sites.
Participants: Subjects included 2,025 patients, 50 years of age or older, with approximately 60% having APOE4 carrier status (10-15% homozygotes and 45-50% heterozygotes), and mild to moderate disease. All subjects were on stable symptomatic drugs.
Intervention: Randomized subjects received placebo, 100 mg BID, or 150 mg BID of tramiprosate.
Measurements: Co-primary outcomes in both studies were change from baseline in the ADAS-cog11 and CDR-SB assessment scales.
Results: Highest efficacy was observed in APOE4/4 homozygotes receiving 150 mg BID of tramiprosate, showing statistically significant effects on ADAS-cog and positive trends on CDR-SB (respectively, 40-66% and 25-45% benefit compared to placebo). APOE4 heterozygotes showed intermediate efficacy, and non-carriers showed no benefit. In 426 patients with MRI scans, no cases of treatment-emergent vasogenic edema were observed. In the three subgroups, the most common adverse events were nausea, vomiting, and decreased weight.
Conclusions: The “APOE4 Gene-Dose effect” is likely explained by the high prevalence of amyloid pathology in symptomatic APOE4 carriers. In APOE4/4 Alzheimer’s disease patients, the high dose of tramiprosate showed favorable safety and clinically meaningful efficacy in addition to standard of care.
Key words: Tramiprosate, Alzheimer’s, APOE4.
Abbreviations: AD: Alzheimer’s disease; Aβ: Beta amyloid; ADAS-cog: Alzheimer’s Disease Assessment Scale-cognitive subscale; APOE4: Apolipoprotein E4, ε4 allele of the apolipoprotein E gene; ARIA-E: Amyloid-Related Imaging Abnormalities-Edema; ARIA-H: Amyloid-Related Imaging Abnormalities-Haemosiderin; CBL: Change from Baseline; CDR-SB: Clinical Dementia Rating Scale-Sum of Boxes; DAD: Disability Assessment for Dementia; EU: European; FLAIR: Fluid-Attenuated Inversion Recovery; ITT: Intent to Treat; MedDRA: Medical Dictionary for Regulatory Activities; MMRM: Mixed Effects Repeated Measures Model; MMSE: Mini-Mental State Examination; MRI: Magnetic Resonance Imaging; NA: North American; NPI: Neuropsychiatric Inventory; OC: Observed Cases; SAE: Serious Adverse Event; SAP: Statistical Analysis Plan; TEAE: Treatment-Emergent Adverse Events
Anavex Life Sciences (AVXL) Phase 2a Alzheimer Study of ANAVEX 2-73 Met Primary and Secondary Endpoints
December 8, 2016
Anavex Life Sciences Corp. (Nasdaq: AVXL) today announced a positive 57-week update from its Phase 2a study in mild-to-moderate Alzheimer’s disease (AD) patients for ANAVEX 2-73, which targets cellular homeostasis. The study met both primary and secondary endpoints.
At 57 weeks, Alzheimer’s patients taking a daily oral dose between 10mg and 50mg, ANAVEX 2-73 was well tolerated. There were no clinically significant treatment-related adverse events and no serious adverse events.
Published AD studies confirmed substantial declines of cognitive (MMSE) and functional (ADCS-ADL) measures as well as Cogstate and EEG/ERP over 12 month in similar AD populations. Pre-specified exploratory analyses of the current study included the cognitive (MMSE) and the functional (ADCS-ADL) as well as Cogstate, HAM-D and EEG/ERP changes from baseline.
Specifically, in comparison to historical control from a pooled placebo arm cohort study conducted by the Alzheimer Disease Cooperative Study Group in mild-to-moderate AD patients of comparable ages and MMSE baselines, over 12 month the ANAVEX 2-73 data shows a calculated treatment benefit of 1.8 points on the MMSE scale (p<0.016) and a calculated treatment benefit of 4 points on the ADCS-ADL score (p<0.019). Furthermore, the correlation was positive with all measured scores (MMSE, ADCS-ADL, Cogstate, HAM-D and EEG/ERP).
George Perry, PhD, Dean and Professor at the University of Texas at San Antonio and Editor-in Chief of the Journal of Alzheimer’s Disease, commented, “In addition to the very encouraging results, which point to the therapeutic potential of targeting cellular homeostasis in a complex CNS disease like Alzheimer’s, this trial has been intelligently designed as a highly informative study, looking unprejudiced at all potential relationships and hence allowing to learn from all correlations of the now available pool of data, in order to execute subsequent trials with much more relevant information at hand.”
Despite non-optimized dosing of ANAVEX 2-73 throughout the 12-month study, continued significant improvements from baseline of cognitive, functional and behavioral scores in a group of patients were observed, respectively. This data will be analyzed using refined mathematical modeling methods in conjunction with the detailed pharmacokinetic (PK) information.
“Alzheimer’s disease is a progressive neurodegenerative disease that causes problems with memory, thinking and behavior. Currently available treatments cannot stop Alzheimer's from progressing; they can only temporarily slow the worsening of dementia symptoms,” said Christopher U. Missling, PhD, President and Chief Executive Officer of Anavex. "We believe this data gives us a solid foundation from which to continue the next phase of rationally designed clinical trials. Anavex is grateful for the dedication of the patients, their families and the clinical investigators who participated in this study."
The Company is presenting findings from the study at the Clinical Trials on Alzheimer's Disease (CTAD) meeting on Saturday, December 10th at 8:45 a.m. PT in the oral communication session. The presentation will be available in the publications section of the Anavex website.
The Company will also conduct a conference call with the investment community in conjunction with the upcoming financial year-end 2016 report.
Antibiotic restores cell communication in brain areas damaged by Alzheimer's-like disease in mice
Date: November 15, 2016
Source: University of British Columbia
Summary: New research has found a way to partially restore brain cell communication around areas damaged by plaques associated with Alzheimer's disease.
Using Ceftriaxone, an FDA-approved antibiotic used to treat bacterial infections, researchers were able to reduce synaptic disruption and clear the lines of neuronal communication in mice.
New research from the Djavad Mowafaghian Centre for Brain Health at UBC has found a way to partially restore brain cell communication around areas damaged by plaques associated with Alzheimer's disease.
The findings, published this week in Nature Communications, demonstrate a possible target and a potential drug treatment to reduce damage to the brain that occurs in the early stages of Alzheimer's disease. Using Ceftriaxone, an FDA-approved antibiotic used to treat bacterial infections, researchers were able to reduce synaptic disruption and clear the lines of neuronal communication in mice.
Amyloid plaques of -amyloid deposits develop in brain regions of patients with Alzheimer's disease, These plaques are linked to the damage found in Alzheimer's disease because they prevent cell communication and are toxic to nerve cells. The researchers found that the brain areas around these plaques show high levels of glutamate, a signaling molecule essential to communication between brain cells, accompanying high levels of hyperactivity in glia, the brain's support cells. It's in this glutamate-rich environment that communication between neurons is changed or disrupted, causing neurons to die in the later stages of the disease.
"By imaging the glial cells and glutamate itself around the plaques, we were able to see that the cells were not able to 'remove' the glutamate accumulating in these brain areas. By using Ceftriaxone, we were able to up-regulate glutamate transport," explains Dr. MacVicar, principal investigator and professor of psychiatry. "By restoring glutamate levels, we were able to mostly restore neuronal activity."
The team's findings have implications for treatment of early symptoms of Alzheimer's disease.
"This dysfunction in cell communication occurs at a very early stage in the disease, before memory impairment is detectable," says Dr. Jasmin Hefendehl, a former Postdoctoral Fellow in Dr. MacVicar's lab and the lead author on the paper. "This makes our discovery particularly interesting, as it opens a window for an early intervention strategy to possibly prevent or delay neuron and memory loss."
Ceftriaxone is an antibiotic that is commonly administered before some types of surgery to prevent infections. Although a recent clinical trial failed to see improvements for treating amyotrophic lateral sclerosis (ALS), the researchers are hopeful about its potential for early intervention in treating Alzheimer's disease.
Materials provided by University of British Columbia. Note: Content may be edited for style and length.
J. K. Hefendehl, J. LeDue, R. W. Y. Ko, J. Mahler, T. H. Murphy, B. A. MacVicar. Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging. Nature Communications, 2016; 7: 13441 DOI: 10.1038/ncomms13441
Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging
J. K. Hefendehl, J. LeDue, R. W. Y. Ko, J. Mahler, T. H. Murphy & B. A. MacVicar
Nature Communications 7, Article number: 13441 (2016)
26 June 2016
04 October 2016
11 November 2016
Amyloid-β (Aβ) plaques, a hallmark of Alzheimer’s disease (AD), are surrounded by regions of neuronal and glial hyperactivity. We use in vivo two-photon and wide-field imaging of the glutamate sensor iGluSnFR to determine whether pathological changes in glutamate dynamics in the immediate vicinity of Aβ deposits in APPPS1 transgenic mice could alter neuronal activity in this microenvironment. In regions close to Aβ plaques chronic states of high spontaneous glutamate fluctuations are observed and the timing of glutamate responses evoked by sensory stimulation exhibit slower decay rates in two cortical brain areas. GLT-1 expression is reduced around Aβ plaques and upregulation of GLT-1 expression and activity by ceftriaxone partially restores glutamate dynamics to values in control regions. We conclude that the toxic microenvironment surrounding Aβ plaques results, at least partially, from enhanced glutamate levels and that pharmacologically increasing GLT-1 expression and activity may be a new target for early therapeutic intervention.
Probiotics can help thinking and memory for people with Alzheimer’s disease
Sarah Knapton, science editor
10 NOVEMBER 2016
Probiotics found in yoghurt and supplements could help improve the thinking and memory for people with Alzheimer’s disease, research has found.
In a clinical trial involving 52 people, those who drank a daily dose of lactobacillus and bifidobacterium bacteria for 12 weeks showed improvements on tests to measure cognitive impairment.
In contrast, those who were not given the probiotic supplements declined over the same period.
Researchers at from Kashan University of Medical Sciences, Kashan, and Islamic Azad University, in Tehran, Iran, say that it suggests altering gut bacteria could help people suffering from neurodegenerative conditions.
"In a previous study, we showed that probiotic treatment improves the impaired spatial learning and memory in diabetic rats, but this is the first time that probiotic supplementation has been shown to benefit cognition in cognitively impaired humans," says Professor Mahmoud Salami from Kashan University, the senior author of the study.
"These findings indicate that change in the metabolic adjustments might be a mechanism by which probiotics affect Alzheimer's and possibly other neurological disorders," says Salami. "We plan to look at these mechanisms in greater detail in our next study."
Probioticsare known to give partial protection against certain conditions such as irritable bowel syndrome, inflammatory bowel disease, eczema, allergies, colds, tooth decay, and periodontal disease.
But scientists have long hypothesized that probiotics might also boost cognition, as there is continuous two-way communication between the intestinal bacteria and the brain along the so-called "microbiota-gut-brain axis" which links the nervous system, the immune system, and hormones.
In mice, probiotics have been shown to improve learning and memory, and reduce anxiety and depression. But until not there has been no evidence of cognitive benefits in humans.
The researchers conducted a trial in which women and men with Alzheimer’s disease, aged between 60 and 95. Half of the patients daily received 200 ml milk enriched with four probiotic bacteria Lactobacillus acidophilus, L. casei, L. fermentum, and Bifidobacterium bifidum - approximately 400 billion bacteria per species -while the other half received untreated milk.
Many probiotic yoghurts and drinks, such as Yakult, contain the same bacteria although in smaller doses. Yakult, for example contains around 6.5 billion L. casei, while most supplements contain around 30 billion.
At the beginning and the end of the 12-week experimental period, the scientists tested the cognitive function of the subjects with Mini-Mental State Examination (MMSE) scale, a standard measure of cognitive impairment, which includes tasks like giving the current date, counting backwards from 100 by sevens, naming objects, repeating a phrase, and copying a picture.
Over the course of the study, the average score on the MMSE questionnaire significantly increased, from 8.7 to 10.6, out of a maximum of 30, in the group receiving probiotics, but not in the control group, where it fell from 8.5 to 8.0.
Even though this increase is moderate, and all patients remained severely cognitively impaired, the results are the first to show that probiotics can improve human cognition.
Walter Lukiw, Professor of Neurology, Neuroscience and Ophthalmology and Bollinger Professor of Alzheimer's disease at Louisiana State University, who reviewed the study but was not involved in the research, said: "This early study is interesting and important because it indicates that probiotics can in principle improve human cognition.
“This is in line with some of our recent studies which indicate that the gastrointestinal tract microbiome in Alzheimer's is significantly altered in composition when compared to age-matched controls.”
Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said: “The brain is often viewed as being separate from the rest of the body but scientists are understanding more about how changes in the body can impact upon the brain too. This new study raises interesting questions about the link between the gut and the brain, and their association with Alzheimer’s disease.
"The improvements in memory and thinking seen in people with Alzheimer’s disease in this study will need to be repeated in much larger studies before we can understand the real benefits of probiotics for the brain. We don’t fully understand how changes in the gut could be affecting the brain, and Alzheimer’s Research UK is funding research in this area to improve our understanding of this link.”
The study was published in the journal Frontiers in Aging Neuroscience.
Front. Aging Neurosci., 10 November 2016 | http://dx.doi.org/10.3389/fnagi.2016.00256
Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial
Elmira Akbari1, Zatollah Asemi2*, Reza Daneshvar Kakhaki3, Fereshteh Bahmani2, Ebrahim Kouchaki3, Omid Reza Tamtaji1, Gholam Ali Hamidi1 and Mahmoud Salami1*
1Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran
2Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
3Department of Neurology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
Alzheimer's disease (AD) is associated with severe cognitive impairments as well as some metabolic defects. Scant studies in animal models indicate a link between probiotics and cognitive function. This randomized, double-blind, and controlled clinical trial was conducted among 60 AD patients to assess the effects of probiotic supplementation on cognitive function and metabolic status. The patients were randomly divided into two groups (n = 30 in each group) treating with either milk (control group) or a mixture of probiotics (probiotic group). The probiotic supplemented group took 200 ml/day probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum (2 × 109 CFU/g for each) for 12 weeks. Mini-mental state examination (MMSE) score was recorded in all subjects before and after the treatment. Pre- and post-treatment fasting blood samples were obtained to determine the related markers. After 12 weeks intervention, compared with the control group (?5.03% ± 3.00), the probiotic treated (+27.90% ± 8.07) patients showed a significant improvement in the MMSE score (P <0.001). In addition, changes in plasma malondialdehyde (?22.01% ± 4.84 vs. +2.67% ± 3.86 μmol/L, P <0.001), serum high-sensitivity C-reactive protein (?17.61% ± 3.70 vs. +45.26% ± 3.50 μg/mL, P <0.001), homeostasis model of assessment-estimated insulin resistance (+28.84% ± 13.34 vs. +76.95% ± 24.60, P = 0.002), Beta cell function (+3.45% ± 10.91 vs. +75.62% ± 23.18, P = 0.001), serum triglycerides (?20.29% ± 4.49 vs. ?0.16% ± 5.24 mg/dL, P = 0.003), and quantitative insulin sensitivity check index (?1.83 ± 1.26 vs. ?4.66 ± 1.70, P = 0.006) in the probiotic group were significantly varied compared to the control group. We found that the probiotic treatment had no considerable effect on other biomarkers of oxidative stress and inflammation, fasting plasma glucose, and other lipid profiles. Overall, the current study demonstrated that probiotic consumption for 12 weeks positively affects cognitive function and some metabolic statuses in the AD patients. Clinical Trial Registration: http://www.irct.ir/, IRCT201511305623N60.
Alzheimer's treatment within reach after successful drug trial
2 November 2016
Tablet that ‘switches off’ production of toxic amyloid proteins could be first treatment licensed in a decade if it is also shown to slow mental decline
An Alzheimer’s drug has been shown to successfully target the most visible sign of the disease in the brain, raising hopes that an effective treatment could be finally within reach.
A small trial of the drug was primarily aimed at assessing safety, but the findings suggest it effectively “switched off” the production of toxic amyloid proteins that lead to the sticky plaques seen in the brains of Alzheimer’s patients.
If the tablet, produced by pharmaceutical giant Merck, is also shown to slow the pace of mental decline ? a crucial question that a major clinical trial should answer when it reports next year ? it could be the first treatment for Alzheimer’s to be licensed in more than a decade.
Prof John Hardy, a neuroscientist at UCL who first proposed that amyloid proteins play a central role in Alzheimer’s disease, welcomed the results. “People are excited,” he said. “This is a very nice drug and I’m sure Merck are feeling very pleased with themselves.”
Matt Kennedy, who led the trial at Merck, said: “Today there are very limited therapeutic options available for people with Alzheimer’s disease, and those that exist provide only short-term improvement to the cognitive and functional symptoms. They do not directly target the underlying disease processes. There is an urgent need for [these].”
The new therapy is designed to do this by halting the steady production of amyloid-beta proteins, which are known to clump together in sticky plaques in the brains of Alzheimer’s patients. A leading theory of Alzheimer’s is that the accumulating proteins kill off healthy neurons, eventually leading to memory loss, cognitive decline and changes to personality.
Kennedy said it was too early to predict when a drug might reach the market if the next step is successful. “We are eagerly awaiting the results of the phase three clinical trials,” he said. “It is premature to speculate on availability.”
In the trial, published in the journal Science Translational Medicine on Wednesday, 32 patients with early stage Alzheimer’s disease were given the drug, called verubecestat, daily for seven days. Healthy volunteers were also given the drug for up to two weeks.
This was not long enough to show visible changes to the accumulation of plaques in the brain, by MRI scans for instance. However, samples taken from the fluid surrounding the brain showed the drug had reduced the levels of two compounds that are known to be the building blocks for abnormal amyloid proteins.
Hardy said that the changes to the biomarkers convince him that the drug is successfully targeting the buildup of plaques in the brain. The real remaining uncertainty, he said, was whether this would convert into cognitive benefits for patients.
“What we have to be worried about is that the plaques have set off other pathologies - that it is too late,” he said.
The drug works by blocking a brain enzyme called BACE1, which fuels the production of two small molecules that link together to form amyloids. Mutations in genes related to BACE1 have been found in people who appear to be protected against Alzheimer’s disease.
There have been previous attempts to develop drugs that inhibit BACE1, but these have mostly failed due to unacceptable side-effects, such as liver toxicity and eye problems.
The Merck drug appears to have very few side-effects and it will be the first of its kind to make it into a large efficacy trial. The company is running two phase three trials, in 1,500 patients with mild to moderate Alzheimer’s and in another 2,000 patients in the earliest stage of the disease. The results of the first of these are due to be reported in July 2017.
There are 850,000 people with dementia in Britain, and this figure is expected to reach one million by 2025. Alzheimer’s is the most common form of the condition.
Rosa Sancho, head of research at Alzheimer’s Research UK, welcomed the findings, adding that the Merck drug is one of several that are heading into the final stages of clinical testing. “There is a wave of potential new treatments currently being tested for dementia, with the results of these studies hotly anticipated over the course of the coming months and years,” she said.
Competing drugs include one developed by the biotech firm Biogen, which reported promising results in August and which also targets the plaques. The Biogen drug aims to sweep the proteins away once they appear rather than halting the production of proteins in the first place, however.
“With us, it’s a question of switching off the tap. With them it’s mopping up the water,” said Ian McConnell, a spokesman for Merck.
Hardy suggested that Merck’s drug is likely to be far cheaper and easier to produce than the Biogen therapy, which involves injecting patients with antibodies.
The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients
Matthew E. Kennedy1,*, Andrew W. Stamford2,*, Xia Chen1, Kathleen Cox3, Jared N. Cumming2, Marissa F. Dockendorf3, Michael Egan4, Larry Ereshefsky5, Robert A. Hodgson1,†, Lynn A. Hyde1, Stanford Jhee5, Huub J. Kleijn3,‡, Reshma Kuvelkar1, Wei Li2, Britta A. Mattson6, Hong Mei3, John Palcza7, Jack D. Scott2, Michael Tanen8, Matthew D. Troyer9,§, Jack L. Tseng9,¶, Julie A. Stone3, Eric M. Parker1,* and Mark S. Forman9,*
Science Translational Medicine 02 Nov 2016:
Vol. 8, Issue 363, pp. 363ra150
β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer’s disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.
Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model
Gerhard Leinenga and J?rgen G?tz*
+ Author Affiliations
?*Corresponding author. E-mail: email@example.com
Science Translational Medicine 11 Mar 2015:
Vol. 7, Issue 278, pp. 278ra33
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.
DEMENTIA PILL Experimental drug ‘REVERSES Alzheimer’s ? clearing the brain of disease-causing toxins’
The drug stops the build up of toxic proteins in the brain - a key hallmark of the most common form of dementia
25th October 2016
A new drug could reverse Alzheimer’s disease, scientists hope.
The experimental therapy restored the memory of mice in the lab ? raising hopes it will pave the way for new treatments in humans.
An experimental drug has been shown to reverse the cause of Alzheimer's in mice, raising hopes it will one day prove effective in humans GETTY IMAGES
An experimental drug has been shown to reverse the cause of Alzheimer’s in mice, raising hopes it will one day prove effective in humans
Experts said it “shows promise”, as it targets the cause as well as the symptoms of dementia.
The drug removes toxic proteins that clump together in the brain, triggering the devastating illness.
Developing a drug for Alzheimer’s is one of the great challenges for modern medicine.
There are 850,000 sufferers in the UK alone, with the figure set to rise to a million by 2025.
The drug, known as NTRX-07, appears to decrease inflammation while preserving neurons and regenerative cells in the brain.
A key characteristic of Alzheimer’s is the development of abnormal clusters of proteins called amyloid plaques and tangled bundles of fibres in the brain.
These changes cause inflammation and damage to the neurons leading to memory loss, confusion and dementia.
Professor Mohamed Naguib, of the Cleveland Clinic, Ohio, said: “This drug may reduce inflammation in the brain, which is linked to Alzheimer’s disease.
“NTRX-07 uses a different mechanism than many other Alzheimer’s drugs currently available, as it targets the cause of the disease, not just the symptoms.”
The researchers tested NTRX-07 on mice who were bred to have a condition similar to Alzheimer’s.
They found inflammation triggered by the disease caused changes in immune cells in the brain ? known as microglia.
These cells are the ones that typically remove the dangerous amyloid plaques in the brain, in healthy people.
As the toxic proteins built up in the brain, the microglia were unable to remove them, causing inflammation and damage to the nerve cells, which reduced cognitive ability.
The researchers noted the drug could activate microglia cells to fight the inflammation.
It helped remove abnormal amyloid plaques and improved memory function and other mental skills in the mice.
The build up of amyloid in the brain has been a treatment target for many years. But there have been many disappointments in Alzheimer’s drug development.
The brain of an Alzheimer’s patient shows significant signs of shrinking compared to a normal brain.
Dementia is a gradual decline of how the brain functions. It is incurable, and slowly interferes with a person’s ability to carry out the normal tasks of daily living.
It can also trigger other mental health problems such as personality changes, anxiety, mood swings and depression.
In the more advanced stages of dementia, the person may lose the ability to get up and move, or the interest to eat or drink.
The drug was unveiled at the Anesthesiology annual meeting in Chicago, which is organised by the American Society of Anesthesiologists.
New drug could slow or halt Alzheimer's, says leader of clinical trials
OCTOBER 17 2016
"The worst thing about dementia is that you progressively lose the person that you love," says Anne Tudor, and she knows it first hand.
Her partner, Edie Mayhew, 65, was diagnosed six years ago with early onset Alzheimer's disease. The Ballarat couple try to stay positive, and travel interstate and overseas giving talks on healthy living.
But Ms Tudor has watched as Ms Mayhew, a former driving instructor, has lost the ability to cook a meal, choose clothes and remember conversations.
They welcomed the news that human trials will begin in Melbourne on Monday for a new drug that has been shown to halt the progression of Alzheimer's disease in mice and to reverse memory loss.
Volunteers who have been diagnosed with mild to moderate Alzheimer's are being sought to take an oral medication and be monitored on its effects.
The study's lead researcher, Austin Health associate professor Michael Woodward, said the drug, called CT1812, had been found in mice to negate the effects of the toxic protein amyloid beta ? which causes Alzheimer's ? at both cellular and behavioural level, and to improve memory.
He said the new drug could slow or halt the human progression of Alzheimer's, from which 350,000 Australians currently suffer, with one million projected to be diagnosed by 2050.
Susan Catalano?, chief science officer of the trial's backers, private US biotech company Cognition Therapeutics, or CogRx, said previous therapies had focused on trying to eliminate plaques caused by the build-up of amyloid beta in the brain.
The new approach focused on how these proteins link together to form clumps called oligomers, which bind to receptors in the synapses responsible for communication between brain cells.
The binding process kills off parts of the receptors and, in turn, disables the synapses. The process of memory formation fails, and Alzheimer's symptoms start to appear.
Dr Catalano said the drug CT1812 had been found ? in mice that had been genetically engineered to over-produce amyloid beta ? to shield synapses from the effects of oligomers It did this by the drug itself binding to one type of receptor, changing the receptor's shape so the oligomers are either unable to take hold, or are displaced.
A selection of CogRx study drugs, including CT1812, reversed the memory loss after one month of treatment and sustained the memory improvement for six months.
Volunteers aged 50 to 80 are needed for the trial at Austin Health, in Heidelberg, Melbourne Health at Parkville, Epworth Hospital in Richmond and with Dr Philip Morris in Southport, Queensland from now until January.
Associate Professor Woodward said previous studies had tried to neutralise amyloid beta, but this therapy was about protecting cells from its effects ? "a very new and refreshing approach".
Ms Mayhew welcomed the trial and said she would consider signing up. "If it can help other people with dementia, then I'm happy to do it. It might help me as well," she said.
Ms Tudor said: "It sounds really promising. We'd love to see something to stop it from getting worse ? or even better, to prevent it from happening in the first place."
Potential drug trial participants and/or carers can call 1800 558 952 or visit this website.
selective induction of PGC-1α
Gene injection to brain could halt Alzheimer's disease
10 OCTOBER 2016
Alzheimer’s disease could be stopped in its tracks with an injection into the memory centres of the brain to boost a gene which clears out destructive sticky plaques, scientists believe.
Four years ago, researchers discovered that a protein called PGC1 -alpha was vital for preventing the build-up of amyloid beta plaques, but people with Alzheimer’s disease do not produce sufficient amounts.
Now scientists have shown it is possible to deliver a gene which produces the plaque-busting protein directly into the brain.
Mice treated with the gene therapy at the early stages of Alzheimer’s disease did not develop any plaques and performed as well in memory tasks as healthy mice after four months.
Dr Magdalena Sastre, senior author of the research from the Department of Medicine at Imperial College, said the findings could one day provide a method of preventing the disease, or halting it in the early stages. “Although these findings are very early they suggest this gene therapy may have potential therapeutic use for patients,” she said.
“There are many hurdles to overcome, and at the moment the only way to deliver the gene is via an injection directly into the brain. However this proof of concept study shows this approach warrants further investigation.
“In a disease that urgently needs new options for patients, this work provides hope for future therapies.
Alzheimer’sdisease affects around 520,000 people in the UK. Symptoms include memory loss, confusion, and change in mood or personality. There is no cure, although current drugs can help treat the symptoms of the disease.
The team used a type of modified virus to deliver a gene to brain cells. The harmless virus, which has been edited to include the gene, infects brain cells and rewrites there genetic code to produce more of the plaque-fighting protein. Injections were given in the hippocampus and cortex of the brain, which are responsible for memory formation and orientation and are the first to be affected by Alzheimer’s disease.
Professor Nicholas Mazarakis, co-author of the study from the Department of Medicine at Imperial added: “Scientists harness the way lentivirus infects cells to produce a modified version of the virus, that delivers genes into specific cells.
“It is being used in experiments to treat a range of conditions from arthritis to cancer. We have previously successfully used the lentivirus vector in clinical trials to deliver genes into the brains of Parkinson’s disease patients.”
The team believes that injections of the gene would be most beneficial in the early stages of the disease, when the first symptoms appear.
Dr David Reynolds, chief scientific officer at Alzheimer’s Research UK, said: “There are currently no treatments able to halt the progression of damage in Alzheimer’s, so studies like this are important for highlighting new and innovative approaches to take us towards that goal.
“This research sets a foundation for exploring gene therapy as a treatment strategy for Alzheimer’s disease, but further studies are needed to establish whether gene therapy would be safe, effective and practical to use in people with the disease.”
Prof Rob Howard, professor of old age psychiatry, UCL, said: “In terms of identifying a potential mechanism for the treatment of people with Alzheimer's disease, this work looks promising.
“Before clinical effectiveness trials of this technology in Alzheimer patients can be conducted, I would anticipate several years of early phase and safety studies. Only time will tell.”
Dr Doug Brown, director of research and development, Alzheimer’s Society, said: “This research takes a new approach to tackling the underlying causes of Alzheimer’s disease ? using a technique called gene therapy to interrupt the production of amyloid protein, one of the key hallmarks of Alzheimer’s.
“So far, potential treatments that directly target amyloid build-ups in the brain have mostly had disappointing results in clinical trials, whereas this study could pave the way for a new plan of attack.”
PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model
Loukia Katsouria, Yau M. Lima, Katrin Blondratha, Ioanna Eleftheriadoub, Laura Lombarderoa, Amy M. Bircha, Nazanin Mirzaeia, Elaine E. Irvinec, Nicholas D. Mazarakisb,1, and Magdalena Sastrea,1
Edited by Gregory A Petsko, Weill Cornell Medical College, New York, NY, and approved August 23, 2016 (received for review April 18, 2016)
AbstractFull TextAuthors & InfoFiguresSIMetricsPDFPDF + SI
The PPARγ-coactivator-1α (PGC-1α) is a transcriptional regulator of genes involved in energy metabolism. We observed previously that PGC-1α decreases the generation of Aβ in cell culture, and its levels are reduced in Alzheimer’s disease (AD) brains. To determine its potential therapeutic role in vivo, we delivered PGC-1α in specific brain areas of an AD model by using viral vectors. We found that PGC-1α?injected mice showed decreased Aβ plaques by reducing the expression of the main enzyme involved in Aβ production, preserving most neurons in the brain and performing as well as wild-type mice in cognitive tests. Therefore, PGC-1α selective delivery shows promising therapeutic value in AD.
Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.
The research, which was funded by Alzheimer’s Research UK and the European Research Council, was published in the journal Proceedings of the National Academy of Sciences.
Study reveals potential new strategy to prevent Alzheimer's disease
October 7, 2016
by Graciela Gutierrez
Taking a pill that prevents the accumulation of toxic molecules in the brain might someday help prevent or delay Alzheimer's disease, according to scientists at Baylor College of Medicine, Texas Children's Hospital and Johns Hopkins University School of Medicine.
The study, published today in Cell Press journal Neuron, took a three-pronged approach to help subdue early events that occur in the brain long before symptoms of Alzheimer's disease are evident. The scientists were able to prevent those early events and the subsequent development of brain pathology in experimental animal models in the lab.
"Common diseases like Parkinson's, Alzheimer's and dementia are caused in part by abnormal accumulation of certain proteins in the brain," said senior author Dr. Huda Zoghbi, professor of molecular and human genetics and of pediatrics - neurology and developmental neuroscience at Baylor and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital. "Some proteins become toxic when they accumulate; they make the brain vulnerable to degeneration. Tau is one of those proteins involved in Alzheimer's disease and dementia."
"Scientists in the field have been focusing mostly on the final stages of Alzheimer's disease," said first author Dr. Cristian Lasagna-Reeves, postdoctoral fellow in the Zoghbi lab. "Here we tried to find clues about what is happening at the very early stages of the illness, before clinical irreversible symptoms appear, with the intention of preventing or reducing those early events that lead to devastating changes in the brain decades later."
The scientists reasoned that if they could find ways to prevent or reduce tau accumulation in the brain, they would uncover new possibilities for developing drug treatments for these diseases.
Cells control the amount of their proteins with other proteins called enzymes. To find which enzymes affect tau accumulation, the scientists systematically inhibited enzymes called kinases.
"We inhibited about 600 kinases one by one and found one, called Nuak1, whose inhibition resulted in reduced levels of tau," said Zoghbi, who is also an investigator at the Howard Hughes Medical Institute.
The scientists screened the enzymes in two different systems, cultured human cells and the laboratory fruit fly. Screening in the fruit fly allowed the scientists to assess the effects of inhibiting the enzymes in a functional nervous system in a living organism.
"Screening hundreds of kinases in the fruit fly animal model was critical because we could assess degeneration caused by tau in the fly's nervous system and measure neuronal dysfunction. Screening such a large number cannot be done with other animal models like the mouse, and cultured cells cannot model complex nervous system functions," said co-senior author Dr. Juan Botas, professor of molecular and human genetics and of molecular and cellular biology at Baylor.
"We found one enzyme, Nuak1, whose inhibition consistently resulted in lower levels of tau in both human cells and fruit flies," said Zoghbi. "Then we took this result to a mouse model of Alzheimer's disease and hoped that the results would hold, and they did. Inhibiting Nuak1 improved the behavior of the mice and prevented brain degeneration."
"Confirming in three independent systems ? human cells, the fruit fly and the mouse ? that Nuak1 inhibition results in reduced levels of tau and prevents brain abnormalities induced by tau accumulation, has convinced us that Nuak1 is a reliable potential target for drugs to prevent diseases such as Alzheimer's," said Zoghbi. "The next step is to develop drugs that will inhibit Nuak1 in hope that one day would be able to lower tau levels with low toxicity in individuals at risk for dementia due to tau accumulation."
Scientific studies like this one that uncover basic biological mechanisms of disease make it possible to develop new strategies to prevent or treat diseases such as Alzheimer's, Parkinson's or dementia.
In the future it might be possible to treat people at risk for Alzheimer's disease by keeping tau low. Think of how taking drugs that lower cholesterol has helped control the accumulation of cholesterol in blood vessels that leads to atherosclerosis and heart disease.
"When people started taking drugs that lower cholesterol, they lived longer and healthier lives rather than dying earlier of heart disease," said Zoghbi. "Nobody has thought about Alzheimer's disease in that light. Tau in Alzheimer's can be compared to cholesterol in heart disease. Tau is a protein that when it accumulates as the person ages, increases the vulnerability of the brain to developing Alzheimer's. So maybe if we can find drugs that can keep tau at levels that are not toxic for the brain, then we would be able to prevent or delay the development of Alzheimer's and other diseases caused in part by toxic tau accumulation."
"Just like people now take their cholesterol-lowering medications, people in the future could be taking medications to keep tau levels low and prevent the development of Alzheimer's disease," said Lasagna-Reeves.
Explore further: Abnormal brain protein may contribute to Alzheimer's disease development
More information: Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model, Neuron, Available online 6 October 2016, ISSN 0896-6273, dx.doi.org/10.1016/j.neuron.2016.09.022.
Journal reference: Neuron
Provided by: Baylor College of Medicine
Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model
Cristian A. Lasagna-Reeves, Maria de Haro, Shuang Hao, Jeehye Park10, Maxime W.C. Rousseaux, Ismael Al-Ramahi, Paymaan Jafar-Nejad11, Luis Vilanova-Velez, Lauren See, Antonia De Maio, Larissa Nitschke, Zhenyu Wu, Juan C. Troncoso, Thomas F. Westbrook, Jianrong Tang, Juan Botas, Huda Y. Zoghbi12,correspondencePress enter key for correspondence informationemailPress enter key to Email the author
10Present address: Program in Genetics and Genome Biology, The Hospital for Sick Children, The University of Toronto, Toronto, ON M5G 0A4, Canada
11Present address: Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA
Publication stage: In Press Corrected Proof
Many neurodegenerative proteinopathies share a common pathogenic mechanism: the abnormal accumulation of disease-related proteins. As growing evidence indicates that reducing the steady-state levels of disease-causing proteins mitigates neurodegeneration in animal models, we developed a strategy to screen for genes that decrease the levels of tau, whose accumulation contributes to the pathology of both Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Integrating parallel cell-based and Drosophila genetic screens, we discovered that tau levels are regulated by Nuak1, an AMPK-related kinase. Nuak1 stabilizes tau by phosphorylation specifically at Ser356. Inhibition of Nuak1 in fruit flies suppressed neurodegeneration in tau-expressing Drosophila, and Nuak1 haploinsufficiency rescued the phenotypes of a tauopathy mouse model. These results demonstrate that decreasing total tau levels is a valid strategy for mitigating tau-related neurodegeneration and reveal Nuak1 to be a novel therapeutic entry point for tauopathies.
Old drug may offer new answers in the fight against Alzheimer's
July 2, 2016
Researchers say that methylene blue, a chemical commonly used by aquarium hobbyists, may offer a promising new way treating memory disorders like Alzheimer's and dementia.
Their findings, published earlier this week, show that small oral doses of the drug improved memory and brain function in a small number of healthy test subjects.
"We're very excited about it," lead researcher Dr. Timothy Duong, a professor of ophthalmology and radiology at the University of Texas Health Science Center, told CTV News.
Researchers say that methylene blue may offer a new way to treat memory disorders like Alzheimer's and dementia.
"If this is proven true, then we have potential to at least slow down progressions of memory disorders."
Duong is hoping to conduct further research.
Methylene blue was first used to treat malaria in the 1890s. Since then, the compound has been used to fight everything from psoriasis to West Nile virus to hepatitis C. Today, it's commonly prescribed to patients with certain blood disorders and psychiatric conditions like schizophrenia. It has also been used as a dye and is sold commercially as an easy way to treat fungal infections in aquarium fish.
There is now growing interest in understanding methylene blue's ability to energize and protect brain cells from damage, making it a potential therapy for strokes, brain injuries and even mental health conditions.
At Dalhousie University, a recent study found that it can also be an effective and inexpensive add-on treatment for bipolar disorder.
"The patients who were taking the medication felt less depressed," psychiatry professor Dr. Martin Alda told CTV News.
"They felt significantly also less anxious and many of them subjectively felt that their thinking was also more clear."
The drug was put into pill form for patients by a compounding pharmacy. When the Dalhousie study ended, some patients ? like 54-year-old Lemuel Boutilier ? asked to stay on the drug.
"Methylene blue has changed my life and I can't say that enough," Boutilier said.
For two decades, Boutilier has struggled with the ups and downs of bipolar disorder, despite taking a host of medications. Methylene blue, Boutilier says, has brought him stability.
"It has reduced the amount of medication that I'm on because it allows a calmness to develop and it cuts down on agitation and depression."
Some researchers think the drug helps brain cells work with reviewed vigour, helping them produce more energy while helping clear disease-causing toxins from the brain ? though they don't yet fully understand how it works.
Because methylene blue is an old medication, it cannot be patented and is considered an orphan drug that offers no profit to pharmaceutical companies, so research has been slow. However, some companies are patenting new drugs that contain components of methylene blue.
Doctors say that however encouraging the data, the drug should not be used without medical supervision.
That isn't stopping some.
Joe Cohen has been self-administering the drug to boost his mental performance.
The California-based blogger with selfhacked.com has posted videos on YouTube of himself taking the chemical.
"I just noticed processing improved," Cohen says. "Short term memory improved -- nothing dramatic… just able to remember more things slightly sharper. So, for these reasons, I continue taking it."
The U.S. Food and Drug Administration, however, warns that the chemical can lead to serotonin toxicity and damaged DNA.
With a report from CTV medical specialist Avis Favaro and producer Elizabeth St. Philip
Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain
Pavel Rodriguez, MD , Wei Zhou, BS , Douglas W. Barrett, PhD , Wilson Altmeyer, MD , Juan E. Gutierrez, MD , Jinqi Li, MD , Jack L. Lancaster, PhD , Francisco Gonzalez-Lima, PhD , Timothy Q. Duong, PhD
From the Research Imaging Institute (P.R., W.Z., J.L., J.L.L., T.Q.D.) and Department of Radiology (P.R., W.A., J.E.G.), The University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, San Antonio, TX 78229; and Department of Psychology and Institute for Neuroscience, The University of Texas at Austin, Austin, Tex (D.W.B., F.G.L.).
Address correspondence to T.Q.D. (e-mail: firstname.lastname@example.org).
To investigate the sustained-attention and memory-enhancing neural correlates of the oral administration of methylene blue in the healthy human brain.
Materials and Methods
The institutional review board approved this prospective, HIPAA-compliant, randomized, double-blinded, placebo-controlled clinical trial, and all patients provided informed consent. Twenty-six subjects (age range, 22?62 years) were enrolled. Functional magnetic resonance (MR) imaging was performed with a psychomotor vigilance task (sustained attention) and delayed match-to-sample tasks (short-term memory) before and 1 hour after administration of low-dose methylene blue or a placebo. Cerebrovascular reactivity effects were also measured with the carbon dioxide challenge, in which a 2 × 2 repeated-measures analysis of variance was performed with a drug (methylene blue vs placebo) and time (before vs after administration of the drug) as factors to assess drug × time between group interactions. Multiple comparison correction was applied, with cluster-corrected P < .05 indicating a significant difference.
Administration of methylene blue increased response in the bilateral insular cortex during a psychomotor vigilance task (Z = 2.9?3.4, P = .01?.008) and functional MR imaging response during a short-term memory task involving the prefrontal, parietal, and occipital cortex (Z = 2.9?4.2, P = .03?.0003). Methylene blue was also associated with a 7% increase in correct responses during memory retrieval (P = .01).
Low-dose methylene blue can increase functional MR imaging activity during sustained attention and short-term memory tasks and enhance memory retrieval.
? RSNA, 2016
Fe2+ chelating agents and resveratrol
PUBLIC RELEASE: 24-JUN-2016
Combination therapy may hold the key to slowing down Alzheimer's disease
The research article 'Resveratrol as a Potential Therapeutic Candidate for the Treatment and Management of Alzheimer's Disease' by Dr. Nady Braidy et al. is published in Current Topics in Medicinal Chemistry, volume 16, issue 17
BENTHAM SCIENCE PUBLISHERS
Resveratrol is a naturally occurring polyphenolic phytochemical produced in several plants, especially grapes skin and seeds. One epidemiological study reported a positive association between moderate red wine consumption and a low incidence of cardiovascular disease, known as the "French Paradox." The neuroprotective effects of resveratrol for the treatment of Alzheimer's disease (AD) have been investigated in various in vitro and in vivo models of AD. Despite the high bioactivity of resveratrol in AD, there is poor bioavailability of resveratrol, that is, the concentrations required producing favourable biological effects in the brain and neuronal cells are insufficient to demonstrate efficacy in humans. Therefore, successful clinical application of resveratrol as a single 'take home' oral therapy alone presents a major challenge for the treatment of AD.
We propose herein a novel combination therapy consisting of an agent for chelating redox-active metals (Fe2+) and/or an antioxidant to reduce damage caused by residual oxygen free radicals, in addition to resveratrol, a modulator of AMPK and sirtuin pathways (nuclear transcription). The addition of resveratrol may have the capacity to increase activity of the NAD+- dependant deacetylases such as sirtuin family enzymes (e.g. SIRT1) and promote improved DNA repair by enhancing PARP enzyme activity through increased production of their essential substrate NAD+, and thus improve cell viability and longevity. A synergistic combination of a selected antioxidant substances, Fe2+ chelating agents and resveratrol may be expected to provide a more clinically successful treatment.
Nady Braidy, Bat-Erdene Jugder, Anne Poljak, Tharusha Jayasena, Hussein Mansour, Seyed Mohammad Nabavi, Perminder Sachdev and Ross Grant.
Affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney
Resveratrol as a Potential Therapeutic Candidate for the Treatment and Management of Alzheimer’s Disease
Current Topics in Medicinal Chemistry, 16(17): 1951-1960.
Author(s): Nady Braidy, Bat-Erdene Jugder, Anne Poljak, Tharusha Jayasena, Hussein Mansour, Seyed Mohammad Nabavi, Perminder Sachdev and Ross Grant.
Affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney.
Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical present in red wine, grapes, berries, chocolate and peanuts. Clinically, resveratrol has exhibited significant antioxidant, anti-inflammatory, anti-viral, and anti-cancer properties. Although resveratrol was first isolated in 1940, it was not until the last decade that it was recognised for its potential therapeutic role in reducing the risk of neurodegeneration, and Alzheimer's disease (AD) in particular. AD is the primary cause of progressive dementia. Resveratrol has demonstrated neuroprotective effects in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that resveratrol also facilitates non-amyloidogenic breakdown of the amyloid precursor protein (APP), and promotes removal of neurotoxic amyloid beta (Aβ) peptides, a critical step in preventing and slowing down AD pathology. Resveratrol also reduces damage to neuronal cells via a variety of additional mechanisms, most notably is the activation of NAD+-dependent histone deacetylases enzymes, termed sirtuins. However in spite of the considerable advances in clarifying the mechanism of action of resveratrol, it is unlikely to be effective as monotherapy in AD due to its poor bioavailability, biotransformation, and requisite synergism with other dietary factors. This review summarizes the relevance of resveratrol in the pathophysiology of AD. It also highlights why resveratrol alone may not be an effective single therapy, and how resveratrol coupled to other compounds might yet prove an effective therapy with multiple targets.
Axon’s Alzheimer’s vaccine hits Phase II as it seeks to prove efficacy
by Ben Adams
Jun 22, 2016
Slovakian biotech Axon Neuroscience has treated the first patient with its closely watched Alzheimer’s vax AADvac1--which is aiming to be the first disease-modifying tau vaccine for the memory-stealing disease.
There are two camps in Alzheimer’s research as to what causes the disease. The first, known as the amyloid cascade theory, sees the onset of Alzheimer’s disease (AD) as being connected to the buildup of an abnormal protein called amyloid-beta (Aβ), and stands as the most studied explanation of AD.
Those who support this viewpoint have been known as “baptists,” and this area has been the focus of Big Pharmas Pfizer ($PFE) and Eli Lilly ($LLY) among others--although a number of recent late-stage results have been disappointing to say the least--with the entire pipeline for drugs against the disease full of flops and failures across the industry. (Overall clinical trial failure rates in Alzheimer's have been estimated as high as 99% in the past decade.)
And then there’s the second hypothesis--which is gaining more research time--that associates the onset of the disease instead to fibrillary tangles called tau protein. Neurofibrillary tangles group in an insoluble form in neurons, affecting normal neuronal functions.
Scientists in support of this theory, the “tauists,” are attempting to target and block tau hyperphosphorylation in Alzheimer’s patients in hopes of relieving the negative consequences of the disease.
Axon is working the latter tau theory and began human testing back in 2013. AADvac1 targets the anti-tau phosphorylation and consists of synthetic polypeptides, which are meant to elicit an immune response against pathogenic tau proteins.
Phase I results, posted last year at the Alzheimer’s Association International Conference, showed it was safe and well tolerated. Now the real work begins, as it starts its larger Phase II safety and efficacy trial where the primary goal is to confirm its earlier results by assessing safety and immunogenicity on a larger sample of patients with mild Alzheimer’s disease.
As a second and more important objective for its future, the study will also evaluate the effect of the AADvac1 vaccine in slowing down or halting the cognitive decline in patients over the period of around 2 years.
The Adamant study will also explore and show the disease-modifying effect on the Clinical Dementia Rating (CDR) Sum of Boxes, supported by a custom cognitive battery (composite standard score) and activities of daily living scale. If it can tick all these boxes, Axon could have a major blockbuster on its hands.
Adamant will be conducted in several countries in Europe, where 185 patients are planned to be enrolled in the study.
“We are grateful for all the efforts of the entire team, investigators, and partners, who helped us to move AADvac1 into the Phase II study, which is a historical milestone for Alzheimer’s research and clinical development,” said Roman Sivak, CEO of Axon Neuroscience, in a release. “This is an exciting era as we believe that the positive results from the phase I study could soon be confirmed by this Phase II study.”
Axon is not the only company gunning for a tau vaccine, however, with AC Immune/Janssen’s ($JNJ) ACI-35, also an anti-tau vaccine, currently in Phase Ib.
Researchers hope the vaccine will help stimulate the patients’ immune systems against misfolded and phosphorylated tau proteins involved in the onset of Alzheimer’s.
Pre and post testing show reversal of memory loss from Alzheimer's disease in 10 patients
Small trial succeeds using systems approach to memory disorders
June 16, 2016
Buck Institute for Research on Aging
A small trial of 10 patients using a personalized systems approach to memory disorders shows an unprecedented reversal of memory loss in those diagnosed with early stage Alzheimers. Pre and post results are based on quantitative MRI and neuropsychological testing. The study is based on a protocol dubbed 'metabolic enhancement for neurodegeneration.'
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This is the first study to objectively show that memory loss in patients can be reversed, and improvement sustained, using a complex, 36-point therapeutic personalized program that involves comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry.
Results from quantitative MRI and neuropsychological testing show unprecedented improvements in ten patients with early Alzheimer's disease (AD) or its precursors following treatment with a programmatic and personalized therapy. Results from an approach dubbed metabolic enhancement for neurodegeneration are now available online in the journal Aging.
The study, which comes jointly from the Buck Institute for Research on Aging and the UCLA Easton Laboratories for Neurodegenerative Disease Research, is the first to objectively show that memory loss in patients can be reversed, and improvement sustained, using a complex, 36-point therapeutic personalized program that involves comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry.
"All of these patients had either well-defined mild cognitive impairment (MCI), subjective cognitive impairment (SCI) or had been diagnosed with AD before beginning the program," said author Dale Bredesen, MD, a professor at the Buck Institute and professor at the Easton Laboratories for Neurodegenerative Disease Research at UCLA, who noted that patients who had had to discontinue work were able to return to work and those struggling at their jobs were able to improve their performance. "Follow up testing showed some of the patients going from abnormal to normal."
One of the more striking cases involved a 66-year old professional man whose neuropsychological testing was compatible with a diagnoses of MCI and whose PET scan showed reduced glucose utilization indicative of AD. An MRI showed hippocampal volume at only the 17th percentile for his age. After 10 months on the protocol a follow-up MRI showed a dramatic increase of his hippocampal volume to the 75th percentile, with an associated absolute increase in volume of nearly 12 percent.
In another instance, a 69-year old professional man and entrepreneur, who was in the process of shutting down his business, went on the protocol after 11 years of progressive memory loss. After six months, his wife, co-workers and he noted improvement in memory. A life-long ability to add columns of numbers rapidly in his head returned and he reported an ability to remember his schedule and recognize faces at work. After 22 months on the protocol he returned for follow-up quantitative neuropsychological testing; results showed marked improvements in all categories with his long-term recall increasing from the 3rd to 84th percentile. He is expanding his business.
Another patient, a 49-year old woman who noted progressive difficulty with word finding and facial recognition went on the protocol after undergoing quantitative neuropsychological testing at a major university. She had been told she was in the early stages of cognitive decline and was therefore ineligible for an Alzheimer's prevention program. After several months on the protocol she noted a clear improvement in recall, reading, navigating, vocabulary, mental clarity and facial recognition. Her foreign language ability had returned. Nine months after beginning the program she did a repeat of the neuropsychological testing at the same university site. She no longer showed evidence of cognitive decline.
All but one of the ten patients included in the study are at genetic risk for AD, carrying at least one copy of the APOE4 allele. Five of the patients carry two copies of APOE4 which gives them a 10-12 fold increased risk of developing AD. "We're entering a new era," said Bredesen. "The old advice was to avoid testing for APOE because there was nothing that could be done about it. Now we're recommending that people find out their genetic status as early as possible so they can go on prevention." Sixty-five percent of the Alzheimer's cases in this country involve APOE4; with seven million people carrying two copies of the ApoE4 allele.
Bredesen' s systems-based approach to reverse memory loss follows the abject failure of monotherapies designed to treat AD and the success of combination therapies to treat other chronic illnesses such as cardiovascular disease, cancer and HIV. Bredesen says decades of biomedical research, both in his and other labs, has revealed that an extensive network of molecular interactions is involved in AD pathogenesis, suggesting that a broader-based therapeutic approach may be more effective. "Imagine having a roof with 36 holes in it, and your drug patched one hole very well--the drug may have worked, a single 'hole' may have been fixed, but you still have 35 other leaks, and so the underlying process may not be affected much," Bredesen said. "We think addressing multiple targets within the molecular network may be additive, or even synergistic, and that such a combinatorial approach may enhance drug candidate performance, as well."
While encouraged by the results of the study, Bredesen admits more needs to be done. "The magnitude of improvement in these ten patients is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective," Bredesen said. "Even though we see the far-reaching implications of this success, we also realize that this is a very small study that needs to be replicated in larger numbers at various sites." Plans for larger studies are underway.
Cognitive decline is often listed as the major concern of older adults. Already, Alzheimer's disease affects approximately 5.4 million Americans and 30 million people globally. Without effective prevention and treatment, the prospects for the future are bleak. By 2050, it's estimated that 160 million people globally will have the disease, including 13 million Americans, leading to potential bankruptcy of the Medicare system. Unlike several other chronic illnesses, Alzheimer's disease is on the rise--recent estimates suggest that AD has become the third leading cause of death in the United States behind cardiovascular disease and cancer.
The above post is reprinted from materials provided by Buck Institute for Research on Aging. Note: Materials may be edited for content and length.
Dale E. Bredesen et al. Reversal of cognitive decline in Alzheimer's disease. Aging, June 2016
Reversal of cognitive decline in Alzheimer's disease
Dale E. Bredesen1,2, Edwin C. Amos3, Jonathan Canick4, Mary Ackerley5, Cyrus Raji6, Milan Fiala7, and Jamila Ahdidan8
Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published . The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4-, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer's disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.
エーザイ 次世代アルツハイマー薬２剤の開発加速 併用試験も検討
MAY 12, 2016
Alzheimer's & Dementia Weekly
Aducanumab Looks Good in Earliest Stages of Alzheimer's
Aducanumab for Alzheimer's is showing encouraging results as Phase 3 trials roll out. See how this new immunotherapy is treating Alzheimer's at Georgetown University.
This year, Biogen Inc. is executing two Phase 3 clinical trials for aducanumab in Alzheimer’s disease.
Two global, placebo-controlled studies named ENGAGE and EMERGE are designed to evaluate the efficacy and safety of aducanumab in slowing cognitive impairment and the progression of disability in people with early Alzheimer’s disease (AD).
“Since the initial readout of our Phase 1b study, we have accelerated our aducanumab clinical program so that we can more fully characterize and confirm the benefit-risk profile of this investigational treatment for Alzheimer’s disease,” said Alfred Sandrock, M.D., Ph.D., group senior vice president and chief medical officer at Biogen. “We continue to work with our colleagues around the world to advance the study of aducanumab.”
Aducanumab (BIIB037) is an investigational compound being developed for the treatment of AD. Aducanumab is a human recombinant monoclonal antibody (mAb) derived from a de-identified library of B cells collected from healthy elderly subjects with no signs of cognitive impairment or cognitively impaired elderly subjects with unusually slow cognitive decline using Neurimmune’s technology platform called Reverse Translational Medicine (RTM). Biogen licensed aducanumab from Neurimmune under a collaborative development and license agreement.
Aducanumab is thought to target aggregated forms of beta amyloid including soluble oligomers and insoluble fibrils deposited into the amyloid plaque in the brain of AD patients. Based on pre-clinical and interim Phase 1b data, treatment with aducanumab has been shown to reduce amyloid plaque levels.
interventions to indirectly support food and drink intake
Holistic approach to mealtimes could help dementia sufferers
Date:May 4, 2016
Source:University of East Anglia
Summary:Eating together could help people with dementia avoid dehydration and malnutrition, new research shows. Researchers looked at mealtime interventions including changing the color of the plate, increasing exercise, waitress service, playing different types of music, singing, doing tai-chi, and boosting the social aspect of eating. They found that eating family-style meals with care givers, playing music, and engaging with multisensory exercise could boost nutrition, hydration and quality of life.
Eating together, providing social support and interaction during meals could help people with dementia avoid dehydration and malnutrition -- according to new NIHR-funded research from the University of East Anglia.
Findings published reveal that while no interventions were unequivocally successful, promising approaches focused on a holistic approach to mealtimes.
The team found that eating family-style meals with care givers, playing music, and engaging with multisensory exercise -- could all help boost nutrition, hydration and quality of life among people with dementia.
Lead researcher Dr Lee Hooper, from UEA's Norwich Medical School, said: "The risk of dehydration and malnutrition are high in older people, but even higher in those with dementia.
"Malnutrition is associated with poor quality of life so understanding how to help people eat and drink well is very important in supporting health and quality of life for people with dementia.
"We wanted to find out what families or carers can do to help people with dementia eat well and drink enough."
The team systematically reviewed research from around the world and assessed the effectiveness of 56 interventions which all aimed to improve, maintain, or facilitate food or drink intake among more than 2,200 people with dementia.
Interventions tested included changing the colour of the plate, increasing exercise, waitress service, playing different types of music, singing, doing tai-chi, creating a home-like eating environment, providing nutrition supplements, and boosting the social aspect of eating.
They also looked at whether better education and training for formal or informal care-givers could help, as well as behavioural interventions -- such as giving encouragement for eating.
The research team assessed whether these interventions improved hydration status and body weight, and whether the intervention helped older people to enjoy the experience of eating or drinking, and improved their quality of life.
Dr Hooper said: "We found a number of promising interventions -- including eating meals with care-givers, having family-style meals, facilitating social interaction during meals, longer mealtimes, playing soothing mealtime music, doing multisensory exercise and providing constantly accessible snacks.
"Providing education and support for formal and informal care-givers were also promising.
"But one of the problems of this research is that many of the studies we looked at were too small to draw any firm conclusions -- so no interventions should be clearly ruled in or out and more research in this area is needed.
"It is probably not just what people with dementia eat and drink that is important for their nutritional wellbeing and quality of life -- but a holistic mix of where they eat and drink, the atmosphere, physical and social support offered, the understanding of formal care-givers, and levels of physical activity enjoyed."
The above post is reprinted from materials provided by University of East Anglia. Note: Materials may be edited for content and length.
Diane K. Bunn, Asmaa Abdelhamid, Maddie Copley, Vicky Cowap, Angela Dickinson, Amanda Howe, Anne Killett, Fiona Poland, John F. Potter, Kate Richardson, David Smithard, Chris Fox, Lee Hooper. Effectiveness of interventions to indirectly support food and drink intake in people with dementia: Eating and Drinking Well IN dementiA (EDWINA) systematic review. BMC Geriatrics, 2016; 16 (1) DOI: 10.1186/s12877-016-0256-8
interleukin 33 (IL-33)
Natural protein 'restores memory in mice with Alzheimer's'
April 19 2016
The protein helped clear out clumps of abnormal proteins
"Alzheimer's symptoms could be reversed by restoring protein in brain," The Daily Telegraph reports.
Researchers say mice with Alzheimer's disease-like symptoms showed improvement in memory tasks after being given the protein interleukin 33 (IL-33), which is thought to boost immune function.
They used mice bred to have Alzheimer's-like symptoms to investigate whether injections of IL-33 into mice was able to reduce or reverse the symptoms of dementia.
People with Alzheimer's have been found to have lower levels of IL-33. It is thought this could lead to the development of the abnormal clumps of proteins known as toxic beta-amyloid protein plaques, the characteristic hallmark of the condition.
Mice who received the protein had improved memory and brain function compared with the control group, as well as a reduction in beta-amyloid protein levels.
This is potentially very exciting as current treatments for Alzheimer's can only temporarily slow the progression of the disease, as opposed to reversing the neurological damage it causes.
Of course, the normal warnings about prematurely assuming that positive animal results will translate into similarly positive results in humans apply.
Even if this treatment approach proves effective in humans, it remains to be seen if it would also be safe and free from significant side effects and complications.
Media estimates that it could take at least five years for this treatment to come to market ? assuming it does prove safe and effective ? seem reasonable.
Where did the story come from?
The study was carried out by researchers from a number of institutions, including the Hong Kong University of Science and Technology and the University of Glasgow.
Funding was provided by the Research Grants Council of Hong Kong SAR, the National Key Basic Research Program of China, a Hong Kong Research Grants Council Theme-based Research Scheme, and the SH Ho Foundation.
The study was published in the peer-reviewed journal, Proceedings of the National Academy of Sciences of the United States of America (PNAS) on an open access basis, so you can read it for free online.
This has been reported widely and accurately by the UK media, with a clear message that this is early research in mice and therefore caution should be taken ? though many of the headline writers failed to pick up on this message.
Many of the reports include the somewhat world-weary, yet realistic, quote from lead author Professor Eddy Liew, who said: "Exciting as it is, there is some distance between laboratory findings and clinical applications.
"There have been enough false 'breakthroughs' in the medical field to caution us not to hold our breath until rigorous clinical trials have been done."
What kind of research was this?
This is an experimental study in an animal model of Alzheimer's disease that aimed to investigate whether injecting the interleukin 33 (IL-33) protein into mice leads to improved dementia symptoms.
IL-33 is a cell signalling protein, and previous studies have shown that levels of a receptor to "catch" IL-33 are increased in people with mild cognitive impairment (pre-dementia).
As the name suggests, cell signalling proteins play an important role in transmitting "messages", or instructions, between cells.
This suggests that impaired IL-33 signalling could contribute to the development of the disease changes seen in Alzheimer's, such as the build-up of beta-amyloid protein plaques.
The researchers therefore speculated there may be a role for IL-33 treatment to stop the changes of Alzheimer's.
Animal studies like this are required to provide a path for further research in humans, but the findings are not directly applicable to people.
What did the research involve?
The researchers took mice aged between 6 and 25 months bred to have brains similar to people with Alzheimer's. The mice were split into two groups: one group received IL-33 injections and the other was a control group.
IL-33 was given by injection into the abdomen for two consecutive days, after which time the two groups of mice were tested for symptoms of cognitive decline, including their:
response to stimulus
retrieval abilities, such as retrieval of fear memories following a fear conditioning test
These abilities were tested by putting the mice in an exploration chamber, which included features such as light beams and electric shock panels, for 15 minutes at a time on consecutive days.
After a further two days of IL-33 treatment, the mice's brains were examined to look at the effect on amyloid plaques.
What were the basic results?
IL-33 was found to reach the brain within 30 minutes of injection and did not affect the general health of the mice.
The IL-33 group were found to have improved memory and cognitive function compared with the control group for learning, memory, response to stimulus and retrieval abilities. There was also a reduction in protein levels and the accumulation of amyloid plaques.
How did the researchers interpret the results?
The researchers concluded their findings indicate IL-33 is able to prevent and break down amyloid plaques, and even at late stages of the disease may represent a new treatment for Alzheimer's disease.
This experimental study in mice aimed to investigate whether injecting the signalling protein interleukin 33 (IL-33) into mice leads to better outcomes in dementia.
People with Alzheimer's disease have been found to have lower levels of the IL-33 protein in the brain than those who do not have the condition. The researchers hoped symptoms could be improved, or even reversed, by restoring levels of the protein.
These preliminary results are promising. In mice, IL-33 did seem to improve learning and memory in the exploration chamber tests, and also reduced beta-amyloid protein levels and the accumulation of amyloid plaques in their brains.
However, while these findings show promise, it is very early days ? caution should be taken in interpreting these findings.
Studies in humans need to be conducted to see if such a treatment has the same effect and whether it is safe.
But human studies could take years, and even then we don't know whether it would result in a licensed treatment.
As the exact cause of Alzheimer's disease is still unknown, there's no way to prevent the condition. But a good rule of thumb is "what is good for the heart is also good for the brain".
Activities known to boost your cardiovascular health may also help reduce your dementia risk. These include:
not drinking large amounts of alcohol
eating a healthy, balanced diet, including at least five portions of fruit and vegetables every day
exercising for at least 150 minutes (2 hours and 30 minutes) every week by doing moderate-intensity aerobic activity (such as cycling or fast walking) ? this will improve both your physical and mental health
make sure your blood pressure is checked and controlled through regular health tests
if you have diabetes, make sure you keep to the diet and take your medication
Read more about preventing dementia.
Analysis by Bazian. Edited by NHS Choices. Follow NHS Choices on Twitter. Join the Healthy Evidence forum.
Analysis by Bazian
Edited by NHS Choices
Early Edition > Amy K. Y. Fu, doi: 10.1073/pnas.1604032113
IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline
Amy K. Y. Fua,b,c, Kwok-Wang Hunga,b,c, Michael Y. F. Yuena,b,c, Xiaopu Zhoua,b,c, Deejay S. Y. Maka,b,c, Ivy C. W. Chana,b,c, Tom H. Cheunga,b,c, Baorong Zhangd, Wing-Yu Fua,b,c, Foo Y. Liewe,f,1, and Nancy Y. Ipa,b,c,1
Contributed by Nancy Y. Ip, March 15, 2016 (sent for review February 6, 2016; reviewed by David Morgan and Luke A. J. O’Neill)
Dysfunction of the innate immune system is involved in the pathogenesis of Alzheimer’s disease (AD); however, the pathophysiological mechanisms underlying these dysfunctions are unclear. Here we report that stimulation of IL-33/ST2 signaling rescues memory deficits and reduces the accumulation of β-amyloid in APP/PS1 mice that exhibit select pathologies associated with AD. Although impaired IL-33/ST2 signaling is associated with early progression of AD, IL-33 injection rescues contextual memory deficits and reduces the accumulation of β-amyloid in APP/PS1 mice. IL-33 skews the microglia toward an alternative activation state with enhanced Aβ phagocytic capacity and elevated antiinflammatory gene expression, which results in a decreased proinflammatory response in the brain. Thus, this study suggests that IL-33 can be developed as a new therapeutic intervention for AD.
Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.
Researchers identify ‘neurostatin’ that may reduce the risk of Alzheimer’s disease
April 13th 2016
An approved anti-cancer drug successfully targets the first step in the toxic chain reaction that leads to the neurodegenerative condition.
Researchers have identified a drug that targets the first step in the toxic chain reaction leading to the death of brain cells, suggesting that treatments could be developed to protect against Alzheimer’s disease, in a similar way to how statins are able to reduce the risk of developing heart disease.
The drug, which is an approved anti-cancer treatment, has been shown to delay the onset of Alzheimer’s disease, both in a test tube and in nematode worms. It has previously been suggested that statin-like drugs ? which are safe and can be taken widely by those at risk of developing disease ? might be a prospect, but this is the first time that a potential "neurostatin" has been reported.
When the drug was given to nematode worms genetically programmed to develop Alzheimer’s disease, it had no effect once symptoms had already appeared. But when the drug was given to the worms before any symptoms became apparent, no evidence of the condition appeared, raising the possibility that this drug, or other molecules like it, could be used to reduce the risk of developing Alzheimer’s disease. The results are reported in the journal Science Advances.
By analysing the way the drug, called bexarotene, works at the molecular level, the international team of researchers, from the University of Cambridge, Lund University and the University of Groningen, found that it stops the first step in the molecular cascade that leads to the death of brain cells. This step, called primary nucleation, occurs when naturally occurring proteins in the body fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. This process also creates smaller clusters called oligomers, which are highly toxic to nerve cells and are thought to be responsible for brain damage in Alzheimer’s disease.
“The body has a variety of natural defences to protect itself against neurodegeneration, but as we age, these defences become progressively impaired and can get overwhelmed,” said Professor Michele Vendruscolo of Cambridge’s Department of Chemistry, the paper’s senior author. “By understanding how these natural defences work, we might be able to support them by designing drugs that behave in similar ways.”
For the past two decades, researchers have attempted to develop treatments for Alzheimer’s that could stop the aggregation and proliferation of oligomers. However, these attempts have all failed, in part because there was not a precise knowledge of the mechanics of the disease’s development: Vendruscolo and his colleagues have been working to understand exactly that.
Finding the molecule
Using a test developed by study co-author Professor Tuomas Knowles, also from the Department of Chemistry, and by Professor Sara Linse, from Lund University, the researchers were able to determine what happens during each stage of the disease’s development, and also what might happen if one of those stages was somehow switched off.
“In order to block protein aggregation, we need accurate understanding of exactly what is happening and when,” said Vendruscolo. “The test that we have developed not only measures the rates of the process as a whole, but also the rates of its specific component sub-processes, so that we can reduce the toxicity of the aggregates rather than simply stopping them forming.”
Johnny Habchi, the first author of the paper, and colleagues assembled a library of more than 10,000 small molecules which interact in some way with amyloid-beta, a molecule that plays a vital role in Alzheimer’s disease. Using the test developed by Knowles and Linse, the researchers first analysed molecules that were either drugs already approved for some other purpose, or drugs developed for Alzheimer’s disease or other similar conditions which had failed clinical trials.
The first successful molecule they identified was bexarotene, which is approved by the US Food and Drug Administration for the treatment of lymphoma. “One of the real steps forward was to take a molecule that we thought could be a potential drug and work out exactly what it does. In this case, what it does is suppress primary nucleation, which is the aim for any neurostatin-type molecule,” said Vendruscolo. “If you stop the process before aggregation has started, you can’t get proliferation.”
One of the key advances of the current work is that by understanding the mechanisms of how Alzheimer’s disease develops in the brain, the researchers were able to target bexarotene to the correct point in the process.
“Even if you have an effective molecule, if you target the wrong step in the process, you can actually make things worse by causing toxic protein assemblies to build up elsewhere,” said study co-author Professor Chris Dobson, Master of St John’s College, University of Cambridge. “It’s like traffic control ? if you close a road to try to reduce jams, you can actually make the situation worse if you put the block in the wrong place. It is not necessarily the case that all the molecules in earlier drug trials were ineffective, but it may be that in some cases the timing of the delivery was wrong.”
Earlier studies of bexarotene had suggested that the drug could actually reverse Alzheimer’s symptoms by clearing amyloid-beta aggregates in the brain, which received a great deal of attention. However, the earlier results, which were later called into question, were based on a completely different mode of action ? the clearance of aggregates ? than the one reported in the current study. By exploiting their novel approach, which enables them to carry out highly quantitative analysis of the aggregation process, the researchers have now shown that compounds such as bexarotene could instead be developed as preventive drugs, because its primary action is to inhibit the crucial first step in the aggregation of amyloid-beta.
“We know that the accumulation of amyloid is a hallmark feature of Alzheimer’s and that drugs to halt this build-up could help protect nerve cells from damage and death,” said Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK. “A recent clinical trial of bexarotene in people with Alzheimer’s was not successful, but this new work in worms suggests the drug may need to be given very early in the disease. We will now need to see whether this new preventative approach could halt the earliest biological events in Alzheimer’s and keep damage at bay in in further animal and human studies.”
Over the next 35 years, the number of people with Alzheimer’s disease is predicted to go from 40 million to 130 million, with 70% of those in middle or low-income countries. “The only way of realistically stopping this dramatic rise is through preventive measures: treating Alzheimer’s disease only after symptoms have already developed could overwhelm healthcare systems around the world.”
The body has a number of natural defences designed to keep proteins in check. But as we get older, these processes can become impaired and get overwhelmed, and some proteins can slip through the safety net, resulting in Alzheimer’s disease and other protein misfolding conditions. While neurostatins are not a cure for Alzheimer’s disease, the researchers say that they could reduce its risk by acting as a backup for the body’s natural defences against misfolding proteins.
“You wouldn’t give statins to someone who had just had a heart attack, and we doubt that giving a neurostatin to an Alzheimer’s patient who could no longer recognise a family member would be very helpful,” said Dobson. “But if it reduces the risk of the initial step in the process, then it has a serious prospect of being an effective preventive treatment.”
But is there hope for those already affected by the disease? The methods that have led to the present advance have enabled the researchers to identify compounds that, rather than preventing the disease, could slow down its progression even when symptoms have become evident. “The next target of our research is also to be able to treat victims of this dreadful disease,” said Vendruscolo.
This article was first published on the University of Cambridge website.
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An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease
Johnny Habchi1, Paolo Arosio1, Michele Perni1, Ana Rita Costa1, Maho Yagi-Utsumi1, Priyanka Joshi1, Sean Chia1, Samuel I. A. Cohen1, Martin B. D. M?ller2, Sara Linse3, Ellen A. A. Nollen2, Christopher M. Dobson1,*, Tuomas P. J. Knowles1,* and Michele Vendruscolo1,*
+ Author Affiliations
?*Corresponding author. E-mail: firstname.lastname@example.org (M.V.); email@example.com (T.P.J.K.); firstname.lastname@example.org (C.M.D.)
Science Advances 12 Feb 2016:
Vol. 2, no. 2, e1501244
The conversion of the β-amyloid (Aβ) peptide into pathogenic aggregates is linked to the onset and progression of Alzheimer’s disease. Although this observation has prompted an extensive search for therapeutic agents to modulate the concentration of Aβ or inhibit its aggregation, all clinical trials with these objectives have so far failed, at least in part because of a lack of understanding of the molecular mechanisms underlying the process of aggregation and its inhibition. To address this problem, we describe a chemical kinetics approach for rational drug discovery, in which the effects of small molecules on the rates of specific microscopic steps in the self-assembly of Aβ42, the most aggregation-prone variant of Aβ, are analyzed quantitatively. By applying this approach, we report that bexarotene, an anticancer drug approved by the U.S. Food and Drug Administration, selectively targets the primary nucleation step in Aβ42 aggregation, delays the formation of toxic species in neuroblastoma cells, and completely suppresses Aβ42 deposition and its consequences in a Caenorhabditis elegans model of Aβ42-mediated toxicity. These results suggest that the prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer’s disease and, more generally, that our strategy provides a general framework for the rational identification of a range of candidate drugs directed against neurodegenerative disorders.
AstraZeneca, Eli Lilly in Final Stage of Testing Alzheimer’s Drug
Industry hopes that a so-called BACE inhibitor could prevent the onset of Alzheimer’s in patients
By DENISE ROLAND
April 8, 2016 4:26 a.m. ET
LONDON? AstraZeneca PLC and Eli Lilly and Co. said they would progress a clinical trial for an Alzheimer’s drug after initial human testing showed it didn’t have harmful side effects.
The drug, called AZD3293, is a so-called BACE inhibitor, a hot new class of drugs the industry hopes could prevent the onset of Alzheimer’s by preventing the buildup of a protein known as amyloid in the brain, thought to be the main cause of the degenerative neurological disease.
AstraZeneca and Lilly said they would progress the drug to a phase three clinical trial. The final stage of testing, in patients with early stage Alzheimer’s. They hope to enroll a total of 2,200 patients across 14 countries in the trial. They said they would also start test the drug in patients with mild Alzheimer’s in a separate trial set to start enrolling participants in the third quarter of 2016.
BACE inhibitors are the latest glimmer of hope in a field dogged by failures, but they could stumble in later-stage development. Eli Lilly scrapped a BACE inhibitor, LY2886721, in 2013 over concerns that the drug could affect liver function. Research released by the trade group Pharmaceutical Research & Manufacturers of America in 2012 showed there had been 101 Alzheimer’s drug failures in the previous 13 years.
It is being co-developed by AstraZeneca and Lilly under a risk-and-reward sharing deal. Under that agreement, Lilly took the lead in designing and running clinical trials for the drug, which was previously under development solely by AstraZeneca. The two will share the costs of development, and, if the drug is successful, future revenues, equally.
Lily also agreed to a series of payments to AstraZeneca as the drug progresses through various milestones. It will pay $100 million now that the drug is moving to late-stage testing.
The deal forms part of AstraZeneca Chief Executive Pascal Soriot’s “externalization” strategy to partner with other drugmakers when the program in question falls outside its core areas of expertise.
The high failure rate of research in Alzheimer’s disease has led to other partnerships in the industry: last year Novartis AG struck a deal with Amgen Inc.
An estimated 5.3 million Americans suffer from the disease, according to the Alzheimer’s Association, a nonprofit organization. Current treatments can help manage symptoms, but there is no cure. The market for Alzheimer’s drugs stood at $4.9 billion in 2013 and is expected to reach $13.3 billion by 2023, according to GlobalData, a research and consulting firm.
17 drugs on pace to launch in the next five years
Growing Optimism That Promising Alzheimer’s Medicines Will Emerge During The Next Five Years
Health Care System Is Not Prepared to Ensure Patients Will Get Access to First Novel Alzheimer’s Therapies Since 2003
WASHINGTON, March 31, 2016—Today’s Alzheimer’s disease drug pipeline, marred by more than a decade of high failure rates and public underinvestment, is offering near-term promise with 17 drugs on pace to launch in the next five years, according to a recent analysis conducted by ResearchersAgainstAlzheimer’s (RA2), an UsAgainstAlzheimer’s (UsA2) network. If only some of those drugs are successful in late-stage trials and cleared by the U.S. Food and Drug Administration (FDA), the potential innovations will be a much-needed stimulus to the goal of stopping America’s most costly disease, one that affects approximately 5.3 million Americans, a number that is expected to rise precipitously during the next few decades.
Findings from the analysis underscore an important question: once the therapies are approved, will those affected by the disease be able to access these drugs?
“Despite the recent history of disappointment for Alzheimer’s disease advancements, we are cautiously optimistic about the progress of this next wave of innovation because we are seeing well-funded trials and concerted efforts to learn from past failures,” said Dr. David Morgan, a founding member of RA2, a distinguished professor of the College of Medicine and Molecular Pharmacology and Physiology at the University of South Florida, and CEO of the Byrd Alzheimer's Institute.
“The analysis confirms that while there is a promising pipeline for Alzheimer’s patients, we must, in parallel, be encouraging more physicians to accurately diagnose and treat this disease, and work with insurers to enable access for patients to these new drugs when they are available.”
According to the RA2 analysis, there are currently 17 Alzheimer’s drugs in Phase 3 clinical trials on course to launch in the next five years. This first-of-its-kind analysis reached its conclusions following extensive examination of SEC filings, company reports, presentations at medical conferences, media releases and interviews with company executives about publicly available information on drugs in late-stage testing. In addition, academic research experts and select RA2 members provided input and review of the analysis.
In the United States, Alzheimer’s, the most common form of dementia, is the third leading cause of death, according to recent studies. Among the top 10 causes of death, it’s the only one that currently can’t be prevented, stopped or slowed. The RA2 analysis’ findings provide the hope that is sorely needed for Alzheimer’s patients and their numerous caregivers who have not seen a novel Alzheimer’s therapy since 2003, when Namenda was approved by the FDA.
“Alzheimer’s disease must be attacked at the scope and scale equal to the challenge. Alzheimer’s is a cancer-size problem requiring a cancer-size solution,” said George Vradenburg, co-founder and chairman of UsAgainstAlzheimer’s. “Our mission is to stop Alzheimer’s by 2020. Our work has focused on disrupting business as usual – increasing research resources, speeding drug development and assuring access of innovative medicines to those with or at risk of the disease. Should drugs in late-stage development prove successful, insurers and physicians will need to step up their game.”
While the analysis takes a positive approach to the innovation pipeline, it also delineates areas that America’s health care system needs to improve upon before new Alzheimer’s treatments are approved.
These areas include:
Enhancing the training and numbers of front-line physicians, including in primary care, to diagnose and treat Alzheimer’s. In addition, the number of geriatricians needs to increase from 7,000 (current) to 30,000 by 2030. Unfortunately, fewer medical students are choosing geriatrics because geriatrics practice is not sustainable financially with a 100 percent Medicare payer mix. Neurologists and psychiatrists typically have a mix of payers.
Improving the accuracy of diagnosis. In some settings, up to half of all cases of Alzheimer’s disease are misdiagnosed, and there is currently a significant under-diagnosis of the disease in populations around the world. The lack of an Alzheimer’s diagnosis can also negatively impact the ability of patients to adhere to other chronic care protocols. Visits to memory care specialists in neurology, psychiatry or geriatrics is encouraged.
Improving communication between patients and physicians. Just 45 percent of people diagnosed with Alzheimer’s were actually informed of their diagnosis by a doctor, compared to 90 percent of people with cancer and cardiovascular disease who are informed of that diagnosis by their doctor.
Treating Alzheimer’s like the fatal disease that it is, rather than as routine clinical care. The average wait time to see a neurologist was 35 days, a 25 percent increase since 2010. In contrast, a study shows that the average wait time for a cardiologist is 16.8 days, about 50 percent less than the wait time to see a neurologist.
Addressing payment and reimbursement. There is no assurance that the Centers for Medicare and Medicaid Services (CMS) and other national health payment authorities and insurance providers will pay for or reimburse for Alzheimer’s treatments.
“The studies of the past were a necessary predicate for the future of Alzheimer’s medicine,” said Dr. Rachelle Doody, professor of neurology at Baylor College of Medicine and reviewer of the analysis. “We have learned a great deal about trials methodologies and disease targets from past studies. While the analysis shows a promising future, it is also a sobering wakeup call reminding us of the importance of health system readiness to prevent and combat this crushing disease.”
For more information, the pipeline analysis will be discussed in depth during a future Alzheimer’s Talks Teleconference on April 11 from 4-5 pm (EST). The discussion, which will be live streamed, will include remarks from Vradenburg, Morgan and study lead and RA2 director Drew Holzapfel. Visit the Alzheimer’s Talks page for more information.
To view the analysis, visit: RA2 Pipeline Report
UsAgainstAlzheimer’s (UsA2) is an innovative non-profit organization demanding – and delivering – a solution to Alzheimer’s. Driven by the suffering of millions of families, UsAgainstAlzheimer’s presses for greater urgency from government, industry and the scientific community in the quest for an Alzheimer's cure – accomplishing this through effective leadership, collaborative advocacy, and strategic investments.
Founded in 2010, UsAgainstAlzheimer’s has worked across sectors to: (1) secure the national goal of preventing and effectively treating Alzheimer’s by 2025 and help secure nearly $500 million in additional public funding for Alzheimer’s research over the past few years; (2) drive global efforts that resulted in the leaders of the world’s most powerful nations, the G7 group, to embrace a similar 2025 goal and to call for greater levels of research investment and collaboration; and (3) forge industry commitments to improve efficiencies for an expedited drug discovery and approval process.
ResearchersAgainstAlzheimer’s (RA2) is a network of more than 400 Alzheimer’s researchers established by UsAgainstAlzheimer’s to advocate for federal research funding and policy reform in order to stop Alzheimer’s disease. RA2 believes that an effective treatment for Alzheimer’s disease is within reach if government, industry and citizens are willing to commit the resources and institute the policy changes that are necessary.
Rifampicin is a candidate preventive medicine against amyloid β and tau oligomers
Tomohiro Umeda, Kenjiro Ono, Ayumi Sakai, Minato Yamashita, Mineyuki Mizuguchi, William L. Klein, Masahito Yamada, Hiroshi Mori, Takami Tomiyama
DOI: http://dx.doi.org/10.1093/brain/aww042 aww042 First published online: 28 March 2016
Amyloid-β, tau, and α-synuclein, or more specifically their soluble oligomers, are the aetiologic molecules in Alzheimer’s disease, tauopathies, and α-synucleinopathies, respectively. These proteins have been shown to interact to accelerate each other’s pathology. Clinical studies of amyloid-β-targeting therapies in Alzheimer’s disease have revealed that the treatments after disease onset have little benefit on patient cognition. These findings prompted us to explore a preventive medicine which is orally available, has few adverse effects, and is effective at reducing neurotoxic oligomers with a broad spectrum. We initially tested five candidate compounds: rifampicin, curcumin, epigallocatechin-3-gallate, myricetin, and scyllo-inositol, in cells expressing amyloid precursor protein (APP) with the Osaka (E693Δ) mutation, which promotes amyloid-β oligomerization. Among these compounds, rifampicin, a well-known antibiotic, showed the strongest activities against the accumulation and toxicity (i.e. cytochrome c release from mitochondria) of intracellular amyloid-β oligomers. Under cell-free conditions, rifampicin inhibited oligomer formation of amyloid-β, tau, and α-synuclein, indicating its broad spectrum. The inhibitory effects of rifampicin against amyloid-β and tau oligomers were evaluated in APPOSK mice (amyloid-β oligomer model), Tg2576 mice (Alzheimer’s disease model), and tau609 mice (tauopathy model). When orally administered to 17-month-old APPOSK mice at 0.5 and 1 mg/day for 1 month, rifampicin reduced the accumulation of amyloid-β oligomers as well as tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent manner. In the Morris water maze, rifampicin at 1 mg/day improved memory of the mice to a level similar to that in non-transgenic littermates. Rifampicin also inhibited cytochrome c release from the mitochondria and caspase 3 activation in the hippocampus. In 13-month-old Tg2576 mice, oral rifampicin at 0.5 mg/day for 1 month decreased amyloid-β oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation, but not amyloid deposition. Rifampicin treatment to 14?15-month-old tau609 mice at 0.5 and 1 mg/day for 1 month also reduced tau oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent fashion, and improved the memory almost completely at 1 mg/day. In addition, rifampicin decreased the level of p62/sequestosome-1 in the brain without affecting the increased levels of LC3 (microtubule-associated protein light chain 3) conversion, suggesting the restoration of autophagy-lysosomal function. Considering its prescribed dose and safety in humans, these results indicate that rifampicin could be a promising, ready-to-use medicine for the prevention of Alzheimer’s disease and other neurodegenerative diseases.
carboxyl methyl cellulose
enzyme-linked immunosorbent assay
microtubule-associated protein light chain 3
nuclear magnetic resonance
photo-induced cross-linking of unmodified proteins
sodium dodecyl sulphate
? The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: email@example.com
Implantable capsule shows promise for Alzheimer's prevention
by Honor Whiteman
There is currently no way to prevent or slow Alzheimer's disease, but a new study details the creation of an implantable capsule that researchers say could stop the condition in its tracks.
In Alzheimer's mouse models, the implantable capsule significantly reduced levels of beta-amyloid protein and plaques in mice.
In the journal Brain, researchers from the ?cole Polytechnique F?d?rale de Lausanne (EPFL) in Switzerland reveal how, when implanted under the skin, the capsule releases antibodies that travel to the brain and trigger the patient's immune system to clear beta-amyloid protein.
Beta-amyloid protein is believed to be a key player in the development of Alzheimer's disease. The protein clumps together in the brain, forming plaques that accumulate in the spaces between nerve cells, which researchers suggest interfere with the processes these cells need to survive.
Scientists have been searching for ways to tackle these plaques, and one idea has been to "tag" beta-amyloid proteins with antibodies that call on the immune system to attack and destroy them, before they can form plaques.
However, the researchers of this latest study - including Patrick Aebischer of the Brain Mind Institute at EPFL - note that such a treatment has to be administered in the early stages of cognitive decline to be most effective. This requires repeat injections, which can lead to adverse side effects.
But Aebischer and colleagues say their implantable capsule could offer a safer and highly effective alternative.
How does the implantable capsule work?
The capsule, described as a "macroencapsulation device," is 27 mm in length, 12 mm wide and 1.2 mm thick.
It consists of cells taken from muscle tissue that have been genetically engineered to produce high levels of antibodies that have the ability to recognize and target beta-amyloid proteins in the brain.
When implanted in tissue under the skin, the capsule gradually releases the antibodies into the bloodstream. From here, they cross from the blood to the brain to seek out and tag beta-amyloid protein, which triggers an immune system attack.
The team notes that not only must these genetically engineered cells release antibodies, but in order to avoid rejection from the immune system, they must be compatible with the patient.
As such, the cells are surrounded by two permeable membranes - fixed together by polypropylene frame - that not only protect them against immune system attack, but enable cells from a single donor to be used on multiple patients.
Furthermore, the permeable membranes allow the cells to soak up all the nutrients and molecules they need from surrounding tissue.
Alzheimer's mice showed reduction in beta-amyloid plaques
For their study, Aebischer and colleagues tested the capsule on mouse models of early Alzheimer's disease and assessed them for around 39 weeks.
On looking at the brains of the mice, the researchers found they showed a significant reduction in levels of beta-amyloid protein and plaques, suggesting that the continuous flow of antibodies produced by the capsule over the 39-week period prevented the plaques from forming.
Additionally, the team found that the mice demonstrated lower phosphorylation of a protein called tau, which is also believed to play a role in Alzheimer's development by forming "tangles" that build up inside nerve cells.
The authors believe that their findings provide proof-of-concept that an implantable, antibody-releasing capsule is an effective preventive option for Alzheimer's and other neurodegenerative diseases in which protein build-up plays a role, such as Parkinson's disease.
Medical News Today recently reported on a study in which researchers suggest it may one day be possible to retrieve 'lost' memories in patients with early Alzheimer's.
Written by Honor Whiteman
A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies
Aur?lien Lathuili?re, Vanessa Laversenne, Alberto Astolfo, Erhard Kopetzki, Helmut Jacobsen, Marco Stampanoni, Bernd Bohrmann, Bernard L. Schneider, Patrick Aebischer
DOI: http://dx.doi.org/10.1093/brain/aww036 aww036 First published online: 8 March 2016
ArticleFigures & dataInformation & metricsExplore
Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer’s disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 ?g/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer’s pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer’s disease and other neurodegenerative disorders.
selective rescue of spine density in engram cells
Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease
Dheeraj S. Roy, Autumn Arons, Teryn I. Mitchell, Michele Pignatelli, Tom?s J. Ryan & Susumu Tonegawa
Nature (2016) doi:10.1038/nature17172
16 March 2016
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions1. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role2. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent3, 4, 5, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.
The true superfood: Snacking on BLUEBERRIES could stop dementia developing decades later
A compound found in fruit may strengthen brain against Alzheimer's
The disease and other forms of dementia affect 850,000 Britons
A nutritional approach represents way to mitigate risk for late-life dementia
By FIONA MACRAE, SCIENCE EDITOR FOR THE DAILY MAIL
13 March 2016
Snacking on blueberries from middle age could prevent dementia developing decades later, scientists say.
Experts told a major US conference that a compound in the berries may strengthen the brain’s defences against Alzheimer’s.
In the absence of effective drugs, a nutritional option ‘represents a potentially potent approach to mitigate risk for late-life dementia’, they said.
Alzheimer’s and other forms of dementia affect some 850,000 Britons and cost the economy ?26billion a year.
With the search for new medicines largely fruitless, despite hundreds of drug trials and billions of pounds of funding, some experts believe more emphasis should be placed on the benefits of a healthy diet.
Candidates include the humble blueberry, a ‘superfood’ already credited with lowering the risk of heart disease and cancer.
University of Cincinnati researcher Robert Krikorian (CORR) studied 47 men and women aged 68-plus who had been diagnosed with mild cognitive impairment.
The term covers the slight memory lapses that often, although not always, develop into full-blown dementia.
All were given a placebo powder or one made of freeze-dried blueberries to take once a day for four months.
The blueberry powder been specially made for the study, and one sachet contained the equivalent of a small teacupful of berries.
The volunteers were also put through a battery of mental tests at the study’s start and end, with a focus on memory and thinking skills that are eroded by dementia.
The results showed that the berries seemed to give the ageing brain a boost.
Dr Krikorian said: ‘There was a significant improvement in cognitive function in those who had the blueberry powder, compared with those who took the placebo.’
In addition scans showed the brain was more active in those who had taken the blueberry powder.
The researcher believes the benefits are due to anthocyanins, the plant chemicals that give the berries their deep blue/purple colour.
They are thought to act on the brain in various ways, including boosting blood flow, cutting inflammation, and enhancing the passage of information between cells.
The chemicals may also boost cells’ defences, an American Chemical Society conference heard.
In a second study of people who hadn’t been diagnosed with any memory problems, but simply felt they were becoming more forgetful, the berries also helped boost cognition, although to a lesser extent.
When previous research is factored in, Dr Krikorian, who received funding from the US government, as well as from berry growers, says all the evidence points to blueberries having the potential to prevent the onset of dementia.
He said: ‘Our findings corroborate those of previous animal studies and preliminary human studies, adding further support to the notion that blueberries can have a real benefit in improving memory and cognitive function in older adults.’
He now wants to study people in their 50s and early 60s whose weight, blood pressure or other medical condition puts them at higher than usual risk of Alzheimer’s.
But, in the meantime, he advises healthy adults to stock up on blueberries.
And with research suggesting Alzheimer’s may eat away at the brain for decades before symptoms start to show, he says it is important to protect the brain from middle-age.
Dr Krikorian said: ‘I believe that berry supplementation and, in particular, blueberry supplementation, may reduce the risk for late-life cognitive decline.
‘The minimum dose is not clear but data suggest that taking blueberries several times a week should be beneficial.’
Alzheimer's can be cured, not just treated, Michigan researcher claims
By Jim Harger
February 22, 2016
ADA TOWNSHIP, MI ? Researcher Dr. Michael Fossel has charted a bold course for the bio-tech company he co-founded from his 180-year-old farmhouse near Ada.
He plans to cure Alzheimer's Disease.
Fossel, a neurobiologist who has studied the science of aging for decades, says there's enough scientific knowledge and research about aging to put together the pieces and cure one of the most tragic age-related diseases in our culture.
"It looks like we can finally begin to address age-related diseases and do something about them," said Fossel, the co-founder of Telocyte, a bio-tech company that hopes to start human trials of its Alzheimer's cure within the next year.
"I think we what we can do is finally show it's not a matter of perhaps slowing and treating the symptoms, but we can do something to reverse the problems of Alzheimer's Disease," said Fossel, a former emergency room physician at Mercy Health St. Mary's and lecturer at Grand Valley State University's bio-medical program.
It's the culmination of 30 years of research Fossel has conducted into the causes of aging. In 1996, he published "Reversing Human Aging," the first of several books he has published about the causes of and research surrounding the aging process.
In his most recent book, "The Telomerase Revolution," Fossel that explains how an enzyme in part of the chromosome holds the key to aging. The book has been well-received by scientists. The Wall Street Journal named it one of 2015's five best books for science lovers.
Telocyte, which Fossel co-founded with British tech-entrepreneur Peter Rayson, is in the process of raising money to support the clinical trial process and get permission for human trials from the Food and Drug Administration
Unlike much of the medical research and treatment surrounding Alzheimer's Disease, Fossel said his company is going for a cure for the cell-aging process that causes the disease, instead of a treatment that might alleviate the symptoms.
"I don't want people to spend 20 years longer in a nursing home," he said. "I want them to spend 20 years wrestling with their grandkids."
Rather that starting with a drug that will modify the course of the disease, Fossel said his approach is to change the cells that trigger the disease. It's an approach that challenges the assumptions surrounding Alzheimer's and its treatment, he said.
While medical industry has created an infrastructure to deal with and treat Alzheimer's, Fossel said his approach would eliminate the need for treatment, just as the polio vaccine eliminated the need for iron lungs in the 1950s.
Connecticut-born Fossel came to West Michigan in 1984 after graduating from Stanford University with a doctorate and medical degree in neurobiology and research methods.
His bride, Joy, was a Southeast Michigan native whose family had spent their summers in Castle Park, a resort along Lake Michigan near Holland. He and Joy, a partner at the Varnum law firm in downtown Grand Rapids, settled on an 180-year-old farmstead in Ada.
While practicing emergency medicine at St. Mary's, Fossel kept abreast on the research associated with aging. He taught at Michigan State University's Medical School and Grand Valley State University and wrote text books on the topic.
In recent months, Fossel has focused on getting Telocyte funded and its "telomerase" treatment approved for human clinical trials.
Fossel compares medical research into aging to the fable of the blind-folded men describing an elephant ? one focusing on the tail, another on the leg and another on the trunk.
While all of the researchers may be correct in their analysis, Fossel he said hopes his latest book will encourage a more holistic approach to the causes of aging on a cellular level rather than the symptoms.
Jim Harger covers business for Mlive Media Group. Email him at firstname.lastname@example.org or follow him on Twitter or Facebook or Google+.
New wonder drug brings hope for dementia
A NEW wonder drug could prevent and even reverse the devastating effects of Alzheimer’s, scientists claim.
Feb 22, 2016
Research suggests a potent experimental drug has the potential to be a “game changer” in tackling the disease.
It is hoped it will lead to a drug ? taken as a daily pill ? that would make nerve cells more resilient to neurological changes associated with the onset of dementia.
Experimental drug LM11A-31 is referred to as C31 by researchers.
In laboratory tests on mice it prevented 10 out of 14 processes within brain cells known to lead to deterioration.
While existing drugs only target symptoms, scientists say C31 could work to keep the brain strong against a whole series of “neurological onslaughts” that happen to the brain in old age.
If clinical trials prove successful, the US Food and Drug Administration could soon licence it for widespread use, making it the first treatment to tackle the causes rather than ease symptoms.
Figures show that 850,000 people live with dementia in the UK, a number set to rocket to two million in 30 years.
Half have a mild form but a third live with moderate symptoms and 15 per cent require around-the-clock care.
A new case is diagnosed every three minutes.
Dr Frank Longo, of Stanford University School of Medicine in California, said: “The general assumption was that the damage caused to brain neurons was irreversible.
“What our studies show is that in mice there is a significant amount of damage that is reversible.”
transcranial magnetic stimulation (TMS) and cognitive training
Drug-Free Alzheimer’s Treatment To Seek FDA Approval
Feb 11th, 2016
Neuronix’s neuroAD is already commercially available in Europe, Asia and Israel for slowing disease progression in mild to moderate Alzheimer cases.
Israel Neuronix NeuroAD1-768x432
Based on expected results of a just-completed multicenter study involving 131 patients, Israel’s Neuronix medical device company will apply next month for US Food and Drug Administration clearance of its neuroAD system to slow and even reverse progression of Alzheimer disease.
The novel technology combines transcranial magnetic stimulation (TMS) and cognitive training of specific brain regions to slow the rate of mental deterioration in patients with mild to moderate Alzheimer’s and other neurodegenerative disorders. Study participants received the intervention daily for six weeks.
Based in Yokneam with offices in Massachusetts, Neuronix already has CE clearance for neuroAD in Europe. The treatment is commercially available in centers across Europe and Asia, as well as two clinics in Israel, in Ramat Gan and Jerusalem.
“We were fortunate to work with some of the world-leading Alzheimer research centers,” said Eyal Baror, Neuronix CEO. “Our previous successful six clinical trials have shown that neuroAD is safe and effective in treatment of mild to moderate Alzheimer patients, significantly improving their cognitive performance and day-to-day activities, and slowing down their mental deterioration for about one year.”
In 2015, Korean researchers published results of a clinical trial that showed neuroAD “was remarkable in the memory and language domains, which are severely affected by Alzheimer disease.”
Pending FDA approval, Neuronix expects to launch neuroAD commercially in the United States during the first half of 2017.
People with dementia gain from learning self-management skills
People with early-stage dementia benefit when they are empowered to manage their own condition, a study led by researchers at the University of Exeter has found.
Research involving Bangor University and published in the journal International Psychogeriatrics, found that attending weekly 'self-management' group sessions which encouraged socialisation, discussion, problem solving and goal setting fostered independence and promoted social support amongst people with dementia.
The groups, led by trained facilitators, were focused on providing people with a better understanding of their dementia and ways to cope with it. Participants were supported in their ability to manage their own symptoms, treatment and lifestyle changes with information and expert help. They were then encouraged to share ideas and strategies for dealing with their condition and were encouraged to record notes and reminders in a handbook.
"Developing dementia can be a scary and isolating experience. We developed a group programme to help people with dementia manage their condition and find ways of dealing with the changes in their lifestyle. We found early evidence that empowering people to manage their own symptoms and bringing them together helped them feel more confident about managing everyday life with dementia," said lead researcher Dr Catherine Quinn, Senior Research Fellow in The Centre for Research in Ageing and Cognitive Health (REACH).
"All this has helped to enhance their quality of life. The group members became friends and supported each other, and we found that they benefited from being able to learn from each other."
The pilot randomised controlled study, which was funded by Health and Care Research Wales, compared a group of people with early stage dementia who attended the 90-minute sessions for eight weeks to a group who received no intervention.
The impact of the sessions was assessed by interviews with people with dementia and their caregivers after three months and then again after six. Results showed that participants benefitted from the facilitator support, information and help provided, and became better able to help themselves and found support in other group members.
"We will need to carry out a larger scale trial to obtain more definitive evidence, but our initial results indicate that enabling people with dementia to take control and manage their condition can be beneficial," added Dr Quinn.
A pilot randomized controlled trial of a self-management group intervention for people with early-stage dementia (The SMART study) by Catherine Quinn, Gill Toms, Carys Jones, Andrew Brand, Rhiannon Tudor Edwards, Fiona Sanders and Linda Clare is published in International Psychogeriatrics. URL: http://www.ncbi.nlm.nih.gov/pubmed/26674087
A pilot randomized controlled trial of a self-management group intervention for people with early-stage dementia (The SMART study)
Catherine Quinna1 c1, Gill Tomsa2, Carys Jonesa3, Andrew Branda4, Rhiannon Tudor Edwardsa3, Fiona Sandersa5 and Linda Clarea1
a1 REACH: The Centre for Research in Ageing and Cognitive Health, Department of Psychology, College of Life and Environmental Sciences, Exeter University, Exeter, EX4 4QG, UK
a2 School of Psychology, Bangor University, Bangor, Gwynedd, LL57 2AS, UK
a3 Centre for Health Economics and Medicines Evaluation, Bangor University, Bangor, Gwynedd, LL57 2PZ, UK
a4 North Wales Organization for Randomized Trials in Health, College of Health and Behavior Sciences (CoHABS), Bangor University, Bangor, Gwynedd, LL57 2PZ, UK
a5 Glan Traeth Community Team, Glan Traeth CPN office, Royal Alexandra Hospital, Betsi Cadwaladr University Health Board, Denbighshire, LL18 3AS, UK
Background: Self-management equips people to manage the symptoms and lifestyle changes that occur in long-term health conditions; however, there is limited evidence about its effectiveness for people with early-stage dementia. This pilot randomized controlled trial (RCT) explored the feasibility of a self-management intervention for people with early-stage dementia.
Methods: The participants were people with early-stage dementia (n = 24) and for each participant a caregiver also took part. Participants were randomly allocated to either an eight-week self-management group intervention or treatment as usual (TAU). Assessments were conducted at baseline, three months and six months post-randomization by a researcher blind to group allocation. The primary outcome measure was self-efficacy score at three months.
Results: Thirteen people with dementia were randomized to the intervention and 11 to TAU. Two groups were run, the first consisting of six people with dementia and the second of seven people with dementia. There was a small positive effect on self-efficacy with the intervention group showing gains in self-efficacy compared to the TAU group at three months (d = 0.35), and this was maintained at six months (d = 0.23). In terms of intervention acceptability, attrition was minimal, adherence was good, and satisfaction ratings were high. Feedback from participants was analyzed with content analysis. The findings suggest the positive aspects of the intervention were that it fostered independence and reciprocity, promoted social support, offered information, and provided clinician support.
Conclusions: This study has provided preliminary evidence that self-management may be beneficial for people with early-stage dementia.
(Received August 14 2015)
(Reviewed October 31 2015)
(Revised November 11 2015)
(Accepted November 11 2015)
psychosocial intervention; Alzheimer’s disease; self-care; support group; self-efficacy
c1 Correspondence should be addressed to: Dr Catherine Quinn, Exeter University. REACH: The Centre for Research in Ageing and Cognitive Health, Department of Psychology, College of Life and Environmental Sciences, Washington Singer, Perry Road, Exeter, EX4 4QG, UK. Phone: +44 01392 726861. Email: C.Quinn@exeter.ac.uk.
PD-1 immune checkpoint blockade
Cancer drugs could be re-purposed to fight Alzheimer's disease
A new generation of immunotherapy drugs for cancer may also help reverse Alzheimer's disease, scientists hope
By Sarah Knapton
18 Jan 2016
Cancer drugs already available on the NHS may help reverse Alzheimer’s disease by boosting the immune system, scientists believe.
A range of immunotherapy treatments, which harness the body’s own defences to ward off tumours are already revolutionising cancer care.
But now scientists believe that a similar immune boost could help people with dementia.
The drugs, known as PD-1 blockers, effectively prevent the immune system from switching off, allowing a continuous cascade of soldier cells to fight disease and clear out damage in the body.
In the case of Alzheimer’s disease sticky amyloid plaques build up which stop brain cells communicating with each other. But when mice, engineered to have Alzheimer’s symptoms, were given injections of the drug the amount of amyloid in their brains halved, and the animals were able to complete a maze task in the same time as control mice.
Last year the first PD-1 blocker drug Keytruda was approved for use on the NHS by the National Institute for Health and Care Excellence so it is already known to be a safe treatment.
Lead author Prof Michal Schwartz of the Weizmann Institute of Science, Rehovot, Israel, said that in Alzheimer’s a weakened immune system could be preventing the body from repairing itself.
"We are extremely excited about our new study, we believe it is a game changer both conceptually and therapeutically," she said.
"There is currently no cure or disease-modifying treatment for Alzheimer’s disease, and the prospect of using PD-1 blockers, may suggest short translation to the clinic.
"Notably, since such a immune therapy empowers the individual immune system to fight the disease, rather than directed against any single disease factor associated with Alzheimer’s disease, we believe that it targets multiple factors associated with the disease, and therefore will be applicable to the various forms of the disease, at different stages of progression, and potentially also to other neurodegenerative conditions."
In cancer the drugs work by disabling an “immune checkpoint” called the programmed cell death receptor 1, or PD-1, which stops immune cells from attacking tumours. These checkpoints are designed to prevent the immune system killing healthy cells but they are exploited by cancer to avoid detection.
The finding is particularly interesting because previously scientists believe that an over active immune system could be responsible for Alzheimer’s and were puzzled why anti-inflammatories did no see to have any impact in trials. The new research suggests the opposite could be true.
“This new research is interesting because it helps us understand the role of the immune system in Alzheimer’s disease,” said Dr Tara Spire-Hones, of the Centre for Cognitive and Neural Systems, at the University of Edinburgh.
“The brain’s immune system becomes over-activated in Alzheimer’s disease and there is a debate surrounding whether this activation is harmful, protective or a bit of both. Many scientists believe that calming down an overactive brain system will be a useful treatment for the disease. However drugs aimed at doing this have not had much success.
“This current research builds on the idea that boosting brain immunity will encourage the immune system’s natural potential to clear toxic substances.“
X-rays showing a patient's tumor, circled, before, leftm and after immunotherapy
Immonthrapy drugs have been shown to kill tumours completely
Around 850,000 people are believed to have dementia in Britain, a figures that is expected to rise to one million by 2025 and two million by 2050.
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society said: “It’s clear that inflammation and the immune system play a highly important role in the development of Alzheimer’s disease, but just how that relationship works is incredibly complex and not fully understood.
“Repurposing drugs that already work for other conditions could provide us with a shortcut to new dementia treatments, and is a key aspect of our Drug Discovery programme.”
Dr Simon Ridley, Director of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, said: “This study in mice suggests that PD-1 blockers may warrant further investigation, but further work in the lab is still needed to take this early-stage research forward.
“The study looked at the effects of the drug at an advanced stage of amyloid build-up, however it is not yet known whether removing amyloid at this late stage will be helpful for memory and thinking in people.
"Ultimately, clinical trials in people will be crucial to determine whether PD-1 blockers can help fight Alzheimer’s.”
Other drugs are also showing promise for Alzheimer’s disease and experts have predicted that if current progress continues, there will be a treatment within the next decade.
Last year, pharmaceutical giant Eli Lilly said that early trials of the drug solanezumab had been shown to slow down the rate of cognitive decline for people with mild symptoms of Alzheimer’s disease. They are expected to release full results within the next two years.
Solanezumab is an antibody which binds to amyloid in its early soluble form allowing it to be cleared by the body before it can form dangerous plaques.
The research was published in the journal Nature Medicine.
NATURE MEDICINE | BRIEF COMMUNICATION
PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease
Kuti Baruch, Aleksandra Deczkowska, Neta Rosenzweig, Afroditi Tsitsou-Kampeli, Alaa Mohammad Sharif, Orit Matcovitch-Natan, Alexander Kertser, Eyal David, Ido Amit & Michal Schwartz
Nature Medicine (2016) doi:10.1038/nm.4022
Received 12 October 2015 Accepted 04 December 2015 Published online 18 January 2016
Systemic immune suppression may curtail the ability to mount the protective, cell-mediated immune responses that are needed for brain repair. By using mouse models of Alzheimer's disease (AD), we show that immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway evokes an interferon (IFN)-γ?dependent systemic immune response, which is followed by the recruitment of monocyte-derived macrophages to the brain. When induced in mice with established pathology, this immunological response leads to clearance of cerebral amyloid-β (Aβ) plaques and improved cognitive performance. Repeated treatment sessions were required to maintain a long-lasting beneficial effect on disease pathology. These findings suggest that immune checkpoints may be targeted therapeutically in AD.
Marijuana helps Alzheimer’s patients, study finds
By David Downs on January 14, 2016 at 9:34 AM
Adding marijuana to the treatment of Alzheimer’s Disease “is safe and a promising treatment option”, Israeli researchers conclude, in the latest study on the burgeoning practice.
Alzheimer’s Disease is a devastating and fatal degenerative neurological disease affecting more than five million Americans today. One in three seniors will die with Alzheimer’s or another dementia, and Alzheimer’s is the sixth leading cause of death in the nation, costing America about $203 billion in 2013.
Past studies indicate the active ingredients in cannabis can provide palliative relief to Alzheimer’s patients with dementia ? calming them down and allowing them to sleep. Cell studies also indicate cannabis’ active ingredients could prevent the onset and progression of Alzheimer’s, by interrupting the cycle of beta-amyloid plaque creation thought to cause Alzheimer’s Disease.
Researchers at the Abarbanel Mental Health Center and the Sackler Faculty of Medicine at Tel-Aviv University, in Israel, along with the Department of Psychology, at Bar-Ilan University conducted one of the first clinical studies of cannabis on human Alzheimer’s patients.
The main active ingredient in cannabis “tetrahydrocannabinol (THC) is a potential treatment for Alzheimer’s disease (AD)” researchers wrote. They wanted to measure the safety and efficacy of giving a medical cannabis oil containing THC as an add-on to existing Alzheimer’s drugs. Their goal: relieving the terrifying behavioral and psychological symptoms of dementia.
Eleven patients were recruited into an open-label, month-long trial. Ten patients finished the trial, and researchers reported “significant reduction” in mental illness severity, especially with regard to delusions, agitation/aggression, irritability, apathy, sleep, and caregiver distress.
“Adding [medical cannabis oil] to [Alzheimer’s Disease] patients’ pharmacotherapy is safe and a promising treatment option,” researchers concluded.
J Alzheimers Dis. 2016 Jan 12.
Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia: An-Open Label, Add-On, Pilot Study.
Shelef A1, Barak Y1, Berger U2, Paleacu D1, Tadger S1, Plopsky I1, Baruch Y1.
Tetrahydrocannabinol (THC) is a potential treatment for Alzheimer's disease (AD).
To measure efficacy and safety of medical cannabis oil (MCO) containing THC as an add-on to pharmacotherapy, in relieving behavioral and psychological symptoms of dementia (BPSD).
Eleven AD patients were recruited to an open label, 4 weeks, prospective trial.
Ten patients completed the trial. Significant reduction in CGI severity score (6.5 to 5.7; p?< ?0.01) and NPI score were recorded (44.4 to 12.8; p?< ?0.01). NPI domains of significant decrease were: Delusions, agitation/aggression, irritability, apathy, and sleep and caregiver distress.
Adding MCO to AD patients' pharmacotherapy is safe and a promising treatment option.
Alzheimer’s disease; behavioral and psychological symptoms of dementia; cannabis; tetrahydrocannabinol
PMID: 26757043 [PubMed - as supplied by publisher]
colony-stimulating factor 1 receptor (CSF1R) inhibition
Blocking brain inflammation 'halts Alzheimer's disease'
Blocking the production of new immune cells in the brain could reduce memory problems seen in Alzheimer's disease, a study suggests.
University of Southampton researchers said their findings added weight to evidence that inflammation in the brain is what drives the disease.
A drug used to block the production of these microglia cells in the brains of mice had a positive effect.
Experts said the results were exciting and could lead to new treatments.
Up until now, most drugs used to treat dementia have targeted amyloid plaques in the brain which are a characteristic of people with the Alzheimer's disease.
But this latest study, published in the journal Brain, suggests that in fact targeting inflammation in the brain, caused by a build-up of immune cells called microglia, could halt progression of the disease.
Previous studies have also suggested that these cells could play an important role.
Dr Diego Gomez-Nicola, lead study author from the university, said: "These findings are as close to evidence as we can get to show that this particular pathway is active in the development of Alzheimer's disease.
"The next step is to work closely with our partners in industry to find a safe and suitable drug that can be tested to see if it works in humans."
In the mice which were given a drug to block a receptor - called CSF1R - responsible for the rise in microglia in their brains, fewer memory and behavioural problems were noted in the study.
The drug also prevented the loss of communication points between nerve cells in the brain which usually happens in people with Alzheimer's.
Dr Mark Dallas, lecturer in cellular and molecular neuroscience at the University of Reading, said this was "an exciting discovery" which could explain "why drugs designed to treat Alzheimer's have so far been unsuccessful".
He added: "While this basic science research provides strong evidence, the challenge will now be to develop medicines for people with dementia, so we await the development of clinical treatments with interest. Too often, this has been the stumbling block in turning observations in the laboratory into a workable therapy."
Dr Doug Brown, director of research at Alzheimer's Society, said the study findings were "encouraging".
"With an ageing population and no new dementia drugs in over a decade, the need to find treatments that can slow or stop disease progression is greater than ever."
A Journal of Neurology
Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology (CC)
Adrian Olmos-Alonso, Sjoerd T. T. Schetters, Sarmi Sri, Katharine Askew, Renzo Mancuso, Mariana Vargas-Caballero, Christian Holscher, V. Hugh Perry, Diego Gomez-Nicola
DOI: http://dx.doi.org/10.1093/brain/awv379 awv379 First published online: 8 January 2016
The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer’s disease. However, the study of microglial proliferation in Alzheimer’s disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer’s disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer’s-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer’s disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer’s disease.