autoimmune diseases
gut microbiota
bacterial amyloid
a dual protective/damaging role for Aβ
out-of-control immune system
impaired thermoregulation
Autosomal dominant Alzheimer’s disease (ADAD)
comorbid neuropathologic abnormalities
adaptive immune cell populations
locus coeruleus
Soluble oligomers
phosphorylated tau accumulation
Vascular amyloidosis
fungal infection
blood-brain barrier (BBB)
Three Types of Alzheimer's
changes in protein turnover kinetics
three sequential phases in the development of autosomal dominant Alzheimer's disease
β2-microglobulin (B2M)
deficiency in PICALM
bacteria in intestines
immune-mediated amino acid catabolism  arginine
Selective intraneuronal amyloid-β accumulation in adult life and oligomerization
molecular chaperone
higher von Economo neuron density in anterior cingulate cortex
bisecting GlcNAc(バイセクト糖鎖)
Primary age-related tauopathy (PART)
tiny silent acute infarcts
Tau protein
HSF-1 (heat shock factor-1)
Brain compensation
absence of MK2/3
S-nitrosylation of myocyte enhancer factor 2 (MEF2)
lateral entorhinal cortex (LEC)
overexpression of TDP-43
cerebral small-vessel disease
misfolded proteins
exaggerated Ca2+ signaling
Amyloid precursor protein
co-aggregation of ferric iron
Golgi fragmentation
loss of SORLA’s Aβ sorting function
lateral entorhinal cortex dysfunction
jugular venous reflux
E280A gene mutation
Lysosomal NEU1 deficiency
receptor CD36
C9orf72 homozygosity
11 new Alzheimer's genes
自食(autophagy in Aβ metabolism)
LilrB2 (leukocyte immunoglobulin-like receptor B2)
U1 snRNP
Metabotropic Glutamate Receptor 5 ( mGluR5)
Microglial Beclin 1
C1q protein


autoimmune diseases

Associations between specific autoimmune diseases and subsequent dementia: retrospective record-linkage cohort study,
Clare J Wotton, Michael J Goldacre

J Epidemiol Community Health
March 1, 2017.

Objective To determine whether hospital admission for autoimmune disease is associated with an elevated risk of future admission for dementia.

Methods Retrospective, record-linkage cohort study using national hospital care and mortality administrative data, 1999?2012. Cohorts of people admitted to hospital with a range of autoimmune diseases were constructed, along with a control cohort, and followed forward in time to see if they developed dementia. 1?833?827 people were admitted to hospital with an autoimmune disease; the number of people in cohorts for each autoimmune disease ranged from 1019 people in the Goodpasture's syndrome cohort, to 316?043 people in the rheumatoid arthritis cohort.

Results The rate ratio for dementia after admission for an autoimmune disease, compared with the control cohort, was 1.20 (95% CI 1.19 to 1.21). Where dementia type was specified, the rate ratio was 1.06 (1.04 to 1.08) for Alzheimer's disease and 1.28 (1.26 to 1.31) for vascular dementia. Of 25 autoimmune diseases studied, 18 showed significant positive associations with dementia at p<0.05 (with 14 significant at p<0.001) including Addison's disease (1.48, 1.34 to 1.64), multiple sclerosis (1.97, 1.88 to 2.07), psoriasis (1.29, 1.25 to 1.34) and systemic lupus erythematosus (1.46, 1.32 to 1.61).

Conclusions The associations with vascular dementia may be one component of a broader association between autoimmune diseases and vascular damage. Though findings were significant, effect sizes were small. Clinicians should be aware of the possible coexistence of autoimmune disease and dementia in individuals. Further studies are needed to confirm or refute our findings and to explore possible mechanisms mediating any elevation of risk.

gut microbiota

Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota
T. Harach, N. Marungruang, N. Duthilleul, V. Cheatham, K. D. Mc Coy, G. Frisoni, J. J. Neher, F. F?k, M. Jucker, T. Lasser & T. Bolmont
Scientific Reports 7, Article number: 41802 (2017)
Published online: 08 February 2017
Alzheimer’s disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer’s disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.


bacterial amyloid

Louisville Doctor Links Gut Bacteria To Alzheimer’s, Parkinson’s

October 10, 2016

Dr. Robert Friedland has been working with Alzheimer’s and Parkinson’s patients for more than 30 years. And he still doesn’t know how they developed the diseases.

Less than 1 percent of patients have a gene that can lead to either disease. For the rest, it’s a big unknown.

But Friedland’s latest research shows that it might be because of gut bacteria.

According to a new study published in the journal Science Reports, Friedland and a team of researchers have found a link between gut bacteria and Alzheimer’s Disease.

“We all have up to 2 kilograms of bacteria in the intestines, and these make proteins that could potentially trigger the clubbing of brain proteins.,” said Friedland, who heads up the neurogeriatric lab at the University of Louisville School of Medicine and led the study. “A kilogram is 2.2 pounds. It’s a lot of bacteria.”

Scientists working on Alzheimer’s already knew that these folding proteins formed hard plaques in the brain. These are called amyloid proteins. They form chains that eventually stretch and kill memory cells from one end of the brain to the other.

There was a groundbreaking discovery by Matthew Chapman at the University of Michigan in 2007: Bacteria make these folding proteins.

“The bacteriologists have made significant advances on how and why bacteria make this, but the scientists working on Alzheimer’s had little awareness about this protein made in the body,” Friedland said. “So it was our idea to investigate whether the amyloid made by bacteria, if that could be the trigger for the similar amyloid proteins in neurons in the brain, and that could be why they become misformed.”

Researchers exposed old but healthy rats and tiny worms to two types of bacterial strains: one that could produce the folding protein, and another that couldn’t.

“We found that rats exposed to amyloid protein had more aggregation of neurons in the gut wall and the brain, and regions that were affected in Alzheimer’s and Parkinson’s. And they had more inflammation, which is an important part of Alzheimer’s.”

And the rats that weren’t exposed to the folding-protein bacteria?

“They had lower levels of the protein, and they didn’t show aggregation of the main protein associated with Parkinson’s,” he said.

Friedland plans to conduct the same study on mice. Much of the research that ends up with an approved drug starts with the animal because their systems model ours. Beyond that, there will be have to be research on the specific bacteria that produce the folding proteins.

“We don’t know precisely what amyloid proteins are involved, or how many there are,” he said.

The road that led to this discovery is a personal one: Friedland’s grandfather likely had Alzheimer’s.

“He threatened my mother with a knife when he was trying to jump out of a window because he believed falsely that the building was on fire,” he said. “And he ended up in a mental hospital in New York. I was only a little boy. It’s likely at those age with those symptoms, it was actually Alzheimer’s.”

Researchers at the Brown Cancer Center, Case Western University in Cleveland and the University of California San Diego were also part of the study.

The funding for the study came from the Michael J. Fox Foundation for Parkinson’s Research. Friedland was turned down by the National Institutes of Health because they don’t generally fund experimental research due to fierce competition for money. He hopes NIH will now see his evidence and consider future funding.

Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans
Shu G. Chen, Vilius Stribinskis, Madhavi J. Rane, Donald R. Demuth, Evelyne Gozal, Andrew M. Roberts, Rekha Jagadapillai, Ruolan Liu, Kyonghwan Choe, Bhooma Shivakumar, Francheska Son, Shunying Jin, Richard Kerber, Anthony Adame, Eliezer Masliah & Robert P. Friedland
Scientific Reports 6, Article number: 34477 (2016)
Download Citation
DementiaNeurological disorders
08 June 2016
14 September 2016
Published online:
06 October 2016
Misfolded alpha-synuclein (AS) and other neurodegenerative disorder proteins display prion-like transmission of protein aggregation. Factors responsible for the initiation of AS aggregation are unknown. To evaluate the role of amyloid proteins made by the microbiota we exposed aged rats and transgenic C. elegans to E. coli producing the extracellular bacterial amyloid protein curli. Rats exposed to curli-producing bacteria displayed increased neuronal AS deposition in both gut and brain and enhanced microgliosis and astrogliosis compared to rats exposed to either mutant bacteria unable to synthesize curli, or to vehicle alone. Animals exposed to curli producing bacteria also had more expression of TLR2, IL-6 and TNF in the brain than the other two groups. There were no differences among the rat groups in survival, body weight, inflammation in the mouth, retina, kidneys or gut epithelia, and circulating cytokine levels. AS-expressing C. elegans fed on curli-producing bacteria also had enhanced AS aggregation. These results suggest that bacterial amyloid functions as a trigger to initiate AS aggregation through cross-seeding and also primes responses of the innate immune system.

a dual protective/damaging role for Aβ

MAY 27, 2016

New Research Uncovers A Possible Cause Of Alzheimer's Disease That Is Both Surprising And Promising

Kevin Murnane

A team of researchers from Harvard has presented evidence that suggests a mechanism for fighting infections in the brain may be a contributing factor to the development of Alzheimer’s disease. The research, reported in Science Translational Medicine, opens up a new and surprising window into the possible causes of Alzheimer’s.

According to the new research, the process that results in Alzheimer’s goes something like this. The blood-brain barrier keeps many bacterial pathogens that are present in the bloodstream out of the brain. As people age, the blood-brain barrier weakens and viruses, bacteria and fungi that were previously contained within the bloodstream begin to enter the brain.

The new research indicates that the brain defends against these invading pathogens by isolating them within cages built from proteins called beta amyloids. Once it is caged, the pathogen dies and the beta amyloid cage is left behind. Over time, the cage can gather a collection of defective tau proteins that normally play a role in the maintenance of cell structure and function. The defective tau proteins kill surrounding nerve cells. If this process goes too far, inflammation that kills more nerve cells around the cage can occur. The loss of these nerve cells is the root cause of Alzheimer’s disease.

In previous research the investigators reported that beta amyloids cage microbial pathogens in vitro (in a preparation outside a living organism). In the new research they confirmed this finding with in vivo (inside a living organism) preparations using roundworms and mice. As yet, the finding has not been demonstrated with humans although there are no compelling reasons to think that beta amyloids function differently in people.

Previously, beta amyloids were thought to be nothing more than leftover junk proteins called plaque that accumulated in the brain over time. No one realized that these plaque deposits were empty cages that had played an important role in fighting bacterial infections in the brain.

How do the new findings hook up with what we know about Alzheimer’s disease? The hippocampus is a brain structure that plays a central role in memory, learning and spatial orientation. It also is one of the first areas of the brain to be damaged by Alzheimer’s. This damage accounts for the disorientation and loss of memory that are symptomatic of the disease. It has long been recognized that the damage in question is the destruction of nerve tissue surrounding the beta amyloid deposits that were previously thought to be nothing more than plaque.

The hippocampus has another part to play in linking Alzheimer’s with the role beta amyloids play in fighting bacterial infections. Remember that this hypothetical process begins with the weakening of the blood-brain barrier that results in pathogens entering the brain. Independent research has shown that Alzheimer’s patients typically show weakening of the blood-brain barrier and that age-related weakening of the blood-brain barrier begins in the hippocampus.

The new findings are very exciting but it is important to recognize that it is early days yet. The role played by beta amyloids in fighting bacterial infection has yet to be demonstrated in humans. However, if these findings hold up, it suggests at least two ways of attacking Alzheimer’s that had not been considered before. First, research can be carried out to find ways to kill the bacterial infections that trigger the beta amyloid response before the cages are constructed. Second, ways can be sought to strengthen the aging blood-brain barrier so that the pathogens don’t get into the brain in the first place. This has the potential to be a game changer.

Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease
Deepak Kumar Vijaya Kumar1,*, Se Hoon Choi1,*, Kevin J. Washicosky1,*, William A. Eimer1, Stephanie Tucker1, Jessica Ghofrani1, Aaron Lefkowitz1, Gawain McColl2, Lee E. Goldstein3, Rudolph E. Tanzi1,† and Robert D. Moir1,†
Science Translational Medicine 25 May 2016:
Vol. 8, Issue 340, pp. 340ra72
DOI: 10.1126/scitranslmed.aaf1059

A protein called Aβ is thought to cause neuronal death in Alzheimer’s disease (AD). Aβ forms insoluble aggregates in the brains of patients with AD, which are a hallmark of the disease. Aβ and its propensity for aggregation are widely viewed as intrinsically abnormal. However, in new work, Kumar et al. show that Aβ is a natural antibiotic that protects the brain from infection. Most surprisingly, Aβ aggregates trap and imprison bacterial pathogens. It remains unclear whether Aβ is fighting a real or falsely perceived infection in AD. However, in any case, these findings identify inflammatory pathways as potential new drug targets for treating AD.

The amyloid-β peptide (Aβ) is a key protein in Alzheimer’s disease (AD) pathology. We previously reported in vitro evidence suggesting that Aβ is an antimicrobial peptide. We present in vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides.

out-of-control immune system

Should we rethink of causes of dementia?

May 12, 2016

A new theory for the causes of dementia and other neurodegenerative diseases has been developed, involving an out-of-control immune system.

University of Adelaide researchers have developed a new theory for the causes of dementia and other neurodegenerative diseases, involving an out-of-control immune system.

Published in the journal Frontiers in Neuroscience, the researchers have assembled strong evidence that the neurological decline common to these diseases is caused by 'auto-inflammation', where the body's own immune system develops a persistent inflammatory response and causes brain cells to die.

"Dementia, including the most common form Alzheimer's Disease, and related neurodegenerative conditions are dramatically rising in frequency as people live longer and our population ages," says study lead Professor Robert Richards, from the University of Adelaide's School of Biological Sciences. "Australia is predicting that by 2050 there will be almost double the number of people with dementia, and the United States similarly says there will be twice as many.

"Currently we have no effective treatments to assist the millions of affected people, and these diseases are an enormous burden on families and the public health care system."

Previously, researchers have focused on the role of protein deposits called amyloid plaques that lodge in the brain of Alzheimer's affected people. But it is now clear that this is an inadequate explanation for Alzheimer's Disease.

There are many distinct forms of neurodegeneration including Alzheimer's, Parkinson's and Huntington's Diseases. These conditions are distinguished by the different types of brain nerve cells that are first affected and by the symptoms that first appear. However, as all of these diseases progress, they become more similar.

Professor Richards believes that instead of many different mechanisms, each disease has the same underlying mechanism, and common pathway of nerve cell loss.

"Our interest in the body's own (innate) immune system as the culprit began when we discovered that immune system agents become activated in a laboratory model of Huntington's Disease," he says. "Remarkably, researchers from other laboratories were at the same time reporting similar features in other neurodegenerative diseases. When we pulled the evidence together, it made a very strong case that uncontrolled innate immunity is indeed the common cause."

The innate immune system is the first line of defense in cells, and normally distinguishes molecules that belong to the body from foreign, disease-causing, molecules. It is an alarm and response system with a self-destruct mechanism to contain and eliminate invaders or abnormal cells, like cancer.

Malfunctions can occur because of various triggers including genetic mutations, infection, toxins or physical injury, all of which have been linked with different forms of neurodegeneration. Initially the innate immune system protects the tissue against these triggers, but prolonged activation becomes self-perpetuating, causing brain cell death to occur.

"We hope this new way of understanding neurodegeneration will lead to new treatments," Professor Richards says. "We now need to further investigate the immune signaling molecules, to identify new drug targets that will delay the onset and/or halt the progression of these devastating diseases."

Story Source:

The above post is reprinted from materials provided by University of Adelaide. Note: Materials may be edited for content and length.

Journal Reference:

Robert I. Richards, Sarah A. Robertson, Louise V. O'Keefe, Dani Fornarino, Andrew Scott, Michael Lardelli, Bernhard T. Baune. The Enemy within: Innate Surveillance-Mediated Cell Death, the Common Mechanism of Neurodegenerative Disease. Frontiers in Neuroscience, 2016; 10 DOI: 10.3389/fnins.2016.00193

impaired thermoregulation

Regulating Body Temperature May Ease Alzheimer’s Disease Symptoms

APRIL 11, 2016

Researchers at Universit? Laval in Canada demonstrated that aging mice in a model of Alzheimer’s disease (AD) were less able to regulate their body temperatures, and when exposed to a cold environment showed increased AD manifestations. These results suggest correction of thermoregulation might be a therapeutic avenue for Alzheimer’s.

The study, “Impaired thermoregulation and beneficial effects of thermoneutrality in the 3xTg-AD model of Alzheimer’s disease (AD),” was published in Neurobiology of Aging.

The accentuated incidence of AD in older people is accompanied by a reduction in energy metabolism and core body temperature. Researchers investigated if changes in body temperature regulation would amplify the debilitating manifestations of the disease, and if such effects would manifest in a vicious circle, as areas of the brain involved in thermoregulation are affected in Alzheimer’s.

To test the hypothesis, the team used a mouse model of AD, the 3xTg-AD, that presents the hallmarks of the disease, including beta-amyloid production, formation of plaque, synapse loss, and memory loss starting at 6 months. Compared to normal mice, the AD mice were less effective in maintaining their body temperature, spontaneously developing a lower basal temperature as they grew older. The difference between transgenic and normal control mice reached almost 1° Celsius (about 1.8° Fahrenheit) at 12 months of age. Moreover, AD mice were more vulnerable to low temperatures, and clinical manifestations of AD more noticeable when they were exposed to a colder environment. After a 24-hour exposure to cold (4°C/39°F), key pathological markers of AD were worse, namely abnormal tau protein and loss of synaptic proteins. Raising the body temperature in the transgenic animals improved memory, and mitigated amyloid and synapse pathologies within a week.

Researchers believe that such findings hint at a possible new therapeutic avenue, warranting investigation in people. “Our findings suggest that it is worth exploring the treatment of thermoregulation among seniors suffering from Alzheimer’s,” Professor Fr?d?ric Calon, the study’s lead author, said in a news release. “If our conclusions are confirmed, it would be a relatively easy therapeutic option to implement because body temperature can be increased through physical activity, diet, drugs, or simply by increasing the ambient temperature.”

Impaired thermoregulation and beneficial effects of thermoneutrality in the 3xTg-AD model of Alzheimer’s disease (AD)

Milene Vandal, White J. Phillip, Marine Tournissac, Cyntia Tremblay, Isabelle St-Amour, Janelle Drouin-Ouellet, Melanie Bousquet, Marie-Th?r?se Traversy, Emmanuel Planel, Andre Marette, Frederic Caloncorrespondenceemail
Article has an altmetric score of 42
DOI: http://dx.doi.org/10.1016/j.neurobiolaging.2016.03.024

The sharp rise in the incidence of Alzheimer’s disease (AD) at an old age coincides with a reduction in energy metabolism and core body temperature. We found that the 3xTg-AD mouse model of AD spontaneously develops a lower basal body temperature and is more vulnerable to a cold environment compared to age-matched controls. This was despite higher non-shivering thermogenic activity, as evidenced by brown adipose tissue (BAT) norepinephrine content and uncoupling protein 1 (UCP1) expression. A 24-h exposure to cold (4°C) aggravated key neuropathological markers of AD such as: tau phosphorylation, soluble Aβ concentrations and synaptic protein loss in the cortex of 3xTg-AD mice. Strikingly, raising the body temperature of aged 3xTg-AD mice via exposure to a thermoneutral environment improved memory function and reduced amyloid and synaptic pathologies within a week. Our results suggest the presence of a vicious cycle between impaired thermoregulation and AD-like neuropathology and it is proposed that correcting thermoregulatory deficits might be therapeutic in AD.

Autosomal dominant Alzheimer’s disease (ADAD)

March 23, 2016

He’s the seventh family member to be diagnosed with Alzheimer’s: now he’s trying to help stop it

By Allison Vuchnich
Senior Network Correspondent
Global News

Ted was diagnosed with early-onset familial Alzheimer’s disease at the age of 44. He lost his mother and four other family members to the disease, now Ted and his uncle are living with it.

“It’s scary, just scary, I didn’t know what was going to happen,” Ted told Global News about his diagnosis in 2008.

In a first-of-its kind study, Canadian researchers are joining an international team testing antibody drugs hoping to slow or stop the development of Alzheimer’s disease, in those genetically destined to develop the illness.

Autosomal dominant Alzheimer’s disease (ADAD) is genetically inherited or passed down. If a parent has the genetic mutation, a child has a 50 per cent chance of carrying the gene.

With early-onset some people experience symptoms as early as their 30s and 40s ? changes in mood and memory. It varies, but on average the course of Alzheimer’s disease from diagnosis to time of death is about 10 years, according to physicians.

That is why Ted and his wife Joanne have travelled to Sunnybrook Health Sciences Centre in Toronto to participate in the study.

“For my kids, and hopefully a cure,” said Ted.

According to his wife Joanne, Ted’s first thought after his diagnosis was of their children and how to help others.

“It’s exciting that they are doing a trial for this very rare form, which hopefully then will lead to something for age (late) onset Alzheimer’s…we are just hoping for great results” said Joanne.

The majority of Alzheimer’s cases are late-onset, ADAD makes up less than one per cent of all cases. What is key ? is early-onset Alzheimer’s may hold important clues.

The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) drug trial is testing two medications in patients and a placebo. Ted and other patients will receive treatment every month for four years.

“We want to stop this disease in its tracks, before symptoms begin to emerge, or when in the very early stages,” said Dr. Mario Masellis, neurologist and lead investigator of the trial at Sunnybrook.

Ted celebrates Father’s Day 2015 with his family.

Researchers are focusing on tackling a “protein problem,” a build-up of a sticky plague in the brain, due to a protein called amyloid and another called tau.

“If we can try to prevent the amyloid from accumulating in the brain then we hopefully can at least slow down or halt the process of the further development of Alzheimer’s in these families,” Masellis told Global News.

Although this study is focused on the genetic forms of the disease, there is hope that clues discovered in this study could help treat or even prevent all Alzheimer’s one day.

“This is where the whole field is moving. Trying to tackle Alzheimer’s disease before it begins, or in the very, very, early stage so the genetic forms of the disease serves as an opportunity,” Masellis told Global News, “to see if we can develop treatments.”

? Shaw Media, 2016

comorbid neuropathologic abnormalities

Beyond Alzheimer's: Study reveals how mix of brain ailments drives dementia

March 21, 2016

A new analysis based on two long-term aging studies?one of Roman Catholic nuns, the other of Japanese American men?provides what may be the most compelling evidence yet that dementia commonly results from a blend of brain ailments, rather than from a single condition. This is often the case even when an Alzheimer's diagnosis has been given, say the researchers.

A team led by Dr. Lon White, with the University of Hawaii and the Veterans Affairs-affiliated Pacific Health Research and Education Institute, analyzed data on more than 1,100 people who had taken part in the Nun Study or the Honolulu-Asia Aging Study. Both studies followed hundreds of aging adults and included brain autopsies upon their death.

The analysis by White's team appears in the March 15, 2016, issue of Neurology.

"The impact on clinical dementia and impairment is largely unrelated to the type of lesion, or type of lesion combination," said White in an email interview. "Rather, the driving factor seems to be just the total burden of disease."
The observation is not new. Based on several studies in the past few years, experts have begun to recognize "mixed pathology" dementia as a relevant model to explain the cognitive losses of older people. White notes that "even the lay public seems to now be appreciating that dementia is often the result not of a single disease process, but of a combination."
But the new study led by the Hawaii team offers the largest-scale, most comprehensive documentation of the trend to date.
The study included data on 334 nuns and 774 Japanese American men, all of whom completed multiple cognitive assessments as they grew older, and whose brains were autopsied after they died. The average age at death was around 90 for the nuns and 88 for the men.
Based on the autopsies, White's team found predictable rates of five different brain pathologies, all of which can bring on dementia. These included Alzheimer's disease, Lewy bodies, hippocampal sclerosis, microinfarcts, and low brain weight.
The researchers found signs of Alzheimer's in about half the brains. But only in about half of those cases was it the main lesion type. Among 279 participants who had severe Alzheimer's pathology, more than three-quarters had at least one other type of lesion.
Along with this, the researchers observed that most of the participants who had displayed significant levels of cognitive impairment during their final years had few or no Alzheimer's-type abnormalities.

By and large, it was combinations of ailments?rather than any single condition?that correlated most strongly with cognitive impairment. Such combinations had a "dramatic" impact on dementia risk, wrote the researchers.
The nuns with the highest level of comorbidity?the most lesion types, with the greatest overall severity?were 99 times more likely to have cognitive impairment, compared with those with no pathology.
The study documented many different combinations. There were no overarching patterns.
"There are a huge number of possible combinations of lesion types, reflecting what appears to be nearly random linkages among the types," said White. "The probability of each is largely unrelated to the probabilities of the others."
White, a neuroepidemiologist, said the effect of comorbidity appears to be multiplicative, rather than additive. This means, for example, if one type of lesion normally raises the risk of cognitive impairment by a factor of three, and another also raises it threefold, the combined risk increase from the two lesions would be not three plus three, but three times three. In other words, the older person with both lesion types would have a nine-fold risk of cognitive impairment, compared with someone without either pathology.
Says White: "I believe it's because all of these lesion types seem to be broadly distributed around the brain, each involving different neuron types and fields. So the result of their summation reflects the wiping out of multiple different systems within the brain, each required for optimal cognition."
"The bad news," he sums up, "is that it is much worse to have comorbid lesions than to have a single lesion type."
By the same token, White says, the upshot of the findings is that the opportunity to ward off dementia may be broader than currently thought.
"The good news is that preventing any [of the pathologies] will be of benefit to the process of aging-related cognitive decline. We can prevent illnesses currently diagnosed as Alzheimer's disease by preventing any of the other four lesion types, even if we cannot directly prevent the Alzheimer's lesions."
White admits there is not currently an abundance of clinical or lifestyle strategies shown to do that.
But he does underscore the importance of maintaining healthy blood pressure. High blood pressure has been implicated as a contributing factor in most of the lesion types his group studied.
"At this point," says White, "prevention by effective treatment of hypertension in midlife seems to be the only solid approach."
Explore further: Can blood pressure drugs reduce the risk of dementia?
More information: L. R. White et al. Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies, Neurology (2016). DOI: 10.1212/WNL.0000000000002480
Journal reference: Neurology

Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies
Lon R. White, MD, MPH, Steven D. Edland, PhD, Laura S. Hemmy, PhD, Kathleen S. Montine, PhD, Chris Zarow, PhD, Joshua A. Sonnen, MD, Jane H. Uyehara-Lock, MD, Rebecca P. Gelber, MD, DrPH, G. Webster Ross, MD, Helen Petrovitch, MD, Kamal H. Masaki, MD, Kelvin O. Lim, MD, Lenore J. Launer, PhD and Thomas J. Montine, MD, PhD
Correspondence to Dr. White: lon@hawaii.edu
Published online before print February 17, 2016
Neurology March 15, 2016 vol. 86 no. 11 1000-1008
AbstractFull TextFull Text (PDF)
Also available: Figures Only Data Supplement PPT Slides of All Figures

Objective: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels.

Methods: The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined.

Results: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy.

Conclusions: Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life.

adaptive immune cell populations

Body’s immune system may play larger role in Alzheimer’s disease than thought

UCI mouse study finds dramatic increase in brain plaques when key cells are lacking

UC Irvine News
FEBRUARY 23, 2016

Irvine, Calif., Feb. 23, 2016 ? Immune cells that normally help us fight off bacterial and viral infections may play a far greater role in Alzheimer’s disease than originally thought, according to University of California, Irvine neurobiologists with the Sue & Bill Gross Stem Cell Research Center and the Institute for Memory Impairments and Neurological Disorders.

The researchers discovered this when Alzheimer’s disease mice genetically modified to lack these key immune cells in their blood developed the distinctive brain plaques associated with the neurodegenerative disorder much more quickly.

According to Mathew Blurton-Jones, assistant professor of neurobiology & behavior, and doctoral student Samuel Marsh, their findings could lead to the creation of new techniques to help identify, or perhaps even treat, individuals at risk of developing the disease.

Alzheimer’s is the leading cause of age-related dementia and is thought to be driven by the accumulation of a protein called beta-amyloid that aggregates to form amyloid plaques in the brain. Microglia, immune cells that reside in the brain, attempt to clear this buildup, but in Alzheimer’s, they appear to be fighting a losing battle. While many studies have explored the role of microglia in Alzheimer’s, very few researchers have asked whether a different set of immune cells called T-cells and B-cells that reside outside the brain and play a large part in autoimmune diseases might also impact Alzheimer’s.

To test this idea, Blurton-Jones and Marsh bred genetically modified Alzheimer’s disease mice to lack three key immune cell types: T-cells, B-cells and NK-cells. Six months later, when the brains of these mice were compared to those of Alzheimer’s mice with intact immune systems, the scientists found a more than twofold increase in beta-amyloid accumulation.

“We were very surprised by the magnitude of this effect,” Blurton-Jones said. “We expected the influence of the deficient immune system on Alzheimer’s pathology to be much more subtle.”

To understand how the loss of these immune cells was increasing beta-amyloid, he and Marsh examined the interactions between these peripheral cells and microglia within the brain.

“We found that in Alzheimer’s mice with intact immune systems, antibodies ? which are made by B-cells ? accumulated in the brain and associated with microglia. This, in turn, helped increase the clearance of beta-amyloid,” Marsh said.

To further confirm the importance of this interplay between immune cells in the blood and those in the brain, the researchers transplanted healthy bone marrow stem cells into the immune-deficient Alzheimer’s mice. Since T-, B- and NK-cells develop from bone marrow stem cells, this transplantation led to a reconstitution of the missing immune cells. This allowed the B-cells to produce antibodies that once again reached the brain and aided microglia in eradicating the beta-amyloid.

“We know that the immune system changes with age and becomes less capable of making T- and B-cells,” Blurton-Jones said. “So whether aging of the immune system in humans might contribute to the development of Alzheimer’s is the next big question we want to ask.”

Study results appear in the early online edition of Proceedings of the National Academy of Sciences. Other researchers who contributed to this work are Edsel Abud, Anita Lakatos, Alborz Karimzadeh, Stephen Yeung, Hayk Davtyan, Gianna Fote, Lydia Lau, Jason Weinger, Thomas Lane, Matthew Inlay and Wayne Poon. The research was supported by the National Institutes of Health (grant RF1AG048099) and the Alzheimer’s Association.

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The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function
Samuel E. Marsha,b, Edsel M. Abuda,b,1, Anita Lakatosc,1, Alborz Karimzadehb,d, Stephen T. Yeungc,2, Hayk Davtyane, Gianna M. Fotea,b, Lydia Lauc, Jason G. Weingerd,3, Thomas E. Laneb,c,d,4, Matthew A. Inlayb,d, Wayne W. Poonc, and Mathew Blurton-Jonesa,b,c,5
Author Affiliations

Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved January 19, 2016 (received for review December 24, 2015)
PNAS Online


Neuroinflammation and activation of innate immunity are pathological hallmarks of Alzheimer’s disease (AD). In contrast, very few studies have examined the impact of the adaptive immune system in AD pathogenesis. Here, we find that genetic ablation of peripheral immune cell populations significantly accelerates amyloid pathogenesis, worsens neuroinflammation, and alters microglial activation state. Critically, it appears that loss of IgG-producing B cells impairs microglial phagocytosis, thereby exacerbating amyloid deposition. Conversely, replacement of IgGs via direct injection or bone marrow transplantation reverses these effects and reduces Aβ pathology. Together, these results highlight the importance of the adaptive immune system and its interactions with microglia in the pathogenesis of AD.

The innate immune system is strongly implicated in the pathogenesis of Alzheimer’s disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting “Rag-5xfAD” mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive?innate immunity cross talk and accelerated disease progression.

locus coeruleus

Revealed, the 'ground zero' of Alzheimer's: Scientists pinpoint the exact area of the brain where devastating disease begins

Vulnerable region in the brain, the locus coeruleus, has been identified
Study: This is first part of the brain to see build-ups of tau, a protein which forms the slow-spreading 'tangles' blamed for Alzheimer's disease
Damage can occur decades before dementia patients show symptoms

16 February 2016

Alzheimer’s ‘ground zero’ - the site in the brain where the disease first strikes - has been discovered, it was announced today.
Researchers say a critical but vulnerable region in the brain, the locus coeruleus, is subject to damage decades before dementia patients start to show symptoms.
Buried towards the base of the brain stem, the locus coeruleus may be more important for cognitive function than previously appreciated, according to a new review of the medical evidence.
In dementia patients, it becomes damaged as early as the mid-twenties, according to the Californian experts

The discovery, published in the journal Trends in Cognitive Sciences, may help doctors develop new methods to ward off Alzheimer’s.
The locus coeruleus is a small, bluish part of the brainstem that releases norepinephrine, a chemical responsible for regulating heart rate, attention, memory and cognition.
But because it is so well linked to other parts of the brain, it is highly susceptible to the effects of toxins and infections, the scientists said.

They found the locus coeruleus is the first part of the brain to see build-ups of tau, a protein which forms slow-spreading ‘tangles’ thought to be a factor behind Alzheimer’s disease.
The team, from the University of Southern California, said engaging the brain in complex tasks - such as playing difficult music, completing word puzzles or having a complicated job - may help ward off dementia.
This is because norepinephrine, which is released from the locus coeruleus when someone is mentally challenged, may help slow brain decline.
Separate studies conducted with rats and mice have shown that norepinephrine helps protect brain cells from inflammation and degeneration

And other research has shown that people who have mentally challenging jobs or play complicated games such as crosswords tend to have lower rates of dementia.
Experts estimate that delaying the onset of Alzheimer's by five years could halve the number who die with the condition.
In 2015 there were an estimated 46.8 million people worldwide living with dementia.
This number will almost double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050, according to Alzheimer's Disease International.

Many are now living longer and healthier lives and so the world population has a greater proportion of older people.
Dementia mainly affects older people, although there is a growing awareness of cases that start before the age of 65.
Figures show there are over 9.9 million new cases of dementia each year worldwide, implying one new case every 3.2 seconds.
Study author Professor Mara Mather, an expert in cognition and ageing, said: ‘Education and engaging careers produce late-life “cognitive reserve”, or effective brain performance, despite encroaching pathology.
‘Activation of the locus coeruleus-norepinephrine system by novelty and mental challenge throughout one’s life may contribute to cognitive reserve.’
Dr Rosa Sancho of Alzheimer’s Research UK said: ‘About half a million people in the UK are living with Alzheimer’s and there are no treatments to halt the damage caused in the disease.
‘This work gathers together years of research into a brain region called the locus coeruleus, which appears to be an early site of damage in Alzheimer’s disease.
‘The research highlights that the locus coeruleus could play an important role in maintaining memory and thinking skills and research is underway to understand how changes in this critical region impact on brain health as we age.
'It’s important that researchers around the world investigate the initial stages of Alzheimer’s and explore why some parts of the brain are more vulnerable to damage than others, as this will help in the hunt for new treatments.’

The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain
Mara Mather
correspondenceemail, Carolyn W. Harley
DOI: http://dx.doi.org/10.1016/j.tics.2016.01.001

Research on cognitive aging has focused on how decline in various cortical and hippocampal regions influence cognition. However, brainstem regions play essential modulatory roles, and new evidence suggests that, among these, the integrity of the locus coeruleus (LC)?norepinephrine (NE) system plays a key role in determining late-life cognitive abilities. The LC is especially vulnerable to toxins and infection and is often the first place Alzheimer's-related pathology appears, with most people showing at least some tau pathology by their mid-20s. On the other hand, NE released from the LC during arousing, mentally challenging, or novel situations helps to protect neurons from damage, which may help to explain how education and engaging careers prevent cognitive decline in later years

soluble oligomers

UCLA Nursing research finds possible answer to why some develop Alzheimer’s ? and others don’t

Laura Perry
January 19, 2016
UCLA School of Nursing

The researchers viewed synapses using a technology called flow cytometry.
Alzheimer’s disease affects millions, but there is no cure and no real test for the diagnosis until death, when an examination of the brain can reveal the amyloid plaques that are a telltale characteristic of the disease.

Interestingly, the same plaque deposits have also been found in the brains of people who had no cognitive impairment, which has led scientists to wonder: Why do some develop Alzheimer’s and some do not?

Researchers at the UCLA School of Nursing, led by Professor Karen Gylys, may have just uncovered the answer. Their study, published in the January issue of the American Journal of Pathology, is the first to look at disease progression in the synapses ? where brain cells transmit impulses.

The researchers analyzed autopsy tissue samples from different locations of the brains of patients who were considered cognitively normal and those who met the criteria for dementia. Using flow cytometry ? a laser-based technology that suspends cells in a stream of fluid and passes them through an electronic detection apparatus ? they measured the concentration of two of the known biochemical hallmarks of Alzheimer’s: amyloid beta and p-tau, proteins that when found in high levels in brain fluid are indicative of Alzheimer’s. This allowed the scientists to see large populations of individual synapses ? more than 5,000 at a time ? versus just two under a microscope.

They found that people with Alzheimer’s had elevated concentrations of synaptic soluble amyloid-beta oligomers ? smaller clusters of amyloid-beta that are toxic to brain cells. These oligomers are believed to affect the synapses, making it harder for the brain to form new memories and recall old ones.

“Being able to look at human synapses has almost been impossible,” Gylys said. “They are difficult to get a hold of and a challenge to look at under an electron microscope.”

To overcome that challenge, the UCLA researchers cryogenically froze the tissue samples ? which prevented the formation of ice crystals that would have otherwise occluded the synapses had the samples been conventionally frozen. Researchers also did a special biochemical assay for oligomers, and found that the concentration of oligomers in patients who had dementia was much higher than in patients who had the amyloid plaque buildup but no dementia.

Researchers also studied the timing of the biochemical changes in the brain. They found that the accumulation of amyloid beta in the synapses occurred in the earliest stages of the amyloid plaques, and much earlier than the appearance of synaptic p-tau, which did not occur until late-stage Alzheimer’s set in. This result supports the currently accepted “amyloid cascade hypothesis” of Alzheimer’s, which says that the accumulation of amyloid-beta in the brain is one of the first steps in the development of the disease.

The researchers now plan to examine exactly how soluble amyloid-beta oligomers lead to tau pathology and whether therapies that slow the accumulation of amyloid-beta oligomers in the synapses might delay or even prevent the onset of Alzheimer’s-related dementia.

“The study indicates there is a threshold between the oligomer buildup and the development of Alzheimer’s,” Gylys said. “If we can develop effective therapies that target these synaptic amyloid beta oligomers, even a little bit, it might be possible to keep the disease from progressing.”

Gylys said people can reduce their risk for Alzheimer’s through lifestyle and diet choices, but added that one solution is not going to be enough. “Alzheimer’s disease, like heart disease or cancer, is a lot of things going wrong,” she said. “But understanding this threshold effect is very encouraging.”

Other investigators involved in the study were Tina Bilousova, Harry Vinters, Eric Hayden, David Teplow, Gregory Cole and Edmond Teng of UCLA; Carol Miller of the University of Southern California; and Wayne Poon, Maria Corrada, Claudia Kawas, Charles Glabe and Ricardo Albay III of UC Irvine.

The research was supported by grants from the National Institutes of Health and National Institute of Aging.

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

January 2016Volume 186, Issue 1, Pages 185?198
The American Journal of Pathology

Amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Aβ and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Aβ and p-tau in large populations of individual synaptic terminals. Soluble Aβ oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Aβ was elevated in patients with early- and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Aβ oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Aβ-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Aβ drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed.


phosphorylated tau accumulation

Proteins Explain Why Some People Function Normally Despite Signs Of Alzheimer's In Their Brains

Dec 21, 2015 12:00 AM By Susan Scutti

Many elderly people function and behave normally despite the fact that a brain scan (or later, an autopsy) will display characteristics of Alzheimer's disease. So, why do some people become demented while others remain mentally sound even though their brains appear similarly diseased? It’s all a matter of proteins and synapses, say UCLA investigators.

Compared to cognitively sound people with signs of disease, early-stage Alzheimer’s patients show high concentrations of amyloid beta, a type of protein, in their synapses, according to the results of a new study. Meanwhile, in the early stages of disease, Alzheimer’s patients do not show increased levels of hyperphosphorylated tau (p-tau), another Alzheimer's-linked protein. Tau levels rise only after a patient enters the late-stage, says the research team.


The UCLA researchers analyzed a collection of brain autopsy samples taken from different regions of the brain: parietal, superior parietal, entorhinal cortex, and hippocampus. A total of 46 people had contributed these samples. Four had been cognitively normal and so served as controls in the experiment. Fifteen functioned normally, but their brains showed signs of Alzheimer’s-related pathology; these people served as high-pathology controls. Twenty-four people had been diagnosed based on both pathology and clinical signs ? both their brains and behavior showed signs of Alzheimer’s. The researchers classified the diagnosed patients as either early-stage or later stage and then included two final cases in their study, two patients who had been diagnosed with an inherited neurological condition that affects movement.

Analyzing the brain samples, the investigators measured concentration levels of amyloid beta and p-tau, hallmarks of Alzheimer’s disease, in the synaptic terminals.

They found little or no evidence of amyloid beta in either of the control groups. However, a rise in concentration levels was linked to later disease stage. Plus, synaptic levels of amyloid beta correlated with the occurrence of plaque, another hallmark of the disease.

Next, the investigators explored how biochemical levels related to demented behavior.

What they observed suggested dementia emerged only after the level of synapse-associated amyloid beta exceeded a certain threshold, a finding which supports the well-known “amyloid cascade hypothesis” for Alzheimer’s disease. This theory suggests amyloid beta oligomers are the primary toxic molecules of Alzheimer’s, yet they eventually initiate downstream tau pathology, which causes the symptoms of disease.

“Our results suggest that effective therapies will need to target synaptic amyloid beta oligomers,” Dr. Karen H. Gylys, lead investigator and researchers at UCLA’s Mary S. Easton Center for Alzheimer's Research, said in a press release.

Source: Bilousova T, Miller CA, Poon WW, et al. Synaptic Amyloid-b Oligomers Precede p-Tau and Differentiate High Pathology Control Cases. The American Journal of Pathology. 2015.

January 2016Volume 186, Issue 1, Pages 185?198
Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Tina Bilousova, Carol A. Miller, Wayne W. Poon, Harry V. Vinters, Maria Corrada, Claudia Kawas, Eric Y. Hayden, David B. Teplow, Charles Glabe, Ricardo Albay III, Gregory M. Cole, Edmond Teng, Karen H. Gylyscorrespondenceemail
DOI: http://dx.doi.org/10.1016/j.ajpath.2015.09.018 |

Amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Aβ and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Aβ and p-tau in large populations of individual synaptic terminals. Soluble Aβ oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Aβ was elevated in patients with early- and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Aβ oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Aβ-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Aβ drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed.

Vascular amyloidosis

Neuroscientists gain insight into cause of Alzheimer's symptoms
Amyloid plaques may be strangling blood flow


Virginia Tech Carilion Research Institute scientists have uncovered a mechanism in the brain that could account for some of the neural degeneration and memory loss in people with Alzheimer's disease.

The researchers, together with scientists at the University of Alabama at Birmingham School of Medicine, discovered that a common symptom of Alzheimer's disease - the accumulation of amyloid plaques along blood vessels - could be disrupting blood flow in the brain. The results were published Monday in the journal Brain.

"We've always been interested in how glial cells interact with blood vessels," said Harald Sontheimer, director of the Center for Glial Biology in Health, Disease, and Cancer at the Virginia Tech Carilion Research Institute and senior author of the paper. "Astrocytes are the most populous cell type in the brain and even outnumber neurons."

Sontheimer also noted the importance of astrocyte function in the brain.

"Astrocytes serve many support functions, such as shuttling nutrients from blood vessels to nerve cells or removing their waste products," said Sontheimer, who is also the I. D. Wilson Chair in Virginia Tech's College of Science. "They also control the diameter of blood vessels to assure proper nutrient and oxygen delivery to the brain and maintenance of the blood-brain barrier. In response to injury and disease, however, astrocytes become reactive and change many of their supportive properties."

Sontheimer's team discovered that the astrocytes' blood flow regulation is disrupted by plaques formed of misfolded amyloid protein around blood vessels. In a healthy brain, amyloid protein fragments are routinely broken down and eliminated.

The presence of amyloid proteins around blood vessels in the brain is a hallmark of Alzheimer's disease, yet it wasn't understood if the proteins did any harm. Now, Sontheimer's team has found that they do.

"We found that amyloid deposits separated astrocytes from the blood vessel wall," said Stefanie Robel, a research assistant professor at the Virginia Tech Carilion Research Institute and a coauthor of the paper. "We also found that these amyloid deposits form an exoskeleton around the blood vessels, a kind of cast that reduces the pliability of the vessels."

The exoskeleton is known as a vascular amyloid. Its inelasticity might result in lower blood flow, which could account for Alzheimer's symptoms, such as memory lapses, impaired decision-making, and personality changes.

"Vascular amyloid may be the culprit in Alzheimer's disease symptoms, especially considering that the amyloid exoskeleton might limit the supply of oxygen and glucose to the brain regions that need them most," Sontheimer said. "This could also explain the cognitive decline in people with Alzheimer's disease, as the disease is associated with reduced cerebral blood flow."

While the scientists don't fully understand the role of vascular amyloid in Alzheimer's disease, they now have a possible therapeutic target to study.

"It may be helpful to remove the deposits to allow for appropriate blood flow," Robel said. "The problem is we don't know. It might be harmful to remove vascular amyloid at late stages of the disease; maybe they're actually holding the vessels together."

The researchers' next step will be to examine blood vessels once the amyloid deposits are removed.

"Vascular amyloid is strangling the blood vessels," Sontheimer said. "By removing them, maybe we'll be able to restore blood flow regulation. Perhaps it'll turn out vascular amyloid is preventing further degeneration. Whatever the case, we'll certainly learn something new."

Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer’s disease
Ian F. Kimbrough, Stefanie Robel, Erik D. Roberson, Harald Sontheimer
DOI: http://dx.doi.org/10.1093/brain/awv327 3716-3733 First published online: 23 November 2015
ArticleFigures & dataInformation & metricsExplore

Reduced cerebral blood flow impairs cognitive function and ultimately causes irreparable damage to brain tissue. The gliovascular unit, composed of neural and vascular cells, assures sufficient blood supply to active brain regions. Astrocytes, vascular smooth muscle cells, and pericytes are important players within the gliovascular unit modulating vessel diameters. While the importance of the gliovascular unit and the signals involved in regulating local blood flow to match neuronal activity is now well recognized, surprisingly little is known about this interface in disease. Alzheimer’s disease is associated with reduced cerebral blood flow. Here, we studied how the gliovascular unit is affected in a mouse model of Alzheimer’s disease, using a combination of ex vivo and in vivo imaging approaches. We specifically labelled vascular amyloid in living mice using the dye methoxy-XO4. We elicited vessel responses ex vivo using either pharmacological stimuli or cell-specific calcium uncaging in vascular smooth muscle cells or astrocytes. Multi-photon in vivo imaging through a cranial window allowed us to complement our ex vivo data in the presence of blood flow after label-free optical activation of vascular smooth muscle cells in the intact brain. We found that vascular amyloid deposits separated astrocyte end-feet from the endothelial vessel wall. High-resolution 3D images demonstrated that vascular amyloid developed in ring-like structures around the vessel circumference, essentially forming a rigid cast. Where vascular amyloid was present, stimulation of astrocytes or vascular smooth muscle cells via ex vivo Ca2+ uncaging or in vivo optical activation produced only poor vascular responses. Strikingly, vessel segments that were unaffected by vascular amyloid responded to the same extent as vessels from age-matched control animals. We conclude that while astrocytes can still release vasoactive substances, vascular amyloid deposits render blood vessels rigid and reduce the dynamic range of affected vessel segments. These results demonstrate a mechanism that could account in part for the reduction in cerebral blood flow in patients with Alzheimer’s disease.

fungal infection

Fungus found in brains raises Alzheimer's questions

By Mariette Le Roux
9 hours ago

Paris (AFP) - Traces of fungus have been discovered in the brains of Alzheimer's sufferers, researchers said Thursday, relaunching the question: might the disease be caused by an infectious microbe?

There is no conclusive evidence, but if the answer turns out to be "yes", it means Alzheimer's Disease (AD) may be targeted with antifungal treatment, a Spanish team reported in the journal Scientific Reports.

"The possibility that AD is a fungal disease, or that fungal infection is a risk factor for the disease, opens new perspectives for effective therapy for these patients," they wrote.

The five-member team had found cells and other material from "several fungal species" in the brain tissue and blood vessels of all 11 deceased Alzheimer's patients analysed, but not in ten Alzheimer's-free controls.

The findings are published just a month after scientists warned in the sister journal Nature of a risk of accidental surgical transmission of Alzheimer's "seeds" from one person to another.

Alzheimer's Disease is the most common form of dementia, which the World Health Organisation (WHO) says affects nearly 50 million people worldwide -- some 7.7 million new cases per year.

Old age is the major risk factor, and there is no therapy to stop or reverse Alzheimer's symptoms, which include memory loss and disorientation, as well as anxiety and aggressive behaviour.

Some researchers have suggested AD may be an infectious disease or, at least, that infection with certain microbes may boost Alzheimer's risk.

Genetic material from viruses and bacteria had previously been found in the brains of Alzheimer's patients, and viruses which cause herpes and pneumonia have been suggested as potential AD "agents", according to the study authors.

- 'Speculation' -

The main suspect in AD to date has been brain "plaques" caused by a build-up of sticky proteins, but trials with drugs targeting these have yielded disappointing results.

The new study adds another possible cause to the list of hypotheses.

Traces of several fungal species were found, said the team, which "might explain the diversity observed in the evolution and severity of clinical symptoms in each AD patient."

A fungal cause would fit well with the characteristics of AD, the researchers added, including the slow progression of the disease and inflammation, which is an immune response to infectious agents such as fungi.

The researchers did point out, however, that fungal infection may be the result, not the cause, of AD.

Alzheimer's sufferers may have a weaker immune response, or changes in diet or hygiene, that could leave them more exposed.

"It is evident that clinical trials will be necessary to establish a causal effect of fungal infection of AD," wrote the team.

"There are at present a number of highly effective antifungal compounds with little toxicity. A combined effort from the pharmaceutical industry and clinicians is needed to design clinical trials to test the possibility that AD is caused by fungal infection."

Outside experts agreed that further study must be done to confirm or disprove the fungus theory.

As they stand, the findings are "very speculative", French neurodegenerative disease expert Sylvain Lehmann told AFP.

"We cannot conclude from this work that such (fungal) infections cause or increase the risk of the disease," added Laura Phipps of Alzheimer's Research UK.

Last month, a study said people injected with hormones extracted from cadaver brains in a long-abandoned medical procedure may have received "seeds" of Alzheimer's -- raising the spectre of it being a transmissible disease.

Different Brain Regions are Infected with Fungi in Alzheimer’s Disease
Diana Pisa, Ruth Alonso, Alberto R?bano, Izaskun Rodal & Luis Carrasco
Scientific Reports 5, Article number: 15015 (2015)
Download Citation
Fungal immune evasion | Fungi
19 May 2015
15 September 2015
Published online:
15 October 2015
The possibility that Alzheimer’s disease (AD) has a microbial aetiology has been proposed by several researchers. Here, we provide evidence that tissue from the central nervous system (CNS) of AD patients contain fungal cells and hyphae. Fungal material can be detected both intra- and extracellularly using specific antibodies against several fungi. Different brain regions including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus and choroid plexus contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi. Fungal infection is also observed in blood vessels, which may explain the vascular pathology frequently detected in AD patients. Sequencing of fungal DNA extracted from frozen CNS samples identifies several fungal species. Collectively, our findings provide compelling evidence for the existence of fungal infection in the CNS from AD patients, but not in control individuals.

blood-brain barrier (BBB)

Trinity College research could lead to ‘novel treatment’ for Alzheimer’s
The disease affects up to 40,000 people in Ireland today.

Updated ? 7:45pm 19/09/2015

RESEARCHERS AT TRINITY College have shed light on a fundamental cause of Alzheimer’s disease which they say could lead to new form of therapy for those living with the condition.
Alzheimer’s is the most common form of dementia globally and affects up to 40,000 people in Ireland today. It is the fourth leading cause of death in individuals over the age of 65 and it is the only cause of death among the top ten that cannot be prevented, cured or even slowed down.
The research was published this week in leading international journal Science Advances. It involves a key characteristic of the disease ? a build-up of a small protein called ‘amyloid beta’ in the brain of patients.
When the brain is unable to clear this protein, plaques build up and this is a major factor in the process of Alzheimer’s.

It is unclear how this protein is usually cleared but Trinity researchers found it can pass between the cells in blood vessels in the brain.
This could offer a new way of removing this protein from the brains of people who have Alzheimer’s.

“We’re quite excited that this could be a novel approach to treating or thinking about treating Alzheimer’s as an adjunct, as an additive therapy to the current therapies that are being developed,” commented Dr Matthew Campbell.
Working with the Dublin Brain Bank, which is based in Beaumont Hospital, the researchers from Trinity examined brain tissues of individuals who were affected by Alzheimer’s disease during their lifetime and then compared results to those observed in model systems in the laboratory.
The next steps now are to consider how periodic clearance of the protein through blood vessels might be achieved.

Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier

James Keaney1, Dominic M. Walsh2, Tiernan O’Malley2, Natalie Hudson1, Darragh E. Crosbie1, Teresa Loftus3, Florike Sheehan3, Jacqueline McDaid1, Marian M. Humphries1, John J. Callanan4,5, Francesca M. Brett3, Michael A. Farrell3, Peter Humphries1 and Matthew Campbell1,*
+ Author Affiliations
Science Advances 18 Sep 2015:
Vol. 1, no. 8, e1500472
DOI: 10.1126/sciadv.1500472


The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1?40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1?40) levels were significantly increased, brain Aβ(1?40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain.

Three Types of Alzheimer's

Study Identifies Three Types of Alzheimer's

By Charlotte Libov
17 Sep 2015

Long thought to be a single disease, Alzheimer’s may actually occur in three different forms, a new study suggests.

There is an urgent need to find an effective treatment for Alzheimer’s disease, which is the most common age-related cause of dementia in the U.S. The number of Americans afflicted is expected to grow from six million today to 15 million in 2050.

Alzheimer’s symptoms vary widely from person to person, which has led experts to suspect that there is more than one form of the brain illness, says Dr. Dale Bredesen, a UCLA neurology professor and the author of a new study.

His team looked at the results of metabolic testing on 50 people with early Alzheimer’s disease or its precursor and identified three subtypes:

? Inflammatory, in which markers such as C-reactive protein and serum albumin to globulin ratios are increased.

? Non-inflammatory, in which these markers are not increased but other metabolic abnormalities are present.

? Cortical, which affects relatively young individuals and is more widely distributed across the brain than the other subtypes. It typically does not cause memory loss at first, but people with this subtype tend to lose language skills.

Dr. Bredesen said the study, published in the journal Aging, may help lead to effective treatments that can be targeted to Alzheimer’s subtypes.


Metabolic profiling distinguishes three subtypes of Alzheimer's disease
Dale E. Bredesen1, 2
1 Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, University of California, Los Angeles, CA 90095, USA;
2 Buck Institute for Research on Aging, Novato, CA 94945, USA
Key words:
inflammation, neurodegeneration, cognition, insulin resistance, biomarkers, dementia, dyscalculia
07/21/15; Accepted: 08/28/15; Published: 08/31/15
Dale E. Bredesen, MD; E-mail: dbredesen@mednet.ucla.edu or dbredesen@buckinstitute.org


The cause of Alzheimer's disease is incompletely defined, and no truly effective therapy exists. However, multiple studies have implicated metabolic abnormalities such as insulin resistance, hormonal deficiencies, and hyperhomocysteinemia. Optimizing metabolic parameters in a comprehensive way has yielded cognitive improvement, both in symptomatic and asymptomatic individuals. Therefore, expanding the standard laboratory evaluation in patients with dementia may be revealing. Here I report that metabolic profiling reveals three Alzheimer's disease subtypes. The first is inflammatory, in which markers such as hs-CRP and globulin:albumin ratio are increased. The second type is non-inflammatory, in which these markers are not increased, but other metabolic abnormalities are present. The third type is a very distinctive clinical entity that affects relatively young individuals, extends beyond the typical Alzheimer's disease initial distribution to affect the cortex widely, is characterized by early non-amnestic features such as dyscalculia and aphasia, is often misdiagnosed or labeled atypical Alzheimer's disease, typically affects ApoE4-negative individuals, and is associated with striking zinc deficiency. Given the involvement of zinc in multiple Alzheimer's-related metabolic processes, such as insulin resistance, chronic inflammation, ADAM10 proteolytic activity, and hormonal signaling, this syndrome of Alzheimer's-plus with low zinc (APLZ) warrants further metabolic, genetic, and epigenetic characterization.

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A newly discovered molecular feedback process may protect the brain against Alzheimer's

It is a hallmark of Alzheimer's disease: Toxic protein fragments known as amyloid-β clumped together between neurons in a person's brain. Neurons themselves make amyloid-β, and for reasons that aren't fully understood, its accumulation ultimately contributes to the memory loss, personality changes, and other symptoms that patients with this degenerative disease often suffer from.

New research by Rockefeller University scientists and their colleagues have identified a series of naturally occurring molecular steps--known as a pathway--that can dampen the production of amyloid-β. These results, reported in Nature Medicine on August 17, suggest a new route in the search for Alzheimer's therapies.

"Our discovery centers on a protein called WAVE1, which we found to be important in the production of amyloid-β. The reduction of WAVE1 appears to have a protective effect against the disease," says study author Paul Greengard, Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience. "When levels of amyloid-β rise, there is an accompanying increase in another molecule, AICD, which reduces the expression of WAVE1. This has the effect of reducing the production of amyloid-β.

"By targeting steps within this newly discovered pathway," he adds, "it may be possible to develop drugs to reduce amyloid-β that potentially could be used to either treat or prevent Alzheimer's disease."

WAVE1 is known to help to build filaments of a protein called actin that serve as basic components of cellular structures. In the current study, the team, including first author Ilaria Ceglia, who conducted this work while a research associate in the lab, examined the levels of WAVE1 in mouse and cellular models of Alzheimer's disease and found that they were unusually low. Research done by a collaborator at Columbia University found this was also true for the brains of human patients with the disease.

To take a closer look at the relationship between amyloid-β and WAVE1, the researchers tested the brains and memories of mice genetically altered to produce high levels of amyloid-β and varying levels of WAVE1. They found a dose-dependent response: Mice brains with low WAVE1 levels produced less amyloid-β, and these animals performed better on memory tests.

Next, the researchers wanted to know how WAVE1 affects the production of amyloid-β. The precursor to this Alzheimer's protein is not harmful by itself, and does not normally yield brain-damaging products. However, sometimes the precursor is processed in such a way that it produces disease-promoting amyloid-β.

The team found high levels of both the amyloid precursor protein and WAVE1 in a compartment within the cell known as the Golgi, which acts as a sort of shipping department. Here proteins are packaged before they are sent out to various destinations within the cell. In the case of the amyloid precursor protein, the first destination is the cell's outer membrane. From there, it travels into the compartments within the cell, where it is processed to produce amyloid-β.

Because the formation of structural filaments is critical to the process by which cargo buds off and leaves the Golgi, the researchers suspected a role for WAVE1. Their experiments showed an interaction between WAVE1 and the amyloid precursor protein, and confirmed that WAVE1 mediates the formation of cargo vesicles containing amyloid precursor protein.

"The result is a negative feedback loop," says corresponding author Yong Kim, a research assistant professor in the lab. "More amyloid-β means more AICD. Our experiments reveal that AICD travels into the nucleus where it reduces the expression of WAVE1. Less WAVE1 means less precursor protein in cargo traveling to the membrane for conversion into amyloid-β. In Alzheimer's disease, this negative feedback appears to lose its protective effect, and the next step for us is to figure out how."



APP intracellular domain?WAVE1 pathway reduces amyloid-β production

Ilaria Ceglia, Christiane Reitz, Jodi Gresack, Jung-Hyuck Ahn, Victor Bustos, Marina Bleck, Xiaozhu Zhang, Grant Martin, Sanford M Simon, Angus C Nairn, Paul Greengard & Yong Kim
AffiliationsContributionsCorresponding author
Nature Medicine (2015) doi:10.1038/nm.3924
Received 14 January 2015 Accepted 14 July 2015 Published online 17 August 2015
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An increase in amyloid-β (Aβ) production is a major pathogenic mechanism associated with Alzheimer's disease (AD)1, 2, but little is known about possible homeostatic control of the amyloidogenic pathway. Here we report that the amyloid precursor protein (APP) intracellular domain (AICD) downregulates Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1 or WASF1) as part of a negative feedback mechanism to limit Aβ production. The AICD binds to the Wasf1 promoter, negatively regulates its transcription and downregulates Wasf1 mRNA and protein expression in Neuro 2a (N2a) cells. WAVE1 interacts and colocalizes with APP in the Golgi apparatus. Experimentally reducing WAVE1 in N2a cells decreased the budding of APP-containing vesicles and reduced cell-surface APP, thereby reducing the production of Aβ. WAVE1 downregulation was observed in mouse models of AD. Reduction of Wasf1 gene expression dramatically reduced Aβ levels and restored memory deficits in a mouse model of AD. A decrease in amounts of WASF1 mRNA was also observed in human AD brains, suggesting clinical relevance of the negative feedback circuit involved in homeostatic regulation of Aβ production.

changes in protein turnover kinetics

Alzheimer's Could Be Driven By Slowdown In Brain's Ability To Clear Amyloid Protein

New findings could help uncover what causes Alzheimer's disease and raises risk later in life.
By Rebekah Marcarelli
Aug 09, 2015
Headlines & Global News (HNGN.com)

A new study reveals that the brain's ability to clear the main ingredient of Alzheimer's plaques.
A new study reveals that the brain's ability to clear the main ingredient of Alzheimer's plaques. (Photo : John Cirrilto)

After the age of 65, the risk of developing Alzheimer's disease doubles every five years, and new research may have pinpointed some key changes in the brain that cause this to happen.

A team of researchers determined changes associates with the amyloid beta 42 protein, which is believed to be the "primary driver" of Alzheimer's disease, Washington University School of Medicine in St. Louis reported.

"We found that people in their 30s typically take about four hours to clear half the amyloid beta 42 from the brain," said senior author Randall J. Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology. "In this new study, we show that at over 80 years old, it takes more than 10 hours."

The slowdown in clearance rates leads to elevated levels of amyloid beta 42 in the brain, increasing the risk of the protein clumping together and forming Alzheimer's plaques.

To make their findings the researchers looked at 100 volunteers between the ages of 60 and 87, half of which had clinical signs of Alzheimer's disease and 67 of which had begun to form Alzheimer's plaques. The participants underwent mental and physical evaluations including brain scans and cerebrospinal fluid analyses. The researchers used technology called stable isotope-linked kinetics (SILK) to evaluate the body's production and clearance of amyloid beta 42.

The study revealed that in patients with signs of Alzheimer's plaques, amyloid beta 42 tended to be more likely to fall from the brain fluid and clump together. Clearance rates of amyloid beta 42 was linked to clinical symptoms of Alzheimer's disease, such as memory loss and personality changes. Researchers believe the key protein is disposed of in four ways: "by moving it into the spine, pushing it across the blood-brain barrier, breaking it down or absorbing it with other proteins, or depositing it into plaques," the researchers reported.

"Through additional studies like this, we're hoping to identify which of the first three channels for amyloid beta disposal are slowing down as the brain ages," Bateman said. "That may help us in our efforts to develop new treatments."

The findings were reported in a recent edition of the journal Annals of Neurology.

Age and amyloid effects on human central nervous system amyloid-beta kinetics

Bruce W. Patterson PhD1, Donald L. Elbert PhD2, Kwasi G. Mawuenyega PhD3, Tom Kasten PhD3, Vitaliy Ovod MS3, Shengmei Ma MS4, Chengjie Xiong PhD4,7, Robert Chott BS1, Kevin Yarasheski PhD1, Wendy Sigurdson RN, MSN3,7, Lily Zhang BS8, Alison Goate D.Phil5,8, Tammie Benzinger MD, PhD6,7, John C. Morris MD3,7, David Holtzman MD3,7,8 andRandall J. Bateman MD3,7,8,*
Article first published online: 20 JUL 2015
DOI: 10.1002/ana.24454
? 2015 American Neurological Association
Annals of Neurology
Early View (Online Version of Record published before inclusion in an issue)
Age is the single greatest risk factor for Alzheimer's disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid-beta (Aβ) kinetics in the central nervous system (CNS) of humans.

Aβ kinetics were analyzed in 112 participants and compared to the ages of participants and the amount of amyloid deposition.

We found a highly significant correlation between increasing age and slowed Aβ turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Aβ42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Aβ42 and a 10-fold higher Aβ42 reversible exchange rate.

These findings reveal a mechanistic link between human aging and the risk of amyloidosis, which may be owing to a dramatic slowing of Aβ turnover, increasing the likelihood of protein misfolding that leads to deposition. Alterations in Aβ kinetics associated with aging and amyloidosis suggest opportunities for diagnostic and therapeutic strategies. More generally, this study provides an example of how changes in protein turnover kinetics can be used to detect physiological and pathophysiological changes and may be applicable to other proteinopathies.

three sequential phases in the development of autosomal dominant Alzheimer's disease

Scientists just took a major step forward in understanding Alzheimer's


Alzheimer’s is a terrible disease that is slowly damaging the brains of an estimated 5.3 million Americans, most of them over age 65, according to the Alzheimer’s Association.

Scientists know that a protein called amyloid builds up in the brains of people with Alzheimer’s, and the clumps of amyloid are likely responsible for the brain damage that makes people with the disease lose their memory, become disoriented in time and space, and have other thinking, mood, and behavioural problems.

Until now, scientists had pieced together what they know about how Alzheimer’s progresses by comparing people at different stages of the disease to each other.

But to really verify what scientists think is going on ? particularly the relationship between amyloid and the development of Alzheimer’s symptoms ? scientists would need to closely follow the disease’s progression from the very beginning in individuals. That’s been very difficult, in part, because usually by the time someone is showing symptoms, the disease is already well underway.

A new paper from Wai-Ying Wendy Yau and colleagues at the University of Pittsburgh, published in The Lancet Neurology, is just the sort of study of individuals with Alzheimer’s that scientists had been missing. The experiment is very small and the findings are preliminary, but the study’s design allowed scientists to examine the progression of disease more closely than ever before.

Tracking changes in the brain
The new study followed seven individuals who had genetic mutations that are all but guaranteed to cause Alzheimer’s; they’re responsible for less than 5% of cases. Alzheimer’s has a complex and partially unknown matrix of causes, but following this subset of patients let researchers track people they knew would eventually develop the disease, even before they were symptomatic.

Over a period of between six to eleven years, the scientists measured the amount of amyloid collecting in the brain of each patient, the extent of their brain damage, and their scores on a test of brain function. With this information, the scientists could track how Alzheimer’s progressed in an individual patient for a longer period of time than they ever have before.

The graph below summarises what they found.

The red line represents amyloid building up in the brain, which increases over time. The green and blue lines stand for two different factors that reflect the neurodegeneration, or progressive brain damage, Alzheimer’s causes. As they go up, that indicates the brain is getting more and more damaged. The graph’s purple line is for a measure of cognition, and the way it goes up shows when in the course of Alzheimer’s disease a person’s ability to think and remember gets worse:

Here’s what all that means: Many years before any symptoms of Alzheimer’s show up, amyloid has already begun to build up in the brain. Progressive brain damage and the various symptoms of the disease only show up after the amount of amyloid in the brain has stabilised.

In other words, the scientists saw Alzheimer’s progressing in three stages:

Amyloid builds up gradually.
Amyloid stops building up, but what’s already in the brain doesn’t go away.
Gradual brain damage starts and causes the symptoms of Alzheimer’s like memory loss and confusion.
Previously, scientists had basically thought stages 1 and 3 overlapped, with no stage 2 separating them.

The scientists note that these findings need to be verified in a study of more patients (they only looked at seven in this experiment). Furthermore, it’s not a given that Alzheimer’s disease progresses the same way in people with the mutations as it does in the general public.

But this study is a step towards being able to detect Alzheimer’s early and monitor how it progresses more reliably than we can now, Giovanni Frisoni and Pieter Jelle Visser write in a commentary on the paper in The Lancet Neurology.

This would be really helpful in the search for a treatment for the disease, because when scientists can monitor disease progression during a clinical trial, they know sooner whether the treatment being tested is actually working. To be able to do that, they need a clear picture of how the disease progresses when it’s not treated.

An effective treatment for Alzheimer’s is still likely a long way off, but this crucial step in understanding the disease is, as Frisoni and Visser say, “much needed.”

Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study

Wai-Ying Wendy Yau
Published Online: 29 June 2015


The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed.


For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ?21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1?2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using 11C-Pittsburgh Compound-B PET, posterior cortical metabolism with 18F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65?89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls).


16 people with mutations in PSEN1, PSEN2, or APP, aged 28?56 years, completed between two and eight assessments (a total of 83 assessments) over 2?11 years. Significant differences in mutation carriers compared with controls (p<0?01) were detected in the following order: increased amyloidosis (7?5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7?5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6?11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline.


Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease?active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline?indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease.


National Institutes of Health and Howard Hughes Medical Institute.

β2-microglobulin (B2M)

Memory loss in old age breakthrough offers dementia hope, say researchers

6 July 2015

Breakthrough linking protein in blood to memory loss raises hopes for dementia treatment, and could be key to keeping people healthy for longer in old age

Researchers may have found a way to slow down or prevent memory problems that arise in old age and which can become devastating in patients with dementia.

The fresh hope comes from a series of studies in humans and mice that identified a protein which causes memory impairment when it builds up in the blood and brain with age.

Scientists found that injections of the protein made young animals’ memories worse and reduced the growth of new neurons in their brains. Further studies showed that blocking the protein prevented memory loss in older animals, making them smarter than untreated animals of the same age.

The findings are the latest to come from researchers in the US who have shown in previous work that blood plasma taken from young animals can rejuvenate the muscles, brains and other tissues of older animals.

Those studies have led scientists to suspect that blood plasma contains a cocktail of factors that either drive or counteract the natural ageing process. Major efforts are now underway to identify the different components at work in the hope of turning them into a therapy. A human trial to test the effects of young plasma on Alzheimer’s patients is already underway.

If scientists can work out which substances in blood affect the ageing process, and prove that they work in humans, they could potentially create a mixture that slows down the ageing process, at least partially. The therapy might not make people live longer, but it could keep them healthy for longer, by staving off conditions of old age, such as dementia.

“I think there are two ways we can improve or reverse the hallmarks of ageing,” said Saul Villeda, the lead author on the study at the University of California, San Francisco. “One of them is to administer pro-youthful factors, but the other is to target these pro-ageing factors.”

Writing in the journal Nature Medicine, the scientists describe how they noticed an age-related rise in the levels of beta-2-microglobulin (B2M), a protein in the blood of mice and humans. Scores of proteins go up and down in the blood as organisms age, but Villeda found evidence from other studies that B2M might play a role in age-related disorders. For example, patients on long-term kidney dialysis can have raised levels of B2M in their blood, and these people tend to suffer the worst cognitive decline.

To test the effect of B2M, Villeda and his colleagues injected young mice with the protein and had them perform different tasks. In the first set of experiments, mice were trained to find a platform hidden just below the surface in a water maze. Mice put into the maze were out of their depth, but used visual clues, including triangles and heart shapes around the room, to find their bearings and then make their way to the platform, which they could climb up onto.

“Young animals are really good at this. They will make perhaps one or two mistakes over the course of three trials. But when you give them B2M, they’ll make perhaps five mistakes. It’s a striking difference,” Villeda said. The effect was stronger when B2M was injected directly into the brain.

In a second set of experiments, mice were put in a chamber and after two minutes given a small electric shock through a grille on the chamber floor. The mice were then removed from the chamber, but returned the next day.

Young mice typically explored the chamber for a few moments before they froze: their natural reaction to remembering where they were. But mice given B2M froze much less, because their memories were not as sharp.

“A normal young mouse will freeze about 50 to 60% of the time in the first minute. But after B2M, they will freeze for about half that time,” said Villeda. The B2M seemed to impair the animals’ memories of the electric shock, making them respond like much older mice. When animals were tested a month after injections of B2M, it had no effect. That is good news, said Villeda, as it means that the harm caused by B2M is not permanent.

The scientists followed up with tests on mice that had been genetically modified to ensure they did not produce B2M. Young animals that had no B2M seemed perfectly normal. But as the animals aged, their memories did not decline at the same rate as other mice. “When we looked at the older animals, they were much smarter. They did not develop the same kinds of memory impairments. I was really surprised,” said Villeda.

The study went found that B2M works alongside a protein complex called MHC1. Villeda suspects that a drug that stopped the two working together could help reduce memory loss. “If we block the interaction between B2M and MHC1, could that either prevent memory loss with old age, if we take it when we are younger? Could it reverse memory loss if we start when we are old?” Villeda said.

But that may not be necessary. “Perhaps we can just get rid of it in old people’s blood”, says Villeda.

Clare Walton at the Alzheimer’s Society said: ‘This research has identified an age-related protein in mice that damages an area of the brain that is important for memory. This interesting study highlights the importance of basic research in helping to find new targets for drugs to help stop cognitive decline.

“As this study is only at the early stages, we first need to see whether the protein causes similar effects in the human brain before the research can be taken forward into potential treatments.”

Nature Medicine | Letter

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Lucas K Smith,
Yingbo He,
Jeong-Soo Park,
Gregor Bieri,
Cedric E Snethlage,
Karin Lin,
Geraldine Gontier,
Rafael Wabl,
Kristopher E Plambeck,
Joe Udeochu,
Elizabeth G Wheatley,
Jill Bouchard,
Alexander Eggel,
Ramya Narasimha,
Jacqueline L Grant,
Jian Luo,
Tony Wyss-Coray
& Saul A Villeda
Corresponding author

Nature Medicine (2015) doi:10.1038/nm.3898 Received 01 May 2015 Accepted 08 June 2015 Published online 06 July 2015

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals1, 2, 3, 4. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain5, 6. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

deficiency in PICALM

Researchers clarify role of genetic risk factor in Alzheimer’s

May 30, 2015

The study sheds light on potential therapeutic targets for treatment of the disease
BY Les Dunseith

Scientists at the Keck School of Medicine of USC have discovered that a protein known as PICALM regulates removal of toxic plaques from the brain, which could be a potential therapeutic target for the treatment of Alzheimer’s disease.

In a study that appeared in a recent edition of Nature Neuroscience, researchers identify this new role for PICALM, which is a known genetic risk factor for Alzheimer’s disease.

Alzheimer’s is the most common type of dementia, characterized by the loss of memory and other mental abilities linked to an accumulation of amyloid-beta and other toxic compounds in the brain.

The study found that a deficiency in PICALM in cerebral blood vessels and in PICALM-related gene variants associated with increased risk for Alzheimer’s, disable amyloid-beta from being cleared out of the brain across a region known as the blood-brain barrier.

There have been many new genes discovered to be associated with Alzheimer’s disease, but the biology of these genes are poorly understood.

Berislav Zlokovic

“There have been many new genes discovered to be associated with Alzheimer’s disease, but the biology of these genes are poorly understood,” said the study’s principal investigator Berislav Zlokovic, director of the Zilkha Neurogenetic Institute and holder of the Mary Hayley and Selim Zilkha chair for Alzheimer’s Disease research at the Keck School of Medicine. “Our new study shows that a deficiency in PICALM in blood vessels and its variants associated with increased risk for the disease inactivate amyloid-beta clearance from the brain, leading to its accumulation and cognitive impairment. This new study provides fundamental new information about PICALM and brings to light novel potential therapeutic targets for increasing amyloid-beta clearance in Alzheimer’s disease.”

Autopsies from Alzheimer’s patients and recent research in experimental models have shown the importance of brain blood vessels in the disease’s initiation and progression.

Molecular mechanisms

For more than two decades, Zlokovic and his research team have studied the cellular and molecular mechanisms of brain blood vessels that maintain normal cognition with hopes of developing new treatments for Alzheimer’s and other neurodegenerative diseases. One focus of their lab at the Zilkha Neurogenetic Institute is on PICALM, or phosphatidylinositol binding clathrin assembly protein, which in humans is encoded by the PICALM gene.

By performing a neuropathological study in humans with Alzheimer’s and using transgenic animals to model the disease, the group found that low levels of PICALM in brain endothelial cells lead to amyloid-beta accumulation in the brain. Genetic variants associated with the PICALM gene have been shown to increase the risk of Alzheimer’s disease.

The researchers also generated human endothelial cells from induced pluripotent stem cells to examine the consequences of a known PICALM variant associated with increased risk for Alzheimer’s; they found that this genetic alteration disrupted amyloid-beta clearance by cerebral blood vessels.

These new findings have prompted Zlokovic to address new questions about the role of PICALM in Alzheimer’s. Future studies will explore how genetic flaws in the PICALM gene influence its expression levels and clearance function at the blood-brain barrier and the general health of cerebral blood vessels. The team also will work on developing therapeutic strategies, including gene therapy, and screening for new drugs to overcome PICALM deficiency.

USC co-authors on the study include Zhen Zhao, Abhay Sagare, Qingyi Ma, Matthew Halliday, Pan Kong, Kassandra Kisler, Ethan Winkler, Anita Ramanathan, Nelly Chuqui Owens, Sanket Rege, Gabriel Si, Ashim Ahuja, Carol Miller, Tohru Sugawara and Justin Ichida.

The study was funded in part by the National Institutes of Health (R37NS34467, R37AG23084, R01AG039452, R01AG035355, R01AG027924, R00NS07743), Cure for Alzheimer Fund, American Cancer Society (RSG?13?379?01?LIB), Rainwater Charitable Foundation, Donald E. and Delia B. Baxter Foundation, and Daiichi Sankyo Foundation of Life Science. The study used sample ND10689 from the National Institute of Neurological Disorders and Stroke Cell Line Repository as well as clinical data.

picture: Snapshot of a neurovascular unit, consisting of neurons (pink), astrocytes (blue), resident microglia (green), a penetrating arteriole and capillaries (white) (Photo/Zlokovic Lab)




理化学研究所(理研)脳科学総合研究センター 理研-MIT神経回路遺伝学研究センターの利根川進センター長らの研究チーム※は、従来記憶の保存に不可欠だと考えられていたシナプス増強[1]がなくても、記憶が神経細胞群の回路に蓄えられていることを発見しました。





センター長 利根川進(とねがわ すすむ)
博士研究員 Tom?s Ryan(トマス・ライアン)


Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE

Scott Ayton, Noel G. Faux, Ashley I. Bush
Nature Communications 6, Article number: 6760 doi:10.1038/ncomms7760

Received 31 October 2014 Accepted 25 February 2015 Published 19 May 2015


Brain iron elevation is implicated in Alzheimer’s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer’s risk allele, APOE-ε4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ε4 being the major genetic risk factor for AD.

bacteria in intestines

Is Alzheimer's linked to bacteria in intestines?

KING 5 Healht
April 20, 2015

It may sound far-fetched, but some scientists think there may be a link between Alzheimer's disease and bacteria in our intestines.

Nothing Pat Scott did could keep her mother from fading away with Alzheimer's .

"They lose their ability to swallow and chew their food. That's basically what ended my mom's life because she kept choking," said Pat.

Neurologist Dr. Robert Friedland thinks there may be a link between Alzheimer's and bacteria.

"We are sampling bacterial content from the nose and also the gut. We are working with collaborators in Ireland to do a complex genomic analysis," said Dr. Friedland.

Humans are born with tens of thousand genes. But we have millions more genes in our bacteria. The majority in our nose, mouth and gut. These may be the genes that cause certain proteins to fold, leading to Alzheimer's and Parkinson's.

"Preliminary results indicate that there may be proteins made by certain groups of bacteria, which lead to more misfolding of proteins in the brain and neurons in the wall of the intestines," said Dr. Friedland.

Because the bacteria in the intestines eat what we eat, Dr. Friedland believes we can change them by consuming more low fat, high fiber foods including fish, vegetables and fruit.

"It could possibly be a way to prevent or reverse or slow down (Alzheimer's)," he said.

Dr. Friedland plans to publish his findings in the Journal of Alzheimer's Disease.

immune-mediated amino acid catabolism  arginine

Scientists have found a new possible cause for Alzheimer’s disease

April 17, 2015

A clearer understanding of Alzheimer’s disease has been one of the the great unmet needs in health care and pharmaceutical research. Billions have been spent developing and testing therapies that have failed.

Now, a team led by doctors Matthew Kan and Jennifer Lee at Duke University are questioning a long-held assumption about a cause of the disease, and this week they released a study in the Journal of Neuroscience that points toward a a possible alternative way of thinking about it and treating it. Rather than the result of an immune system activation and overreaction, as current thinking about the causes of the disease suggests, the researchers unexpectedly found it might be the result of immune suppression.

Their study of genetically modified mice designed to model humans with Alzheimer’s found that a type of immune cell that protects the brain began behaving abnormally in affected areas, and was consuming a semi-essential amino acid (a building block for proteins) called arginine.

Blocking that process with a drug called difluoromethylornithine (or DFMO, which has been tested on human subjects as a cancer treatment) helped prevent the buildup of beta-amyloid, protein fragments that make up plaques long thought to be a major cause of Alzheimer’s, and memory loss.

The idea that arginine deprivation and local immune suppression might contribute to the disease?the previous assumption was that an inflammatory response and an overproduction of certain molecules were the primary culprit?is new and potentially fascinating. Alzheimer’s is so poorly understood that any potential advance is important.

But the results of the latest study shouldn’t be interpreted as a near-term step toward a cure. There are many caveats to consider?among them, animal models of Alzheimer’s rarely translate to people, and beta-amyloid plaques (if it is even the right thing to be targeting with treatment) have proven a tricky substance to reduce.

Indeed, drugs developed to treat Alzheimer’s fail at a much greater rate than other types of medicines. A full 99.5% of compounds intended to treat the disease have failed, and those that exist are minimally effective. The average attrition for drugs is a less bad 95.8% across all stages:

This latest study used a new type of genetically modified mouse that better models the human immune system, the authors write, but it’s tough to produce relevant results from mice for something as complicated as the human brain and memory. Some of the study’s findings are dependent on measuring mRNA molecules in mouse brains, which can be highly variable and tough to draw robust conclusions from.

Another reason for caution: the study is entirely dependent on the idea that amyloid plaque buildup (resistant to the drugs that have attempted to treat it thus far) is the reason for the disease’s cognitive effects. A recent study by researchers at the Mayo Clinic points to tau protein. Or it might be something else entirely.

In any case, once you have amyloid plaque buildup, the damage to the brain is already done. Research exploring alternate methods that could help identify risk and potential interventions far earlier might be more fruitful.

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

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

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


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


JAMA Neurol. 2015 Mar 16. doi: 10.1001/jamaneurol.2014.4821.

Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span.

Jack CR Jr1, Wiste HJ2, Weigand SD2, Knopman DS3, Vemuri P1, Mielke MM2, Lowe V1, Senjem ML1, Gunter JL1, Machulda MM4, Gregg BE1, Pankratz VS2, Rocca WA5, Petersen RC3.



Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging.


To compare age, sex, and APOE ε4 effects on memory, brain structure (adjusted hippocampal volume [HVa]), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old.

Design, Setting, and Participants:

Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old.

Main Outcomes and Measures:

Memory, HVa, and amyloid PET.


Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P?<?.001) and more specifically beyond age 40 years. The HVa was lower in men than in women overall (P?<?.001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ε4 status at any age. From age 70 years onward, APOE ε4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for noncarriers.

Conclusions and Relevance:

Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.


Surprising finding provides more support for Alzheimer's being an autoimmune

Brain levels of the lipid ceramide are high in Alzheimer's disease, and now scientists have found increased levels of an antibody to the lipid in their disease model.

March 9, 2015

While some members of this lipid family are a plus in skin cream, inside the brain, ceramide appears to increase beta amyloid production and help the iconic plaque kill brain cells in Alzheimer's, said Dr. Erhard Bieberich, neuroscientist at the Medical College of Georgia at Georgia Regents University.

Bieberich's lab and others have identified elevated ceramide levels as a risk factor for Alzheimer's and have shown that amyloid triggers excess production of the lipid, although precisely how and why remain a mystery. That synergy had the scientists expecting that generating antibodies against ceramide would hamper plaque formation. Studies published last summer in Neurobiology of Aging showed that a drug that inhibited ceramide formation did just that.

Instead they found that the excessive ceramide had already worked its way into the bloodstream, generating antibodies that supported disease progression, particularly in female mice.

The surprising science, published in the Journal of Alzheimer's Disease, appears to support the theory that Alzheimer's is an autoimmune disease, which tends to be more common in women and is characterized by the immune system producing antibodies against a patient's tissue, said Bieberich, corresponding author.

It also has them thinking that measuring blood levels of the lipid or some of its byproducts could be an early test for Alzheimer's since ceramide levels were elevated well before mice showed signs of substantial plaque formation.

"It's a chicken-egg situation," said Dr. Michael B. Dinkins, MCG postdoctoral fellow and the study's first author. "We don't know if the anti-ceramide antibodies that may develop naturally during disease might be a result or a cause of the disease."

They do know that excess ceramide in the brain results in the production of vesicles, which Dinkins likens to "lipid bubbles," called exosomes, that start piling up around brain cells. What's in them depends on which cell type makes them, but Bieberich's lab had previous evidence that when exosomes get taken up by other cells, they trigger cell death, which is one way his team thought ceramide contributes to neurodegeneration in Alzheimer's.

"It takes a while before that becomes toxic because you have ongoing traffic and clearance mechanisms," he said. At some point - they are not certain at exactly what point - the clearance system stops working, and toxic levels of amyloid and ceramide pile up. That's what led them to adjust the ceramide levels downward by injecting even more ceramide under the skin, where it would mount an immune response and ideally slow disease progression.

That's when they found elevated antibody levels already existed in their animal model, and when they gave more ceramide, it not only increased antibody levels, but levels of plaque and exosomes, Dinkins said.

"We thought, we can immunize the mouse against its own ceramide; it develops antibodies, which neutralize the ceramide; and we get a similar affect as blocking its production, like a vaccination against it," Bieberich said. It should also block the subsequent chain of events that contribute to brain cell loss.

Instead they found female Alzheimer's mice treated with more ceramide experienced about a 33 percent increase in amyloid formation and that serum exosome levels increased 2.4 times.

"They immunize themselves," Bieberich said. The finding also has them wondering if maybe exosomes, which can have a variety of functions including aiding communication, may be trying to intervene and that ceramide antibodies are blocking their efforts.

"We don't really know what the exosomes do in Alzheimer's. Maybe it's not always bad to have them around," Bieberich said. "Maybe the antibodies actually interrupt some good functions of exosomes."

Now they are circling back to a previous approach of more directly blocking ceramide, this time, using a genetically engineered mouse that from birth lacks the enzyme, which was targeted in previous drug studies and is needed to make ceramide, then crossbreeding it with an Alzheimer's mouse model.

And this time, they expect to be right: that the mice genetically programmed to get Alzheimer's will produce less ceramide, less exosomes, and less plaques. "In the face of more antibody, there is more plaque, but that is because there is more ceramide," Bieberich said.

One in nine individuals over age 65 has Alzheimer's, and nearly two-thirds of Americans with it are women, possibly because women tend to live longer, according to the Alzheimer's Association.

The leading hypothesis of Alzheimer's is that an accumulation of beta amyloid plaque first alters communication between brain cells, then prompts cell death.

The researchers note that ceramide is pervasive throughout the human body as well as other animal and plant species. "We synthesize it in each and every cell in the body," Bieberich said. His team reported in 2007 in the Journal of Biological Chemistry that, in the first few days of life, ceramide helps stem cells line up to form the primitive ectoderm from which embryonic tissue develops. In 2012, they reported in Molecular Biology of the Cell that ceramide additionally helps with wayfinding by helping cells keep their natural antennas up.

Explore further: Neurogeneticists harness immune cells to clear Alzheimer's-associated plaques

Journal reference: Journal of Alzheimer's Disease search and more info website

Provided by Medical College of Georgia search and more info website

Journal of Alzheimer's Disease
Volume 46, Number 1, IN PROGRESS
Short Communication
Michael B. Dinkins, Somsankar Dasgupta, Guanghu Wang, Gu Zhu, Qian He, Ji Na Kong, Erhard Bieberich (Handling Associate Editor: Michelle Mielke)
The 5XFAD Mouse Model of Alzheimer’s Disease Exhibits an Age-Dependent Increase in Anti-Ceramide IgG and Exogenous Administration of Ceramide Further Increases Anti-Ceramide Titers and Amyloid Plaque Burden
Abstract:We present evidence that 5XFAD Alzheimer’s disease model mice develop an age-dependent increase in antibodies against ceramide, suggesting involvement of autoimmunity against ceramide in Alzheimer’s disease pathology. To test this, we increased serum anti-ceramide IgG (2-fold) by ceramide administration and analyzed amyloid plaque formation in 5XFAD mice. There were no differences in soluble or total amyloid-β levels. However, females receiving ceramide had increased plaque burden (number, area, and size) compared to controls. Ceramide-treated mice showed an increase of serum exosomes (up to 3-fold using Alix as marker), suggesting that systemic anti-ceramide IgG and exosome levels are correlated with enhanced plaque formation.

Selective intraneuronal amyloid-β accumulation in adult life and oligomerization

Brain plaque buildup tied to Alzheimer's found in young adults

March 4, 2015

People as young as 20 have amyloid buildup, but researchers aren't sure what it means.

Brain plaque buildup, long linked to the onset of Alzheimer's disease, has been identified in the brains of men and women as young as 20, researchers say.

"One thing this means is that the resource, the machinery, for making the clumps of plaque we see among Alzheimer's patients is already available in young individuals," said study co-author Changiz Geula, a research professor at the Northwestern University Feinberg School of Medicine in Chicago.

"The implication appears to be that if we want to prevent these clumps from forming when a person becomes old, we may need to intervene much earlier than we have thought, to try and get rid of amyloid very early in life," Geula said.

Geula and his colleagues analyzed brain tissue of 48 deceased people ranging in age from 20 to 99.

At issue is an abnormal protein, or "amyloid," known to accumulate and surround specialized brain cells called neurons in seniors and those suffering from Alzheimer's. Amyloid buildup is known as plaque.

"Amyloid is bad," said Geula. "We don't know the exact mechanism by which it causes damage, or if amyloid buildup is the main trigger for Alzheimer's, so we can't say that it actually causes the disease. But for a long time we have known that it causes toxic damage, and it cannot be good for you when it accumulates."

What is new here, and "very surprising, is that we found an accumulation of this amyloid actually inside the nerve cells of individuals as young as 20," Geula added.

The findings appear in the March 2 issue of Brain.

Alzheimer's disease, a progressive brain disorder, is the most common form of dementia among older people. It's estimated that 5 million Americans have the disease, and that number is growing.

The study team analyzed the brains of 13 people aged 20 to 66 with no mental health issues; 14 dementia-free people between 70 and 99; and 21 Alzheimer's patients between 60 and 95.

Particular attention was paid to a certain type of neuron -- the "basal forebrain cholinergic neuron" -- that researchers say is especially vulnerable to cell death among Alzheimer's patients. Such neurons are key to memory and attention.

Toxic amyloid buildup was seen among such cells across the entire age and health spectrum. Similar signs of buildup were not seen to the same degree among other types of nerve cells in different regions of the brain.

Clumps were usually larger in older brains and those with Alzheimer's, the study found. The authors said the growing clumps likely damage and kill the neurons.

"But just how much variability there is among the general population remains unclear," Geula admitted. Some of the old people studied had amounts of amyloid that were closer to levels seen among the young, the study found.

"What we need to do now is look at a large number of elderly to see whether the ones who have more amyloid face a higher risk for Alzheimer's or poorer [thinking] abilities," Geula said.

Striking a cautionary note, Dr. Yvette Sheline, a professor of psychiatry, radiology and neurology at the University of Pennsylvania Perelman School of Medicine, highlighted the "complicated" nature of the findings.

Sheline, who wasn't involved in the study, stressed the conclusions were based on just a handful of brain samples. They also were confined solely to plaque growth in a specific part of the brain and neuron type, she noted.

"Nonetheless, it is interesting that amyloid accumulation could occur so early in the basal forebrain," Sheline said.

But in such a small sample and with no mental assessment in life and no follow-up , she said it's impossible to know if these people would progress to Alzheimer's disease, or if this is part of normal human physiology.

Still, Dr. Stephen Salloway, director of the neurology and the memory and aging program at Butler Hospital in Providence, R.I., said the findings may ultimately point to "a key step" in the beginning of Alzheimer's disease.

"This process seems to occur earlier in these cells than other brain regions," Salloway noted. Determining why these particular basal neurons are more prone to plaque buildup than other types of neurons "will provide important clues for solving the mystery of Alzheimer's disease," he said.

Copyright ? 2014 HealthDay. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer’s disease

Alaina Baker-Nigh , Shahrooz Vahedi , Elena Goetz Davis , Sandra Weintraub , Eileen H. Bigio , William L. Klein , Changiz Geula

DOI: http://dx.doi.org/10.1093/brain/awv024 First published online: 2 March 2015


The mechanisms that contribute to selective vulnerability of the magnocellular basal forebrain cholinergic neurons in neurodegenerative diseases, such as Alzheimer’s disease, are not fully understood. Because age is the primary risk factor for Alzheimer’s disease, mechanisms of interest must include age-related alterations in protein expression, cell type-specific markers and pathology. The present study explored the extent and characteristics of intraneuronal amyloid-β accumulation, particularly of the fibrillogenic 42-amino acid isoform, within basal forebrain cholinergic neurons in normal young, normal aged and Alzheimer’s disease brains as a potential contributor to the selective vulnerability of these neurons using immunohistochemistry and western blot analysis. Amyloid-β1?42 immunoreactivity was observed in the entire cholinergic neuronal population regardless of age or Alzheimer’s disease diagnosis. The magnitude of this accumulation as revealed by optical density measures was significantly greater than that in cortical pyramidal neurons, and magnocellular neurons in the globus pallidus did not demonstrate a similar extent of amyloid immunoreactivity. Immunoblot analysis with a panel of amyloid-β antibodies confirmed accumulation of high concentration of amyloid-β in basal forebrain early in adult life. There was no age- or Alzheimer-related alteration in total amyloid-β content within this region. In contrast, an increase in the large molecular weight soluble oligomer species was observed with a highly oligomer-specific antibody in aged and Alzheimer brains when compared with the young. Similarly, intermediate molecular weight oligomeric species displayed an increase in aged and Alzheimer brains when compared with the young using two amyloid-β42 antibodies. Compared to cortical homogenates, small molecular weight oligomeric species were lower and intermediate species were enriched in basal forebrain in ageing and Alzheimer’s disease. Regional and age-related differences in accumulation were not the result of alterations in expression of the amyloid precursor protein, as confirmed by both immunostaining and western blot. Our results demonstrate that intraneuronal amyloid-β accumulation is a relatively selective trait of basal forebrain cholinergic neurons early in adult life, and increases in the prevalence of intermediate and large oligomeric assembly states are associated with both ageing and Alzheimer’s disease. Selective intraneuronal amyloid-β accumulation in adult life and oligomerization during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer’s disease.

Amyloid plaques on axons of neurons affected by Alzheimer's disease??ISTOCKPHOTO

molecular chaperone

A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers

Samuel I A Cohen, Paolo Arosio, Jenny Presto, Firoz Roshan Kurudenkandy, Henrik Biverst?l, Lisa Dolfe, Christopher Dunning, Xiaoting Yang, Birgitta Frohm, Michele Vendruscolo, Jan Johansson, Christopher M Dobson, Andr? Fisahn, Tuomas P J Knowles & Sara Linse

Nature Structural & Molecular Biology (2015) doi:10.1038/nsmb.2971
Received 17 August 2014 Accepted 08 January 2015 Published online 16 February 2015

Abstract? References? Author information? Supplementary information
Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the ?amyloid-β peptide (?Aβ42). Recent studies have revealed that once ?Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human ?Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

Molecule could protect against Alzheimer's disease

February 17 2015

"Alzheimer's breakthrough: scientists home in on molecule which halts development of disease," The Daily Telegraph reports. The so-called "chaperone molecule", known as "Brichos", helps prevent the clumping of proteins, which can lead to the death of brain cells.

Scientists don't know what causes Alzheimer's disease, but people who have the condition tend to have abnormally high amounts of stringy proteins called amyloid plaques in their brains. The plaques interfere with brain cells, damaging brain function.

News of a molecule that could stop some of this damage is encouraging, but declaring a "breakthough" is premature. We don't know if this molecule has an effect on humans, because the experiments were all carried out on mice.

Although Brichos stopped damage occurring in a specific amyloid-related biological pathway, some of the damage associated with Alzheimer's disease could occur via other routes.

As the researchers point out, Brichos would probably not be a suitable candidate for a drug treatment. Because of its composition, it could be absorbed by the body before it reached the brain.

The hope is that there may be more "chaperone molecules" out there that do have the ability to cross the blood-brain barrier and help prevent brain cell damage.

Where did the story come from?

The study was carried out by researchers from the University of Cambridge, a trio of Swedish institutions ? Karolinska Institutet, Lund University, and the Swedish University of Agricultural Sciences ? and Tallinn University in Estonia.

It was funded by several health foundations, charities and research grants from national and international non-commercial organisations. No conflicts of interest were declared.

The study was published in the peer-reviewed science journal, Nature Structural and Molecular Biology.

The UK media's reporting was somewhat overexcited, with most framing the study as a breakthrough, implying that a treatment was inevitable.

Many showed no restraint by failing to talk about the drawbacks of the research, which were outlined by the researchers themselves in their conclusion.

Headlines from The Independent and The Guardian reporting a "possible breakthrough" were the most balanced. The Mirror went bigger, reporting a "Major Alzheimer's breakthrough".

The Mail Online and Daily Telegraph also towed the "breakthrough" line. Arguably, these are all overstatements as there is no guarantee that any of this works when used on humans. At the moment, we only know it works in mice.

Some sources, such as The Times, talked about the possibility of this research leading to a statin-type drug, taken as a preventative measure by people who were free of any dementia-like symptoms. This development is, currently, just speculation.

We also suspect that many people would be reluctant to take such a drug if they were free of any symptoms ? a suspicion prompted by the ongoing controversy about statins, and whether the potential benefits outweigh any risk of side effects.

What kind of research was this?

This was mainly laboratory research, looking into the complex biological processes involved in Alzheimer's disease.

Alzheimer's disease is the most common type of dementia, affecting almost 500,000 people in the UK. Symptoms of Alzheimer's include progressive loss of mental ability, associated with the gradual death of brain cells.

While the cause is unknown, Alzheimer's disease has been associated with the build-up of proteins called amyloid plaques in the brain.

The researchers say fine fibres (fibrils) that make up the amyloid plaques kick-start toxic reactions around them, which ultimately cause further damage to the surrounding brain cells. The researchers wanted to see if they could stop or lessen this secondary damage.

What did the research involve?

The research studied purified amyloid protein fibrils under a variety of controlled conditions in the laboratory. They used these experiments to better understand how the fibrils formed, and how they catalysed other toxic reactions that could be causing damage to brain cells.

They also tested a short protein section (a molecule of amino acids) called Brichos to see if it could interfere with the processes they were seeing, and lessen the damage.

Experiments used lab-grown human cells, as well as mouse brain tissue.

None of the experiments investigated whether Brichos could prevent symptoms of dementia or Alzheimer's in mice or people. It was looking at chemical reactions, not symptoms.

What were the basic results?

The Brichos protein stopped reactions caused by the amyloid fibrils, reducing their toxicity in mice brain cells.

The experiments showed that Brichos did this by binding to the surfaces of amyloid fibrils. This specific binding stopped the toxic chain reactions that usually lead to damaging aggregation of other proteins. In essence, some of the disease process had been stopped.

How did the researchers interpret the results?

The authors summarised: "These results reveal that molecular chaperones [like Brichos] can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation."

They said Brichos was just the first protein they had investigated, and there may be other molecules that work in a similar way.


This study showed that a molecule called Brichos can selectively block some of the toxic effects linked to the accumulation of amyloid protein in the brains of mice. The research on Brichos is at a very early stage, having only been tested in mice.

Dr Laura Phipps of Alzheimer's Research UK says: "This study has revealed clues on how to block one important chain of events in the disease." Dr Doug Brown of the Alzheimer's Society added: "This revelation is exciting, as it gives scientists a whole new way of looking at the problem, opening the doors to possible new treatments."

Contrast this with the Mail Online outlining that this discovery "raises the prospect of a treatment which could be routinely taken in middle age to stop dementia. It could even result in a pill that could be used to treat dementia in the same way that statins are used to prevent heart disease today".

While the Mail's vision ? among other news sources ? is certainly possible, it is premature. There is no guarantee this research will lead to effective treatments for Alzheimer's disease.

And it should also be noted this study has limitations, which should be considered.

Brichos stopped secondary damage occurring in a specific amyloid-related disease pathway. But damage could occur by other means. And it doesn't appear to reverse existing damage.

Most people with Alzheimer's disease are diagnosed when they already have significant damage to their brain that has caused symptoms severe enough to affect their daily lives. So any "treatment" would need to be taken before symptoms appear, thereby acting as more of a prevention.

Similarly, as Brichos doesn't stop the amyloid plaques forming, it is unlikely to be fully preventative. There may also be side effects when using Brichos on people. It is also likely that Brichos will be absorbed by the body before it reaches the brain.

All these issues and many more will need to be ironed out by further research.

This study is certainly a step in the right direction, because it improves our understanding of the biology of Alzheimer's disease. But it is too early to say whether Brichos will lead to useful treatments or preventative medicines in the future.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

higher von Economo neuron density in anterior cingulate cortex

February 15, 2015
Alzheimer's & Dementia Weekly

SuperAgers Have 90% Fewer Tangles

SuperAgers, aged 80+, have memories as sharp as persons decades younger. They share 3 components:
1.A thicker cortex region
2.90% fewer tangles (Alzheimer's main marker)
3.A whopping supply of "social intelligence" neurons.
Learn about this new avenue of research to prevent and treat dementia.

Brains of cognitively elite "SuperAgers" look distinctly different than their elderly peers:
1.Brains of 80-year-old SuperAgers look 30 years younger
2.They have nearly 90 percent fewer tangles linked to Alzheimer's
3.Brains have whopping supply of neuron related to higher social intelligence
4.Research may lead to protecting memories of normal elders, treating dementia.

SuperAgers, aged 80 and above, have distinctly different looking brains than those of normal older people, according to new Northwestern Medicine? research that is beginning to reveal why the memories of these cognitively elite elders don't suffer the usual ravages of time.

SuperAgers have memories that are as sharp as those of healthy persons decades younger.

Understanding their unique "brain signature" will enable scientists to decipher the genetic or molecular source and may foster the development of strategies to protect the memories of normal aging persons as well as treat dementia.

Published in the Journal of Neuroscience, the study is the first to quantify brain differences of SuperAgers and normal older people.

Cognitive SuperAgers were first identified in 2007 by scientists at Northwestern's Cognitive Neurology and Alzheimer's Disease Center at Northwestern University Feinberg School of Medicine.
Their unusual brain signature has three common components when compared with normal persons of similar ages: a thicker region of the cortex; significantly fewer tangles (a primary marker of Alzheimer's disease) and a whopping supply of a specific neuron -- von Economo -- linked to higher social intelligence.

"The brains of the SuperAgers are either wired differently or have structural differences when compared to normal individuals of the same age," said Changiz Geula, study senior author and a research professor at the Cognitive Neurology and Alzheimer's Disease Center. "It may be one factor, such as expression of a specific gene, or a combination of factors that offers protection."

The Center has a new NIH grant to continue the research.

"Identifying the factors that contribute to the SuperAgers' unusual memory capacity may allow us to offer strategies to help the growing population of 'normal' elderly maintain their cognitive function and guide future therapies to treat certain dementias," said Tamar Gefen, the first study author and a clinical neuropsychology doctoral candidate at Feinberg.

MRI imaging and an analysis of the SuperAger brains after death show the following brain signature:
1. MRI imaging showed the anterior cingulate cortex of SuperAgers (31 subjects) was not only significantly thicker than the same area in aged individuals with normal cognitive performance (21 subjects), but also larger than the same area in a group of much younger, middle-aged individuals (ages 50 to 60, 18 subjects). This region is indirectly related to memory through its influence on related functions such as cognitive control, executive function, conflict resolution, motivation and perseverance.
2. Analysis of the brains of five SuperAgers showed the anterior cingulate cortex had approximately 87 percent less tangles than age-matched controls and 92 percent less tangles than individuals with mild cognitive impairment. The neurofibrillary brain tangles, twisted fibers consisting of the protein tau, strangle and eventually kill neurons.
3. The number of von Economo neurons was approximately three to five times higher in the anterior cingulate of SuperAgers compared with age-matched controls and individuals with mild cognitive impairment.
Von Economo neurons are sophisticated cells present in more advanced species such as whales, elephants, dolphins and higher apes. "It's thought that these von Economo neurons play a critical role in the rapid transmission of behaviorally relevant information related to social interactions," Geula said, "which is how they may relate to better memory capacity."


Other Northwestern authors on the study include Melanie Peterson, Steven T. Papastefan, Adam Martersteck, Kristen Whitney, Alfred Rademaker, Eileen Bigio, Sandra Weintraub, Emily Rogalski and Dr. M. Marsel Mesulam.

The research was funded by National Institute on Aging, National Institutes of Health grant AG045571, The Davee Foundation, the Northwestern University Alzheimer's Disease Core Center grant AG13854 from the National Institute on Aging, a fellowship from the National Institute on Aging grant F31-AG043270 and others.

For more information on the SuperAger study, visit http://www.brain.northwestern.edu/

If you are interested in participating in research at Northwestern University, please call the NU Study line at 1-855-NU-STUDY. Or get connected by visiting http://bit.ly/NUCATSRegistry to sign up for Northwestern's Research Registry.

Morphometric and Histologic Substrates of Cingulate Integrity in Elders with Exceptional Memory Capacity

The Journal of Neuroscience, 28 January 2015, 35(4): 1781-1791; doi: 10.1523/JNEUROSCI.2998-14.2015


This human study is based on an established cohort of “SuperAgers,” 80+-year-old individuals with episodic memory function at a level equal to, or better than, individuals 20?30 years younger. A preliminary investigation using structural brain imaging revealed a region of anterior cingulate cortex that was thicker in SuperAgers compared with healthy 50- to 65-year-olds. Here, we investigated the in vivo structural features of cingulate cortex in a larger sample of SuperAgers and conducted a histologic analysis of this region in postmortem specimens. A region-of-interest MRI structural analysis found cingulate cortex to be thinner in cognitively average 80+ year olds (n = 21) than in the healthy middle-aged group (n = 18). A region of the anterior cingulate cortex in the right hemisphere displayed greater thickness in SuperAgers (n = 31) compared with cognitively average 80+ year olds and also to the much younger healthy 50?60 year olds (p < 0.01). Postmortem investigations were conducted in the cingulate cortex in five SuperAgers, five cognitively average elderly individuals, and five individuals with amnestic mild cognitive impairment. Compared with other subject groups, SuperAgers showed a lower frequency of Alzheimer-type neurofibrillary tangles (p < 0.05). There were no differences in total neuronal size or count between subject groups. Interestingly, relative to total neuronal packing density, there was a higher density of von Economo neurons (p < 0.05), particularly in anterior cingulate regions of SuperAgers. These findings suggest that reduced vulnerability to the age-related emergence of Alzheimer pathology and higher von Economo neuron density in anterior cingulate cortex may represent biological correlates of high memory capacity in advanced old age.

bisecting GlcNAc(バイセクト糖鎖)







本研究は、欧州の医学専門誌『EMBO Molecular Medicine』オンライン版(1月15日付け:日本時間1月15日)に掲載されます。


理化学研究所 グローバル研究クラスタ システム糖鎖生物学研究グループ 疾患糖鎖研究チーム
チームリーダー 谷口 直之(たにぐち なおゆき)
副チームリーダー 北爪 しのぶ (きたづめ しのぶ)
基礎科学特別研究員 木塚 康彦 (きづか やすひこ)

理化学研究所 脳科学総合研究センター 神経蛋白制御研究チーム
チームリーダー 西道 隆臣 (さいどう たかおみ)

広島大学大学院 先端物質科学研究科
准教授 中の 三弥子 (なかの みやこ)

東京都健康長寿医療センター 研究所
副所長 遠藤 玉夫 (えんどう たまお)
神経内科部長 村山 繁雄 (むらやま しげお)

An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease

Yasuhiko Kizuka1,
Shinobu Kitazume1,*,
Reiko Fujinawa1,
Takashi Saito2,
Nobuhisa Iwata2,3,
Takaomi C Saido2,
Miyako Nakano4,
Yoshiki Yamaguchi5,
Yasuhiro Hashimoto6,
Matthias Staufenbiel7,
Hiroyuki Hatsuta8,
Shigeo Murayama8,
Hiroshi Manya9,
Tamao Endo9 and
Naoyuki Taniguchi1,*

Article first published online: 15 JAN 2015

DOI: 10.15252/emmm.201404438

? 2015 The Authors. Published under the terms of the CC BY 4.0 license

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


The β-site amyloid precursor protein cleaving enzyme-1 (BACE1), an essential protease for the generation of amyloid-β (Aβ) peptide, is a major drug target for Alzheimer's disease (AD). However, there is a concern that inhibiting BACE1 could also affect several physiological functions. Here, we show that BACE1 is modified with bisecting N-acetylglucosamine (GlcNAc), a sugar modification highly expressed in brain, and demonstrate that AD patients have higher levels of bisecting GlcNAc on BACE1. Analysis of knockout mice lacking the biosynthetic enzyme for bisecting GlcNAc, GnT-III (Mgat3), revealed that cleavage of Aβ-precursor protein (APP) by BACE1 is reduced in these mice, resulting in a decrease in Aβ plaques and improved cognitive function. The lack of this modification directs BACE1 to late endosomes/lysosomes where it is less colocalized with APP, leading to accelerated lysosomal degradation. Notably, other BACE1 substrates, CHL1 and contactin-2, are normally cleaved in GnT-III-deficient mice, suggesting that the effect of bisecting GlcNAc on BACE1 is selective to APP. Considering that GnT-III-deficient mice remain healthy, GnT-III may be a novel and promising drug target for AD therapeutics.


Targeting sleep-wake protein may prevent Alzheimer's
Medical News Today

A new study reported in The Journal of Experimental Medicine suggests an approach to preventing Alzheimer's disease may lie in targeting orexin - a small protein that arouses the brain from sleep.

Researchers slowed the production of brain plaques - a hallmark of Alzheimer's disease - in mice by eliminating the protein orexin, which plays a key role in arousing the brain from sleep.
Researchers from the School of Medicine at Washington University in St. Louis (WUSTL) came to this conclusion after they found eliminating orexin in mice made them sleep longer and significantly slowed the production of brain plaques.

Brain plaques are abnormal clusters of amyloid beta protein fragments that build up between nerve cells and a known hallmark of Alzheimer's disease. Scientists believe that slowing or stopping this build up could slow or stop the disease.

Orexin is a protein that stimulated wakefulness. It is produced by cells located in the hypothalamus - a small section of the brain that controls many functions, including sleep.

Low levels of orexin are linked to narcolepsy, a condition marked by excessive sleepiness and frequent periods of daytime sleeping.

Blocking orexin to increase sleep may be a way to reduce risk of Alzheimer's
In previous studies, WUSTL researchers have shown that in both people and mice, sleep loss contributes to the production of brain plaques and increases the risk of developing dementia.

Professor David M. Holtzman, senior author of the new study and head of the Department of Neurology at WUSTL School of Medicine, says the new study shows "we should be looking hard at orexin as a potential target for preventing Alzheimer's disease," and:

"Blocking orexin to increase sleep in patients with sleep abnormalities, or perhaps even to improve sleep efficiency in healthy people, may be a way to reduce the risk of Alzheimer's. This is important to explore further."

Mice lacking orexin slept longer and developed only half as many brain plaques
For the new study, the team used mice that had been genetically engineered to develop brain plaques. But when they bred these same mice lacking the gene for orexin, their offspring slept longer and only developed half the number of plaques as mice that could still produce orexin.

Prof. Holtzman says the hypothalamus cells that produce orexin "have branches that carry orexin throughout the brain, and the protein acts like a switch. If you stimulate orexin production in sleeping mice, they wake up immediately."

The team found that the mice with no orexin typically slept an extra hour or more during the 12-hour period when mice with orexin were more active.

When they repeated the experiment the other way around and artificially increased orexin levels throughout the brain, the researchers found the mice were awake for longer periods and developed more brain plaques.

Orexin 'only affects plaque levels when it also affects sleep'
But when the team altered orexin levels in only part of mice's brain - not throughout the brain - this did not alter the amount of time the animals slept for and neither did it change plaque levels.

This last experiment shows orexin only affects plaque levels when it also affects sleep, says Prof. Holtzman, which means "we will have to think carefully about how to target it for Alzheimer's prevention. But the declines in plaque levels that we saw in the mice were very strong, so we're still very interested in exploring its potential for reducing risk."

The team is now looking at how sleep medication might affect the production of amyloid beta and the accumulation of plaques. They hope to assess drugs like the recently FDA-approved Belsomra - the first to target orexin.

In October 2014, Medical News Today learned of a study that found diets enriched with walnuts slow Alzheimer's progression in mice. The finding follows previous research that found an extract in walnuts may protect against oxidative stress caused by beta amyloid protein.

Written by Catharine Paddock PhD

Copyright: Medical News Today
Not to be reproduced without permission.

Brief Definitive Report
Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease
Jee Hoon Roh,1,2,3,4 Mary Beth Finn,1,2,3 Floy R. Stewart,1,2,3 Thomas E. Mahan,1,2,3 John R. Cirrito,1,2,3 Ashish Heda,1,2,3 B. Joy Snider,1,2,3 Mingjie Li,1,2,3 Masashi Yanagisawa,5 Luis de Lecea,6 and David M. Holtzman1,2,3
+ Author Affiliations
1Department of Neurology, 2Hope Center for Neurological Disorders, and 3Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110
4Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, South Korea
5Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390
6Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305
CORRESPONDENCE David M. Holtzman: holtzman@neuro.wustl.edu

Age-related aggregation of amyloid-β (Aβ) is an upstream pathological event in Alzheimer’s disease (AD) pathogenesis, and it disrupts the sleep?wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aβ aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aβ pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aβ pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aβ pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aβ pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aβ pathology in the brain.

Primary age-related tauopathy (PART)

November 16, 2014
Alzheimer's & Dementia Weekly

P.A.R.T. Dementia is Alzheimer's without the Plaque

As doctors get better at diagnosing different types of dementia, treatment and research improves. The new discovery of a dementia type called primary age-related tauopathy (PART) may help people who have been misdiagnosed with Alzheimer's. In Alzheimer's, amyloid plaque is the most distinguishing feature. Find out how people diagnosed with Alzheimer's may actually lack any amyloid plaque and really have P.A.R.T. dementia.

LEXINGTON, Ky ? A multi-institutional study has defined and established criteria for a new neurological disease closely resembling Alzheimer’s disease called primary age-related tauopathy (PART). Patients with PART develop cognitive impairment that can be indistinguishable from Alzheimer’s disease, but they lack amyloid plaques. Awareness of this neurological disease will help doctors diagnose and develop more effective treatments for patients with different types of memory impairment.

The study, co-led by Peter T. Nelson, MD, PhD, of the University of Kentucky's Sanders-Brown Center on Aging, and John F. Crary, MD, PhD, of Mount Sinai Hospital, was published in the current issue of Acta Neuoropathologica.

“To make an Alzheimer's diagnosis you need to see two things together in a patient’s brain: amyloid plaques and structures called neurofibrillary tangles composed of a protein called tau,” said Dr. Nelson, a professor of neuropathology at the University of Kentucky's Sanders-Brown Center on Aging. “However, autopsy studies have demonstrated that some patients have tangles but no plaques and we’ve long wondered what condition these patients had.”

Plaques in the brain, formed from the accumulation of amyloid protein, are a hallmark of Alzheimer’s disease. Until now, researchers have considered cases with only tangles to be either very early-stage Alzheimer’s or a variant of the disease in which the plaques are harder to detect. However, previous in-depth biochemical and genetic studies have failed to reveal the presence of any abnormal amyloid in these patients. Although tangle-only patients can have memory complaints, the presence of plaques is a key requirement for an Alzheimer’s diagnosis.

In the current study, investigators from the United States (including five from Sanders-Brown), Canada, Europe, and Japan came together to formalize criteria for diagnosing this new neurological disorder. The study establishes that PART is a primary tauopathy, a disease directly caused by the tau protein in tangles. Many of the neurofibrillary tangles in Alzheimer’s brain, in contrast, are thought to arise secondarily to amyloid or some other stimuli. The researchers propose that individuals who have tangles resembling those found in Alzheimer's but have no detectable amyloid plaques should now be classified as PART.

PART is most severe in patients of advanced age, but is generally mild in younger elderly individuals. The reason for this is currently unknown, but unlike Alzheimer’s disease, in which the tangles spread throughout the brain, in PART cases the tangles are restricted mainly to structures important for memory.

It is too early to tell how common PART is, but given that tangles are nearly universal in the brains of older individuals, it might be more widespread than generally recognized. While further studies are required, new diagnostic tests using brain scans and cerebrospinal fluid biomarkers for amyloid and tau are finding surprisingly high proportions of patients (as many as 25% in some studies) with mild cognitive impairment that are positive for tau but negative for amyloid.

“Until now, PART has been difficult to treat or even study because of lack of well-defined criteria,” said Dr. Nelson. “Now that the scientific community has come to a consensus on what the key features of PART are, this will help doctors diagnose different forms of memory impairment early. These advancements will have a big impact on our ability to recognize and develop effective treatments for brain diseases seen in older persons.”

Identifying the type of neurological disorder in the early stages of disease is critical if treatment is to begin before irreparable brain damage has occurred. However, in the absence of clear criteria, different forms of neurological disorders have been hard to distinguish. As a result, PART patients may have confounded clinical trials of amyloid-targeting drugs for Alzheimer’s disease as these treatments are unlikely to be effective against tangles. Along with the development of better biomarkers and genetic risk factors for dementia, the new diagnosis criteria will help PART patients to receive more targeted therapy and improve the accuracy of clinical trials for Alzheimer’s drugs.

University of Kentucky

The University of Kentucky’s Sanders-Brown Center on Aging http://www.centeronaging.uky.edu was established in 1979 and is one of the original ten National Institutes of Health (NIH)-funded Alzheimer’s disease Research Centers. The SBCoA is internationally acclaimed for its progress in the fight against illnesses facing the aging population.

The article is titled, “Primary age-related tauopathy (PART): a common pathology associated with human aging.” The other contributors are: John Q. Trojanowski, Steven E. Arnold, Jonathan B. Toledo, Juan C. Troncoso (University of Pennsylvania); Julie A. Schneider (Rush University Medical Center); Jose F. Abisambra, Erin L. Abner, Gregory A. Jicha, Janna H. Neltner, Masahito Yamada (University of Kentucky); Irina Alafuzoff (Uppsala University); Johannes Attems (Newcastle University); Thomas G. Beach (Banner Sun Health Research Institute); Eileen H. Bigio (Northwestern University); Nigel J.Cairns, Walter A. Kukull, Thomas J. Montine (University of Washington); Dennis W. Dickson, David S. Knopman, MelissaE. Murray (Mayo Clinic); Marla Gearing (Emory University); Lea T. Grinberg (UC San Francisco and University of Sao Paulo); Patrick R. Hof (Mount Sinai); Bradley T.Hyman (Harvard Medical School); Kurt Jellinger (Institute of Clinical Neurobiology, Vienna); Gabor G. Kovacs (Medical University Vienna); Julia Kofler (University of Pittsburgh); Ian R. Mackenzie (University of British Columbia); Eliezer Masliah (University of California, San Diego); Ann McKee (Boston University); Ismael Santa-Maria, Michael L. Shelanski, Jean Paul Vonsattel (CUMC); William W. Seeley (UC San Francisco); Alberto Serrano-Pozo (University of Iowa); Thor Stein (VA Medical Center & Boston University); Masaki Takao (Tokyo Metropolitan Geriatric Hospital); Dietmar R. Thal (University of Ulm; Charles L. White 3rd (University of Texas); Thomas Wisniewski (New York University); and Randall L. Woltjer (Oregon Health Sciences University).

The study was supported by grants from: the Society for Supporting Research in Experimental Neurology, Vienna, Austria; the National Institutes of Health; Medical Research Council ; National Institute for Health Research ; the Dunhill Medical Trust; Alzheimer's Research UK (ARUK), and the Alzheimer's Society, Louis V. Gerstner, Jr., Foundation; Alzheimer’s Association, FP7 EU Project Develage, Comprehensive Brain Research Network, Grant-in-Aid for Scientific Research, and Daiwa Health Science Foundation, BrightFocus Foundation, Alzheimer’s Association NIRGD-12- 242642, Alzheimer Forschung Initiative; German Ministry for Research and Education (BMBF) FTLD-Net, Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation.

Acta Neuropathologica
December 2014, Volume 128, Issue 6, pp 755-766
Date: 28 Oct 2014

Primary age-related tauopathy (PART): a common pathology associated with human aging

We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer’s disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ?” brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

tiny silent acute infarcts

Krembil researchers potentially discover major cause of dementia

October 31, 2014

Researchers at the Krembil Neuroscience Centre have potentially discovered a major cause of dementia. In this type of dementia, there is damage to the white matter (nerve fibres) of the brain apparent on computerized tomography (CT) and magnetic resonance imaging (MRI) scans of older individuals.

Approximately 50 per cent of older individuals have evident white matter damage on their medical imaging scans. For most patients, these changes are harmless but when this damage is severe, it can cause impairment.

Previous studies have already established that the more white matter disease there is in the brain, the more likely patients are to have symptoms of dementia such as cognitive impairment or changes in behaviour. What was not understood is why this white matter disease develops - the traditional assumption was that it might be the result of the natural aging process.

Krembil researchers hypothesized that the white matter disease (also called leukoaraiosis) may actually be the result of many tiny unnoticed strokes accumulating over time - a finding that points to a potentially treatable form of dementia. The research was published today in the journal Annals of Neurology.

The researchers conducted an intensive study to observe the development of this white matter disease over a short period of time, rather than on an annual basis - the interval at which previous studies have performed repeat brain imaging. The study involved 5 patients with white matter disease undergoing detailed MRI scanning of their brains every week for 16 consecutive weeks.

The weekly MRI scans revealed new tiny spots arising in the brain's white matter that were, based on their MRI appearance, characteristic of small new strokes (cerebral infarcts). The lesions had no symptoms but, with time, came to resemble the existing white matter disease in the subjects' brains. In the study's random sampling, the majority of subjects had this phenomenon: Tiny strokes occurring without symptoms, and developing into the kind of white matter disease that causes dementia

"We were surprised by the study findings" said Dr. Daniel Mandell, Neuroradiologist, Joint Department of Medical Imaging, Toronto Western Hospital and the principal investigator of the study. "The findings suggest that the tiny, silent strokes are likely much more common than physicians previously appreciated, and these strokes are likely a cause of the age-related white matter disease that can lead to dementia."

Unlike degenerative types of dementia where there are no treatments, this type, based on vascular disease, is more treatable as it is caused by tiny episodes affecting the blood vessels in the brain over time. It may be possible to prevent or stop this process.

"We don't yet know whether these small strokes are responsible only some or most of the white matter disease seen in older patients," said Dr. Frank Silver, Neurologist and Medical Director, Stroke Program, Krembil Neuroscience Centre and a co-author of the study. "But in those where it is the cause, the detection of white matter disease on brain imaging should trigger physicians to treat patients aggressively when managing stroke risk factors such as high blood pressure, diabetes, high cholesterol, cigarette smoking and lack of exercise not only to prevent further strokes, but also to reduce the development of cognitive impairment over time."

Although more research is needed to further investigate these findings with a larger sample size, if most white matter disease is found to be caused by these tiny strokes, it could eventually lead to interventions to delay its progression in the brain.

Krembil Neuroscience Centre

Brief Communication

Are acute infarcts the cause of leukoaraiosis? Brain mapping for 16 consecutive weeks

John Conklin MD, MSc1,
Frank L. Silver MD2,
David J. Mikulis MD1,3 and
Daniel M. Mandell MD, PhD1,3,*

Article first published online: 30 OCT 2014

DOI: 10.1002/ana.24285

Neuroimaging of older adults commonly reveals abnormality (leukoaraiosis) in the cerebral white matter. Studies have established that extensive leukoaraiosis predicts dementia and disability, but the pathogenesis of leukoaraiosis remains unclear. We recruited 5 patients with leukoaraiosis and performed magnetic resonance mapping of the brain for 16 consecutive weeks. We observed tiny lesions arising de novo in the cerebral white matter. These lesions were clinically silent. They had the signature features of acute ischemic stroke. With time, the characteristics of these lesions approached those of pre-existing leukoaraiosis. Together, these findings suggest that tiny silent acute infarcts are a cause of leukoaraiosis. Ann Neurol 2014

Tau protein

Tau protein, not plaque, may cause Alzheimer’s, study says
By Nicole Kwan
October 31, 2014

New research has found that plaques are not the main cause of Alzheimer’s disease, but rather the protein tau, also known as “tangles.”

“For a very long time, we believed, for almost 100 years, that [amyloid-beta] plaques are the main culprit in Alzheimer’s disease,” the study's senior investigator, Charbel E-H Moussa, MB, assistant professor of neuroscience at Georgetown University Medical Center, told FoxNews.com. “This study shows it’s another protein -- a very, very important one, called tau, is basically the main guilty one.”

Researchers found that tau modulates how much amyloid protein stays inside a cell, and how much is secreted outside the cell to form plaque. This build-up is what leads to neuron death. The plaque that forms outside a cell are not toxic, as previously believed, they found.

If tau is functioning normally, the amyloid-beta (Abeta) protein in a cell is “digested,” and what is not degraded is expelled outside the cell and accumulated as plaque. This pool of amyloid builds up in the cell, causing it to die.

Moussa likened tau to a train track? if it’s functioning normally, the train can run. If it’s disrupted, the train can’t move debris from one end of the cell to the other. There needs to be a ratio of “good” to “bad” tau -- the “good” holds the tracks together, but the “bad” makes it fall apart.

“…We know that the ratio of amyloid inside the cell to the outside is very small,” Moussa said. “So what gets out is basically an attempt by the cell to expel toxic amyloid.”

For their study, researchers worked with animal models. The mice who did not have tau were unable to digest Abeta, and had about twice as much plaque as those who had tau. However, looking at the toxicity, the mice with less plaque but more intercellular build-up were more toxic.

According to researchers, their findings have major implications for designing therapies for Alzheimer’s disease, a type of dementia which affects more than 5 million Americans and is the sixth leading cause of death in the U.S. The disease causes problems with memory, thinking and behavior.

Current treatments for Alzheimer’s are immunotherapy-based and have the goal of binding to the plaque outside a cell and killing it.

“You give them a year, do a scan, and see the plaque has dissolved, but still have the scientific problem, [the patient] still declined the same way as a placebo patient,” Moussa said.

Their findings indicate that using drugs to restore normal function of tau will allow intracellular Abeta to be cleared out, thus avoiding cell death.

“It’s much more likely that people will develop degenerative cell death and dementia if they have tau modifications than if they have Abeta plaques,” he said.

The researchers studied nilotinib, an anti-cancer drug that is approved for use in adult-onset leukeumia patients, as a solution to clear intracellular debris and reduce the “bad” level of tau. The drug works by entering the cell to clear debris, but also reduces plaques outside the cell to prevent progression of the disease. This reduction of plaque is necessary because researchers believe that when plaque is secreted, some of it is internalized inside the cell, and clearing outside plaque reduces inflammation in the brain.

Clinical trials of nilotinib will begin in a matter of weeks, Moussa said. The study will use a dose that’s at least ten times lower than the amount used for leukemia treatment. Patients in the trial have Lewy Body dementia, a disease that shares characteristics of both Parkinson’s and Alzheimer’s? instead of having plaque in the brain, patients have tau modifications, as well as the protein alpha-synuclein, a pathological hallmark of Parkinson’s.

The study helps explain why past research has found that some older patients who have a lot of plaque accumulation do not have dementia. Additionally, in earlier onset dementias that are not Alzheimer’s, normally there are no plaques in the brain, but patients still have very similar symptoms. Researchers predict any drug that reduces bad tau in the brain will stabilize a patient’s Alzheimer’s symptoms.

Currently, there are no screenings for Alzheimer’s. While there are genetic variants that can increase risk, it doesn’t necessarily mean the disease will develop. However, there is a technique that scans for tau that Moussa believes doctors should be using instead of scanning for plaques.

Tau screening will likely detect signs of Alzheimer’s much earlier and be more rigorous in predicting if a patient will develop dementia, Moussa noted.

“Recent evidence suggests is appears that tau modification happens much earlier than amyloid plaques … and because almost every patient who has tau modification has dementia, it’s going to be a much more reliable and precise predictor of Alzheimer’s and other dementias than Abeta,” Moussa said.

With earlier screenings and a drug that clears bad tau in the brain, patients could prevent further tau modification and build up in the plaques to avoid Alzheimer’s or dementia, Moussa said.

“If I’m 40 years old, and you do tau screening and find some, then screen five years from now and see more tau modifications, compared to the general population, if a drug can reduce the level of that bad tau, that would present or at least delay the onset of dementia,” he said. “That’s absolutely like preventative care.”

“The dogma has been for a very long time, if you have Alzheimer’s disease, you have to have plaques or tangles [twisted fibers of tau]… what we’re finding here is you probably have to have tangles and tau losing function, but don’t necessarily have to have plaque to have Alzheimer’s disease, because it’s only a product, not the cause.”

HSF-1 (heat shock factor-1)

Contact: Robert Sanders
University of California - Berkeley

New front in war on Alzheimer's and other protein-linked brain diseases

When suffering heat shock, cells first stabilize their cytoskeleton to maintain communication

A surprise discovery that overturns decades of thinking about how the body fixes proteins that come unraveled greatly expands opportunities for therapies to prevent diseases such as Alzheimer's and Parkinson's, which have been linked to the accumulation of improperly folded proteins in the brain.

"This finding provides a whole other outlook on protein-folding diseases; a new way to go after them," said Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair of Stem Cell Research in the Department of Molecular and Cell Biology and Howard Hughes Medical Institute investigator at the University of California, Berkeley.

Dillin, UC Berkeley postdoctoral fellows Nathan A. Baird and Peter M. Douglas and their colleagues at the University of Michigan, The Scripps Research Institute and Genentech Inc., will publish their results in the Oct. 17 issue of the journal Science.

Cells put a lot of effort into preventing proteins ? which are like a string of beads arranged in a precise three-dimensional shape ? from unraveling, since a protein's activity as an enzyme or structural component depends on being properly shaped and folded. There are at least 350 separate molecular chaperones constantly patrolling the cell to refold misfolded proteins. Heat is one of the major threats to proteins, as can be demonstrated when frying an egg ? the clear white albumen turns opaque as the proteins unfold and then tangle like spaghetti.

For 35 years, researchers have worked under the assumption that when cells undergo heat shock, as with a fever, they produce a protein that triggers a cascade of events that field even more chaperones to refold unraveling proteins that could kill the cell. The protein, HSF-1 (heat shock factor-1), does this by binding to promoters upstream of the 350-plus chaperone genes, upping the genes' activity and launching the army of chaperones, which originally were called "heat shock proteins."

Injecting animals with HSF-1 has been shown not only to increase their tolerance of heat stress, but to increase lifespan.

Because an accumulation of misfolded proteins has been implicated in aging and in neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases, scientists have sought ways to artificially boost HSF-1 in order to reduce the protein plaques and tangles that eventually kill brain cells. To date, such boosters have extended lifespan in lab animals, including mice, but greatly increased the incidence of cancer.

Dillin's team found in experiments on the nematode worm C. elegans that HSF-1 does a whole lot more than trigger release of chaperones. An equal if not more important function is to stabilize the cell's cytoskeleton, which is the highway that transports essential supplies ? healing chaperones included ? around the cell.

"We are suggesting that, rather than making more of HSF-1 to prevent diseases like Huntington's, we should be looking for ways to make the actin cytoskeleton better," Dillin said. Such tactics might avoid the carcinogenic side effects of upping HSF-1.

Dillin is codirector of the Paul F. Glenn Center for Aging Research, a new collaboration between UC Berkeley and UC San Francisco supported by the Glenn Foundation for Medical Research. Center investigators will study the many ways that proteins malfunction within cells, ideally paving the way for novel treatments for neurodegenerative diseases.

A cell at war

Dillin compares a cell experiencing heat shock to a country under attack. In a war, an aggressor first cuts off all communications, such as roads, train and bridges, which prevents the doctors from treating the wounded. Similarly, heat shock disrupts the cytoskeletal highway, preventing the chaperone "doctors" from reaching the patients, the misfolded proteins.

"We think HSF-1 not only makes more chaperones, more doctors, but also insures that the roadways stay intact to keep everything functional and make sure the chaperones can get to the sick and wounded warriors," he said.

The researchers found specifically that HSF-1 up-regulates another gene, pat-10, that produces a protein that stabilizes actin, the building blocks of the cytoskeleton.

By boosting pat-10 activity, they were able to cure worms that had been altered to express the Huntington's disease gene, and also extend the lifespan of normal worms.

Dillin suspects that HSF-1's main function is, in fact, to protect the actin cytoskeleton. He and his team mutated HSF-1 so that it no longer boosted chaperones, demonstrating, he said, that "you can survive heat shock with the normal level of heat shock proteins, as long as you make your cytoskeleton work better."

He noted that the team's results ? that boosting chaperones is not essential to surviving heat stress ? were so contradictory to current thinking that "I made my post-docs' lives hell for three years" insisting on more experiments to rule out errors. Yet, when Dillin presented the results recently to members of the protein-folding community, he said the first reaction of many was, "That makes perfect sense."

Dillin's colleagues include Milos S. Simic and Suzanne C. Wolff of UC Berkeley, Ana R. Grant of the University of Michigan in Ann Arbor, James J. Moresco and John R. Yates III of Scripps in La Jolla, Calif., and Gerard Manning of Genentech, South San Francisco, Calif. The work is funded by the Howard Hughes Medical Institute as well as by the National Institute of General Medical Sciences (8 P41 GM103533-17) and National Institute on Aging (R01AG027463-04) of the National Institutes of Health.

Caption:?A cell suffering heat shock is like a country besieged, where attackers first sever lines of communications. The pat-10 gene helps repair communication to allow chaperones to treat misfolded proteins.


発症前にタンパク質異常 アルツハイマー病
2014.9.17 23:46




Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer's disease brain
Kazuhiko Tagawa1,$, Hidenori Homma1,$, Ayumu Saito2,$, Kyota Fujita1, Xigui Chen1, Seiya Imoto2, Tsutomu Oka1, Hikaru Ito1, Kazumi Motoki1, Chisato Yoshida1, Hiroyuki Hatsuta4, Shigeo Murayama4, Takeshi Iwatsubo3, Satoru Miyano2 and Hitoshi Okazawa1,*
+ Author Affiliations

1Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
2Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 113-8639, Japan
3Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
4Department of Neuropathology, Brain Bank for Aging Research, Tokyo Metropolitan Institute of Gerontology, 35-2, Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
?*Corresponding author. Tel:+81 358035847; Fax: +81 358035847; Email: okazawa-tky@umin.ac.jp; okazawa.npat@mri.tmd.ac.jp
?$ KT, HH and AS are co-first authors.

Human Molecular Genetics
Received August 4, 2014.
Revision received September 8, 2014.
Accepted September 9, 2014.

Using a high-end mass spectrometry, we screened phosphoproteins and phosphopeptides in four types of Alzheimer's disease (AD) mouse models and human AD postmortem brains. We identified commonly changed phosphoproteins in multiple models and also determined phosphoproteins related to initiation of Aβ deposition in the mouse brain. After confirming these proteins were also changed in and human AD brains, we put the proteins on experimentally verified protein-protein interaction databases. Surprisingly most of the core phosphoproteins were directly connected, and they formed a functional network linked to synaptic spine formation. The change of the core network started at a preclinical stage even before histological Aβ deposition. Systems biology analyses suggested phosphorylation of MARCKS by over-activated kinases including PKCs and CaMKs initiates synapse pathology. Two-photon microscopic observation revealed recovery of abnormal spine formation in the AD model mice by targeting a core protein MARCKS or by inhibiting candidate kinases, supporting our hypothesis formulated based on phosphoproteome analysis.

? The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Brain compensation

14 September 2014

Brain may 'compensate' for Alzheimer's damage

By Smitha Mundasad
Health reporter, BBC News

The human brain may be able to compensate for some of the early changes seen in Alzheimer's disease, research in Nature Neuroscience shows.

The study suggests some people recruit extra nerve power to help maintain their ability to think.

Scientists hope the findings could shed light on why only some people with early signs of the condition go on to develop severe memory decline.

But experts warn much more research is needed to understand these processes.

'Protein tangles'
The study, led by researchers at the University of California, involved 71 adults with no signs of mental decline.

Brain scans showed 16 of the older subjects had amyloid deposits - tangles of protein that are considered a hallmark of Alzheimer's disease.

All participants were asked to memorise a series of pictures in detail while scanners were used to track their brain activity.

They were then asked to recall the gist and later the detail of all the pictures they had seen.

Both groups performed equally well but those with tangles of amyloid in their brains showed more brain activity when remembering the images in detail.

Scientists say this suggests their brains have an ability to adapt to and compensate for any early damage caused by the protein.

Brain stimulation
Dr Laura Phipps, at the charity Alzheimer's Research UK, said: "This small study suggests that our brains may have ways of resisting early damage from these Alzheimer's proteins but more research is needed to know how to interpret these results.

She added: "Longer term studies are needed to confirm whether the extra brain activity seen in this research is a sign of the brain compensating for early damage, and if so, how long the brain might be able to fight this damage."

Scientists say they need to understand why some people with an accumulation of this protein are better at using different parts of their brain than others.

Dr William Jagust, a researcher on the study, said: "I think it is very possible that people who spend a lifetime involved in cognitively stimulating activity have brains that are better able to adapt to potential damage."

Neural compensation in older people with brain amyloid-β deposition

Jeremy A Elman, Hwamee Oh, Cindee M Madison, Suzanne L Baker, Jacob W Vogel, Shawn M Marks, Sam Crowley, James P O'Neil & William J Jagust

Nature Neuroscience (2014) doi:10.1038/nn.3806
Received 10 June 2014 Accepted 14 August 2014 Published online 14 September 2014

Recruitment of extra neural resources may allow people to maintain normal cognition despite amyloid-β (Aβ) plaques. Previous fMRI studies have reported such hyperactivation, but it is unclear whether increases represent compensation or aberrant overexcitation. We found that older adults with Aβ deposition had reduced deactivations in task-negative regions, but increased activation in task-positive regions related to more detailed memory encoding. The association between higher activity and more detailed memories suggests that Aβ-related hyperactivation is compensatory.

absence of MK2/3

August 26, 2014

Lack of naturally occuring protein linked to dementia

Scientists at the University of Warwick have provided the first evidence that the lack of a naturally occurring protein is linked to early signs of dementia.

Published in Nature Communications, the research found that the absence of the protein MK2/3 promotes structural and physiological changes to cells in the nervous system. These changes were shown to have a significant correlation with early signs of dementia, including restricted learning and memory formation capabilities.

An absence of MK2/3, in spite of the brain cells (neurons) having significant structural abnormalities, did not prevent memories being formed, but did prevent these memories from being altered.

The results have led the researchers to call for greater attention to be paid to studying MK2/3.

Lead researcher and author Dr Sonia Corr?a says that "Understanding how the brain functions from the sub-cellular to systems level is vital if we are to be able to develop ways to counteract changes that occur with ageing.

"By demonstrating for the first time that the MK2/3 protein, which is essential for neuron communication, is required to fine-tune memory formation this study provides new insight into how molecular mechanisms regulate cognition".

Neurons can adapt memories and make them more relevant to current situations by changing the way they communicate with other cells.

Information in the brain is transferred between neurons at synapses using chemicals (neurotransmitters) released from one (presynaptic) neuron which then act on receptors in the next (postsynaptic) neuron in the chain.

MK2/3 regulates the shape of spines in properly functioning postsynaptic neurons. Postsynaptic neurons with MK2/3 feature wider, shorter spines (Fig.1) than those without (Fig2) - see attached diagram and photo.

The researchers found that change, caused by MK2/3's absence, in the spine's shape restricts the ability of neurons to communicate with each other, leading to alterations in the ability to acquire new memories.

"Deterioration of brain function commonly occurs as we get older but, as result of dementia or other neurodegenerative diseases, it can occur earlier in people's lives", says Dr Corr?a. "For those who develop the early signs of dementia it becomes more difficult for them to adapt to changes in their life, including performing routine tasks.

"For example, washing the dishes; if you have washed them by hand your whole life and then buy a dishwasher it can be difficult for those people who are older or have dementia to acquire the new memories necessary to learn how to use the machine and mentally replace the old method of washing dishes with the new. The change in shape of the postsynaptic neuron due to absence of MK2/3 is strongly correlated with this inability to acquire the new memories".

Dr Corr?a argues that "Given their vital role in memory formation, MK2/3 pathways are important potential pharmaceutical targets for the treatment of cognitive deficits associated with ageing and dementia."

Explore further: Amplifying communication between neurons

More information: Nature Communications, www.nature.com/ncomms/2014/140… full/ncomms5701.html

Journal reference: Nature Communications search and more info website

Provided by University of Warwick search and more info website

The MK2/3 cascade regulates AMPAR trafficking and cognitive flexibility
Katherine L. Eales,
Oleg Palygin,
Thomas O’Loughlin,
Seyed Rasooli-Nejad,
Matthias Gaestel,
J?rgen M?ller,
Dawn R. Collins,
Yuriy Pankratov
& Sonia A.L. Corr?a

Nature Communications 5, Article number: 4701 doi:10.1038/ncomms5701 Received 19 May 2014 Accepted 16 July 2014 Published 19 August 2014

The interplay between long-term potentiation and long-term depression (LTD) is thought to be involved in learning and memory formation. One form of LTD expressed in the hippocampus is initiated by the activation of the group 1 metabotropic glutamate receptors (mGluRs). Importantly, mGluRs have been shown to be critical for acquisition of new memories and for reversal learning, processes that are thought to be crucial for cognitive flexibility. Here we provide evidence that MAPK-activated protein kinases 2 and 3 (?MK2/3) regulate neuronal spine morphology, synaptic transmission and plasticity. Furthermore, mGluR-LTD is impaired in the hippocampus of ?MK2/3 double knockout (DKO) mice, an observation that is mirrored by deficits in endocytosis of ?GluA1 subunits. Consistent with compromised mGluR-LTD, ?MK2/3 DKO mice have distinctive deficits in hippocampal-dependent spatial reversal learning. These novel findings demonstrate that the ?MK2/3 cascade plays a strategic role in controlling synaptic plasticity and cognition.
Synapses are shown with (Fig 1) and without (Fig 2) MK2/3. Credit: University of Warwick

Synapses are shown in this diagram with (Fig 1) and without (Fig 2) MK2/3. Credit: University of Warwick




神経培養細胞が分泌するナノ顆粒のエクソソームを投与すると、アルツハイマー病の発症原因とされる脳内アミロイドベータ(Aβ)濃度が低下してアミロイド斑の蓄積も減ることを、北海道大学大学院先端生命科学研究院の湯山耕平特任助教と五十嵐靖之特任教授らがマウスの実験で突き止めた。エクソソームがアルツハイマー病の発症に関わっている可能性を示すもので、新しい予防や治療につながりうる成果として注目される。7月18日付の米科学誌The Journal of Biological Chemistryオンライン版に発表した。




Decreased Amyloid-β Pathologies by Intracerebral Loading of Glycosphingolipid-enriched Exosomes in Alzheimer Model Mice

Kohei Yuyama1,
Hui Sun1,
Shota Sakai1,
Susumu Mitsutake2,
Megumi Okada3,
Hidetoshi Tahara3,
Jun-ichi Furukawa1,
Naoki Fujitani1,
Yasuro Shinohara1 and
Yasuyuki Igarashi1*

Author Affiliations
1 Hokkaido University, Japan;
2 Saga University, Japan;
3 Hiroshima University, Japan
?* Corresponding author; email: yigarash@pharm.hokudai.ac.jp


Background: Exosome, a type of extracellular vesicles, can associate with Aβ in vitro.

Results: Intracerebrally injected exosomes trapped Aβ on surface glycosphingolipids and transported it into microglia in AD mouse brains, resulting in reductions in Aβ pathology.

Conclusion: Exogenous exosomes act as potent scavengers for Aβ in mouse brains.

Significance: The findings provide a novel therapeutic approach for AD.


Elevated levels of amyloid-β peptide (Aβ) in the human brain are linked to the pathogenesis of Alzheimer disease (AD). Recent in vitro studies have demonstrated that extracellular Aβ can bind to exosomes, which are cell-secreted nanovesicles with lipid membranes that are known to transport their cargos intercellulary. Such findings suggest that the exosomes are involved in Aβ metabolism in brain. Here, we found that neuroblastoma-derived exosomes exogenously injected into mouse brains trapped Aβ and with the associated Aβ were internalized into brain-resident phagocyte microglia. Accordingly, continuous intracerebral administration of the exosomes into amyloid-β precursor protein (APP) transgenic mice resulted in marked reductions in Aβ levels, amyloid depositions, and Aβ-mediated synaptotoxicity in the hippocampus. In addition, we determined that glycosphingolipids (GSLs), a group of membrane glycolipids, are highly abundant in the exosomes, and the enriched glycans of the GSLs are essential for Aβ binding and assembly on the exosomes, both in vitro and in vivo. Our data demonstrate that intracerebrally administered exosomes can act as potent scavengers for Aβ by carrying it on the exosome surface GSLs, and suggest a role of exosomes in Aβ clearance in the central nervous system. Improving Aβ clearance by exosome administration would provide a novel therapeutic intervention for AD.


Hints of epigenetic role in Alzheimer's disease

17 August 2014

Pioneering studies of post-mortem brain tissues have yielded the first evidence of a potential association between Alzheimer's disease and the epigenetic alteration of gene function. The researchers stress, however, that more research is needed to find out if the changes play a causal role in the disease or occur as a result of it.

We already have some evidence that the risk of developing Alzheimer's might be elevated by poor diet, lack of exercise, and inflammatory conditions such as diabetes, obesity and clogging of blood vessels with fatty deposits. The new research hints that the lifestyle changes that raise Alzheimer's risk may be taking effect through epigenetic changes.

The idea is strengthened by the fact that the brain tissue samples studied in the new work came from hundreds of people, many of whom had Alzheimer's when they died, and that a number of genes identified were found by two teams working independently, one in the UK and one in the US.

"The results are compelling and consistent across four cohorts of patients taken across the two studies," says Jonathan Mill at the University of Exeter, who led the UK-based team. "It's illuminated new genetic pathways affecting the disease and, given the lack of success tackling Alzheimer's so far, new leads are going to be vital."

"We can now focus our efforts on understanding how these genes are associated with the disease," says Philip De Jager of the Brigham and Women's Hospital in Boston, who headed the US team.

That might not be easy. Because the samples came from the brains of people who had died, the researchers cannot say yet whether the gene changes help cause the disease, or occur as a result of it. One Alzheimer's researcher not involved in the study even wonders whether the epigenetic changes are simply a natural part of ageing.

Screen test

Both teams screened DNA from the brain samples for chemical changes that switch genes off through methylation ? the addition of chemical methyl groups to DNA. These epigenetic changes don't alter the underlying sequence of DNA that someone has inherited, but they can change dramatically the pattern of genes that are expressed in a way that can encourage the development of cancers and mental disorders, for example.

De Jager's team looked at methylation patterns in samples from the prefrontal cortex of 708 people, about 60 per cent of whom had Alzheimer's when they died. The prefrontal cortex is vital for higher cognitive thinking and invariably damaged in people with Alzheimer's.

Mill's team screened tissue from the same region, and from two other brain areas that also suffer disproportionate damage in Alzheimer's: the entorhinal cortex and the temporal gyrus. As control tissue, Mill's team also screened tissue from the cerebellum ? which is usually not damaged by the disease ? and blood. They initially screened for methylation changes in samples from 122 people who had Alzheimer's when they died, then to validate the initial results they repeated the procedure in further post-mortem samples, taken from about 220 people who had also died with the condition.

The most dramatic methylation differences between tissue affected by Alzheimer's and control tissue samples, especially in the entorhinal cortex, were in a gene called ANK1, which has not previously been linked with Alzheimer's. That gene produces ankyrin 1, an essential ingredient of the outer membranes of cells that is vital for keeping cell structure intact.

"There's not been any evidence linking it to dementia previously," says Mill. "But genetic studies have linked it to type 2 diabetes, which, in turn, has links to dementia, so there could be some common pathway linking the two diseases," he says.

In all, De Jager's research highlighted 11 genes, while Mill's research identified seven ? four of which were also among De Jager's 11, including ANK1.

"This innovative research has discovered a potential new mechanism involved in Alzheimer's by linking the ANK1 gene to the disease," says Simon Ridley, Head of Research at Alzheimer's Research UK, which also provided funding for the study. "We will be interested to see further research into the role of ANK1 in Alzheimer's and whether other epigenetic changes may be involved in the disease," he says.

Cause or effect?

The key challenge now for both teams is to establish whether these epigenetic changes can accelerate the progression of the disease. That is important because some of the epigenetic effects were as pronounced in people who died with the disease as in those who had classic signs of the disease in their brains at death but had shown no symptoms of Alzheimer's.

This point drew criticism from some researchers, who said it reduced the case for causation. "Is it Alzheimer's or simply ageing causing these changes?" asks Ewan McNay of the State University of New York in Albany, who is exploring links between diabetes and Alzheimer's. "It's very preliminary work, and more is needed to further explore the associations."

Mill and De Jager say that the changes seen occur very early in the disease, and so at the very least they might be useful for predicting whether people are at raised risk of developing symptoms later on. De Jager also points out that methylation is a reversible process, so with the right drugs it might be possible to treat the epigenetic changes.

Journal references: Nature Neuroscience, DOI: 10.1038/nn.3782 (UK team) and DOI: 10.1038/nn.3786 (US team)

Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease
Katie Lunnon,
Rebecca Smith,
Eilis Hannon,
Philip L De Jager,
Gyan Srivastava,
Manuela Volta,
Claire Troakes,
Safa Al-Sarraj,
Joe Burrage,
Ruby Macdonald,
Daniel Condliffe,
Lorna W Harries,
Pavel Katsel,
Vahram Haroutunian,
Zachary Kaminsky,
Catharine Joachim,
John Powell,
Simon Lovestone,
David A Bennett,
Leonard C Schalkwyk
& Jonathan Mill
Corresponding author
Nature Neuroscience (2014) doi:10.1038/nn.3782 Received 26 April 2014 Accepted 07 July 2014 Published online 17 August 2014


Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and cognitive decline. We performed a cross-tissue analysis of methylomic variation in AD using samples from four independent human post-mortem brain cohorts. We identified a differentially methylated region in the ankyrin 1 (ANK1) gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as being substantially hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex), but not in the cerebellum, a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from three independent brain cohorts. This study represents, to the best of our knowledge, the first epigenome-wide association study of AD employing a sequential replication design across multiple tissues and highlights the power of this approach for identifying methylomic variation associated with complex disease.

Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci
Philip L De Jager,
Gyan Srivastava,
Katie Lunnon,
Jeremy Burgess,
Leonard C Schalkwyk,
Lei Yu,
Matthew L Eaton,
Brendan T Keenan,
Jason Ernst,
Cristin McCabe,
Anna Tang,
Towfique Raj,
Joseph Replogle,
Wendy Brodeur,
Stacey Gabriel,
High S Chai,
Curtis Younkin,
Steven G Younkin,
Fanggeng Zou,
Moshe Szyf,
Charles B Epstein,
Julie A Schneider,
Bradley E Bernstein,
Alex Meissner,
Nilufer Ertekin-Taner

Nature Neuroscience (2014) doi:10.1038/nn.3786 Received 05 May 2014 Accepted 16 July 2014 Published online 17 August 2014


We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.


July 20, 2014
Alzheimer's & Dementia Weekly

TDP-43 Amplifies Alzheimer's 10 Times


Beta-amyloid and tau proteins have long been considered the culprits behind Alzheimer's. Yet many people have plenty of amyloid and tau protein, but no Alzheimer's. Is TDP-43 the reason why?

Abnormal build-up of beta-amyloid and tau proteins are considered the primary indicators of Alzheimer's disease in the brain. Yet many people, like the ladies in the "Nun Study", seem to have "resilient cognition", and do quite well despite the fact that their brains are filled with these destructive proteins.

Researchers have been scratching their heads about this anomaly for years. TDP-43 may finally hold the answer.

3 Partners Behind Alzheimer's?
Amyloid “plaques” and tau “tangles” form and increase for years in the brains of people with the disease, usually well before symptoms such as memory loss become apparent.

Little is known about the role in memory loss and dementia of another protein, TAR DNA binding protein of 43kDa (TDP-43). TDP-43 is seen in ALS and frontotemporal dementia.

Keith Josephs, M.D. of the Mayo Clinic and colleagues conducted a study to determine whether TDP-43 has an effect, independent of amyloid and tau, on the course and symptoms of Alzheimer's. The results were reported at the Alzheimer's Association International Conference.

The researchers conducted post-mortem examinations on the brains of 342 people who were determined to have Alzheimer's disease based on the extent of tau tangles in the cortex. The subjects' brains were screened for the presence, amount, and distribution of TDP-43, and these findings were correlated with the results of tests of memory and cognition taken when the subjects were alive. The researchers also used MRI to assess atrophy in several brain regions.

After controlling for other factors including age at death, amyloid deposition, genetic risk for Alzheimer's, and vascular disease, the scientists concluded that the 195 study subjects with TDP-43 were 10 times more likely to have been cognitively impaired at death than subjects without TDP-43. They found that the “third protein” had strong correlations with cognition, memory loss, and shrinkage of the hippocampus, an area of the brain that is important to memory and is especially damaged in Alzheimer's.

The scientists speculate that absence of TDP-43 may help explain why some people have plaques and tangles in their brain, but do not experience dementia.

“These findings show that TDP-43 amplifies memory loss and hippocampal atrophy in Alzheimer's disease, and also appears to overpower what has been termed ‘resilient cognition' in Alzheimer's, where subjects remain cognitively normal in spite of high levels of Alzheimer's brain changes,” said Josephs. “This suggests that TDP-43 is a key player in the Alzheimer's neurodegenerative process, and should be considered a potential therapeutic target for treatment of the disease.”

S-nitrosylation of myocyte enhancer factor 2 (MEF2)

Researchers discover a “switch” in Alzheimer’s and stroke patient brains

15 hours 10 minutes ago

A new study by researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) has identified a chemical “switch” that controls both the generation of new neurons from neural stem cells and the survival of existing nerve cells in the brain.

The switch that shuts off the signals that promote neuron production and survival is in abundance in the brains of Alzheimer’s patients and stroke victims. The study, published July 3 in Cell Reports, suggests that chemical switch, MEF2, may be a potential therapeutic target to protect against neuronal loss in a variety of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and autism.

“We have shown that when nitric oxide (NO)?a highly reactive free radical?reacts with MEF2, MEF2 can no longer bind to and activate the genes that drive neurogenesis and neuronal survival,” said Stuart Lipton, M.D., Ph.D., director and professor in the Neuroscience and Aging Research Center at Sanford-Burnham, and a practicing clinical neurologist. “What’s unique here is that a single alteration to MEF2 controls two distinct events?the generation of new neurons and the survival of existing neurons,” added Lipton, who is senior author of the study.

In the brain, transcription factors are critical for linking external stimuli to protein production, enabling neurons to adapt to changing environments. Members of the MEF2 family of transcription factors have been shown to play an important role in neurogenesis and neuronal survival, as well as in the processes of learning and memory. And, mutations of the MEF2 gene have been associated with a range of neurodegenerative disorders, including Alzheimer’s and autism.

The process of NO-protein modifications?known as S-nitrosylation?was first described by Lipton and collaborators some 20 years ago. S-nitrosylation has important regulatory functions under normal physiological conditions throughout the body. However, with aging, environmental toxins, or stress-related injuries, abnormal S-nitrosylation reactions can occur, contributing to disease pathogenesis.

“Our laboratory had previously shown that S-nitrosylation of MEF2 controlled neuronal survival in Parkinson’s disease,” said Lipton. “Now we have shown that this same reaction is more ubiquitous, occurring in other neurological conditions such as stroke and Alzheimer’s disease. While the major gene targets of MEF2 may be different in various diseases and brain areas, the remarkable new finding here is that we may be able to treat each of these neurological disorders by preventing a common S-nitrosylation modification to MEF2.

“The findings suggest that the development of a small therapeutic molecule?one that can cross the blood-brain barrier and block S-nitrosylation of MEF2 or in some other way increase MEF2 transcriptional activity?could promote new brain cell growth and protect existing cells in several neurodegenerative disorders,” added Lipton.

“We have already found several such molecules in our high-throughput screening and drug discovery efforts, so the potential for developing new drugs to attack this pathway is very exciting,” said Lipton.

Sanford-Burnham Medical Research Institute.

S-Nitrosylation-Mediated Redox Transcriptional Switch Modulates Neurogenesis and Neuronal Cell Death

Cell Reports
DOI: http://dx.doi.org/10.1016/j.celrep.2014.06.005

Redox-mediated posttranslational modifications represent a molecular switch that controls major mechanisms of cell function. Nitric oxide (NO) can mediate redox reactions via S-nitrosylation, representing transfer of an NO group to a critical protein thiol. NO is known to modulate neurogenesis and neuronal survival in various brain regions in disparate neurodegenerative conditions. However, a unifying molecular mechanism linking these phenomena remains unknown. Here, we report that S-nitrosylation of myocyte enhancer factor 2 (MEF2) transcription factors acts as a redox switch to inhibit both neurogenesis and neuronal survival. Structure-based analysis reveals that MEF2 dimerization creates a pocket, facilitating S-nitrosylation at an evolutionally conserved cysteine residue in the DNA binding domain. S-Nitrosylation disrupts MEF2-DNA binding and transcriptional activity, leading to impaired neurogenesis and survival in vitro and in vivo. Our data define a molecular switch whereby redox-mediated posttranslational modification controls both neurogenesis and neurodegeneration via a single transcriptional signaling cascade.

lateral entorhinal cortex (LEC)

June 16, 2014
Alzheimer's & Dementia Weekly

Where Alzheimer's Begins

Columbia University researchers have pinpointed 3 discoveries about Alzheimer's:
?Where it starts
?Why it starts there
?How it spreads.
Learn why this can help researchers treat Alzheimer's sooner and better.

Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journal Nature Neuroscience.

"It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex," said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer's Disease Research Center. "But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The study also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads "functionally," that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's," said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.

In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.

"Dr. Richard Mayeux's WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer's disease," said Dr. Small. "This study has given us a unique opportunity to image and characterize patients with Alzheimer's in its earliest, preclinical stage."

The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer's disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) -- a measure of metabolic activity -- in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

To answer this question, explained first author Usman Khan, an MD-PhD student based in Dr. Small's lab, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.

The study has implications for both research and treatment. "Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions," said Dr. Small. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer's drugs during the disease's early stages.

The paper is titled, "Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease." The other contributors are Li Liu, Frank Provenzano, Diego Berman, Caterina Profaci, Richard Sloan and Richard Mayeux, all at CUMC.

The study was supported by grants from National Institutes of Health (AG034618, AG025161, AG07232, AG037212, NS074874, and HL094423.


Columbia University Medical Center, via Newswise.

Journal Reference:
1.Usman A Khan, Li Liu, Frank A Provenzano, Diego E Berman, Caterina P Profaci, Richard Sloan, Richard Mayeux, Karen E Duff, Scott A Small.
Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease
Nature Neuroscience, 2013; DOI: 10.1038/nn.3606


The entorhinal cortex has been implicated in the early stages of Alzheimer's disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer's disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.

overexpression of TDP-43

Molecular 'scaffold' could hold key to new dementia treatments

June 3, 2014 - 9:30am

Researchers at King's College London have discovered how a molecular 'scaffold' which allows key parts of cells to interact, comes apart in dementia and motor neuron disease, revealing a potential new target for drug discovery.

The study, published today in Nature Communications, was funded by the UK Medical Research Council, Wellcome Trust, Alzheimer's Research UK and the Motor Neurone Disease Association.

Researchers looked at two components of cells: mitochondria, the cell 'power houses' which produce energy for the cell; and the endoplasmic reticulum (ER) which makes proteins and stores calcium for signalling processes in the cell. ER and mitochondria form close associations and these interactions enable a number of important cell functions. However the mechanism by which ER and mitochondria become linked has not, until now, been fully understood.

Professor Chris Miller, from the Institute of Psychiatry at King's and lead author of the paper, says: "At the molecular level, many processes go wrong in dementia and motor neuron disease, and one of the puzzles we're faced with is whether there is a common pathway connecting these different processes. Our study suggests that the loosening of this 'scaffold' between the mitochondria and ER in the cell may be a key process in neurodegenerative diseases such as dementia or motor neuron disease."

By studying cells in a dish, the researchers discovered that an ER protein called VAPB binds to a mitochondrial protein called PTPIP51, to form a 'scaffold' enabling ER and mitochondria to form close associations. In fact, by increasing the levels of VAPB and PTPIP51, mitochondria and ER re-organised themselves to form tighter bonds.

Many of the cell's functions that are controlled by ER-mitochondria associations are disrupted in neurodegenerative diseases, so the researchers studied how the strength of this 'scaffold' was affected in these diseases. TPD-43 is a protein which is strongly linked to Amyotrophic Lateral Sclerosis (ALS, a form of motor neuron disease) and Fronto-Temporal Dementia (FTD, the second most common form of dementia), but exactly how the protein causes neurodegeneration is not properly understood.

The researchers studied how TPD-43 affected mouse cells in a dish. They found that higher levels of TPD-43 resulted in a loosening of the scaffold which reduced ER-mitochondria bonds, affecting some important cellular functions that are linked to ALS and FTD.

Professor Miller concludes: "Our findings are important in terms of advancing our understanding of basic biology, but may also provide a potential new target for developing new treatments for these devastating disorders."

Source: King's College London

ER-mitochondria associations are regulated by the VAPB?PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43

Radu Stoica,
Kurt J. De Vos,
S?bastien Paillusson,
Sarah Mueller,
Rosa M. Sancho,
Kwok-Fai Lau,
Gema Vizcay-Barrena,
Wen-Lang Lin,
Ya-Fei Xu,
Jada Lewis,
Dennis W. Dickson,
Leonard Petrucelli,
Jacqueline C. Mitchell,
Christopher E. Shaw
& Christopher C. J. Miller
Nature Communications 5, Article number: 3996 doi:10.1038/ncomms4996 Received 13 March 2014 Accepted 29 April 2014 Published 03 June 2014

Mitochondria and the endoplasmic reticulum (ER) form tight structural associations and these facilitate a number of cellular functions. However, the mechanisms by which regions of the ER become tethered to mitochondria are not properly known. Understanding these mechanisms is not just important for comprehending fundamental physiological processes but also for understanding pathogenic processes in some disease states. In particular, disruption to ER?mitochondria associations is linked to some neurodegenerative diseases. Here we show that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER?mitochondria associations. Moreover, we demonstrate that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER?mitochondria interactions and that this is associated with disruption to the VAPB?PTPIP51 interaction and cellular Ca2+ homeostasis. Finally, we show that overexpression of TDP-43 leads to activation of glycogen synthase kinase-3β (GSK-3β) and that GSK-3β regulates the VAPB?PTPIP51 interaction. Our results describe a new pathogenic mechanism for TDP-43.

cerebral small-vessel disease

Alzheimer's and Cerebral Small-Vessel Disease Interconnected
Megan Brooks

May 22, 2014
Medscape Medical

The pathology of cerebral small-vessel disease (SVD) and Alzheimer's disease (AD) appear to be interconnected, new research shows.

Cerebral SVD "could provoke amyloid pathology while AD-associated cerebral amyloid pathology may lead to auxiliary vascular damage," Maartje I. Kester, MD, PhD, from the VU University Medical Center, Amsterdam, the Netherlands, and colleagues say.

Their study was published online May 12 in JAMA Neurology.

Pathophysiologic Synergy

Prior studies have suggested that SVD and vascular risk factors raise the risk for AD, and signs of AD pathology have been seen in both SVD and vascular dementia (VaD). But it remains unclear whether and how associations between SVD and AD pathology lead to cognitive decline and dementia, the authors note in their article.

To investigate, they did a cross-sectional analysis of cerebrospinal fluid (CSF) and MRI data from 914 patients in the Amsterdam Dementia Cohort; 547 had AD, 30 had VaD, and 337 were control participants with subjective memory symptoms only.

The presence of microbleeds was associated with lower CSF levels of β-amyloid 1-42 (Aβ42) in patients with AD (P = .003) and patients with VaD (P = .01), and higher CSF tau in controls (P = .03).

The presence of white matter hyperintensities (WMHs) was associated with lower Aβ42 in control participants (P = .002) and patients with VaD (P = .02) but not in patients with AD.

Dr. Kester and colleagues say the association of microbleeds and WMHs with lower CSF levels of Aβ42 points to a "direct relationship between SVD and AD pathology."

"Amyloid pathology appears aggravated in patients with vascular damage, which supports pathophysiological synergy," they add. "In control participants, tau levels were elevated in the presence of MBs [microbleeds], which could indicate that this increase of tau is a result of neuronal cell death in patients not diagnosed as having AD."

They note that the effects on CSF Aβ42 levels were greatest in APOE ε4 carriers, indicating APOE ε4 genotype seems to upregulate the association between AD and vascular pathology.

Dr. Kester and colleagues think treatment trials for vascular risk factors should consider amyloid reduction, especially in APOE ε4 carriers. In addition, evaluation of the effects of amyloid-reducing therapies, such as immune-directed therapies, should be stratified for the presence of microbleeds and WMHs, they conclude.

WMHs Predict More Rapid Decline

In a related article published online May 12 in JAMA Neurology, researchers with the Alzheimer's Disease Neuroimaging Initiative report evidence that the severity of WMH predicts the likelihood that people with mild cognitive impairment (MCI) will have an aggressive clinical course.

In 322 adults with MCI, greater WMH at baseline was associated with an increased risk for aggressive decline (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.05 - 1.43; P = .01), they report.

APOE ε4 status (HR, 1.49; 95% CI, 1.09 - 2.05; P = .04) and diminished entorhinal cortex volume (ECV), a marker of AD-related neurodegeneration (HR, 0.66; 95% CI, 0.55 - 0.79; P < .001) at baseline also increased the risk for aggressive decline.

"Importantly, the 2 biological markers interact such that individuals with large ECV and a small amount of WMH burden appear to have synergistically diminished risk for decline. This latter finding suggests a mechanistic interaction between the 2 pathologic markers on clinical course," write Giuseppe Tosto, MD, from the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University, New York, New York, and colleagues.

Their findings contribute to a growing body of work that implicates small-vessel cerebrovascular disease in AD pathogenesis and clinical expression, they say.

"Furthermore, because many of the risk factors for WMH have been established and are modifiable through lifestyle or pharmacological intervention, our findings suggest avenues for prevention or treatment of rapid-progressing course among patients with MCI," they note.

A complete list of author disclosures and funding agencies can be found with the original articles.

JAMA Neurol. Published online May 12, 2014. Kester abstract Tosto abstract

Original Investigation | May 12, 2014

Associations Between Cerebral Small-Vessel Disease and Alzheimer Disease Pathology as Measured by Cerebrospinal Fluid Biomarkers


Maartje I. Kester, MD, PhD1; Jeroen D. C. Goos, MD, PhD1; Charlotte E. Teunissen, PhD2; Marije R. Benedictus, MSc1; Femke H. Bouwman, MD, PhD1; Mike P. Wattjes, MD, PhD3; Frederik Barkhof, MD, PhD3; Philip Scheltens, MD, PhD1; Wiesje M. van der Flier, PhD1,4

JAMA Neurol. Published online May 12, 2014. doi:10.1001/jamaneurol.2014.754


Importance It remains unclear if and how associations between cerebral small-vessel disease and Alzheimer disease (AD) pathology lead to cognitive decline and dementia.

Objective To determine associations between small-vessel disease and AD pathology.

Design, Setting, and Participants Cross-sectional study from January 2002 to December 2012 using the memory clinic?based Amsterdam Dementia Cohort. The study included 914 consecutive patients with available cerebrospinal fluid (CSF) and magnetic resonance imaging; 547 were patients diagnosed as having AD (54% female, mean [SD], 67 [8]; Mini-Mental State Examination score, mean [SD], 21 [5]), 30 were patients diagnosed as having vascular dementia (37% female, mean [SD], 76 [9]; Mini-Mental State Examination score, mean [SD], 24 [4]), and 337 were control participants with subjective memory complaints (42% female, mean [SD], 59 [59]; Mini-Mental State Examination score, mean [SD], 28 [2]). Linear regressions were performed with CSF biomarkers (log transformed) as dependent variables and magnetic resonance imaging measures (dichotomized) as independent, adjusted for sex, age, mediotemporal lobe atrophy, and diagnosis. An interaction term for diagnosis by magnetic resonance imaging measures was used for estimates per diagnostic group.

Main Outcomes and Measures We examined the associations of magnetic resonance imaging white matter hyperintensities (WMH), lacunes, microbleeds with CSF β-amyloid 42 (Aβ42), total tau, and tau phosphorylated at threonine 181 (P-tau181) as well as for a subset of apolipoprotein E (APOE) ε4 carriers and noncarriers.

Results Microbleed presence was associated with lower CSF Aβ42 in AD and vascular dementia (standardized beta?=??0.09, P?=?.003; standardized beta?=??0.30, P?=?.01), and higher CSF tau in controls (standardized beta?=?0.10, P?=?.03). There were no effects for P-tau181. The presence of WMH was associated with lower Aβ42 in control participants and patients with vascular dementia (standardized beta?=??0.18, P?=?.002; standardized beta?=??0.32, P?=?.02) but not in patients with AD. There were no effects for tau or P-tau181. The presence of lacunes was associated with higher Aβ42 in vascular dementia (standardized beta?=?0.17, P?=?.07) and lower tau in AD (standardized beta?=??0.07, P?=?.05) but there were no effects for Aβ42 or P-tau181. Stratification for apolipoprotein E genotype revealed that these effects were mostly attributable to ε4 carriers.

Conclusions and Relevance Deposition of amyloid appears aggravated in patients with cerebral small-vessel disease, especially in apolipoprotein E ε4 carriers, providing evidence for pathophysiological synergy between these 3 biological factors.

misfolded proteins

07:23 Saturday 17 May 2014

Cambridge University researchers 'excited' by double scientific breakthrough in Alzheimer's and Parkinson's treatments

Written by ADAM LUKE

Two scientific breakthroughs which could boost future treatment of diseases like Alzheimer’s and Parkinson’s have been announced by Cambridge researchers.

The pair of Cambridge University studies further our understanding of the early development of neurodegenerative disorders and how they might be prevented.

The conditions are known as protein ‘misfolding’ diseases because while proteins need to fold into a particular shape to carry out their assigned function in the body, they can misfold.

And in some cases these misfolded proteins then clump together into fibre-like threads, called amyloid fibrils, and can become toxic to other cells.

The first study found evidence that early spread of the protein associated with Parkinson’s happens quicker in mildly acidic conditions, suggesting sections of brain cells with acidic characteristic could provide the best targets for treatments.

Dr Tuomas Knowles, a St John’s College Fellow, said: “This tells us much more about the molecular mechanisms underlying protein aggregation in Parkinson’s and suggests that mildly acidic microenvironments within cells may enhance that process by several orders of magnitude.

“Not every sub-cellular compartment offers these conditions, so it takes us much closer to understanding how the disease might spread.”

The second study ? which also appears in the latest issues of Proceedings of the National Academy of Sciences of the USA ? identified how molecular ‘chaperones’, responsible for limiting the damage caused by the proteins when they misfold, can be strengthened.

The scientists found when a chaperone called a2-macroglobulin (a2M) came into contact with the oxidant hypochlorite ? found our immune systems ? its structure modified making it a much more dynamic defence which triggers the cell to break down potentially harmful proteins.

Dr Janet Kumita, from the Department of Chemistry, said: “Increasing its potency in this way is an exciting prospect. If we could find a way of developing a drug that introduces the same structural alterations, we would have a therapeutic intervention capable of increasing this protective activity in patients with Alzheimer’s Disease.”

Prof Chris Dobson, of the Department of Chemistry and Master of St John’s College, added: “These studies add very substantially to our detailed understanding of the molecular origins of neurodegenerative diseases, which are now becoming one of the greatest threats to healthcare in the modern world.”

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

Amy R. Wyatta,b,
Janet R. Kumitaa,
Richard W. Mifsuda,
Cherrie A. Goodenb,
Mark R. Wilsonb,1, and
Christopher M. Dobsona,1

Edited by Susan Lindquist, Whitehead Institute for Biomedical Research, Cambridge, MA, and approved March 27, 2014 (received for review February 24, 2014)


Hypochlorite, an oxidant generated in vivo by the innate immune system, kills invading pathogens largely by inducing the misfolding of microbial proteins. Concomitantly, the nonspecific activity of hypochlorite also damages host proteins, and the accumulation of damaged (misfolded) proteins is implicated in the pathology of a variety of debilitating human disorders (e.g., Alzheimer’s disease, atherosclerosis, and arthritis). It is well-known that cells respond to oxidative stress by up-regulating proteostasis machinery, but the direct activation of mammalian chaperones by hypochlorite has not, to our knowledge, been previously reported. In this study, we show that hypochlorite-induced modifications of human α2-macroglobulin (α2M) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric α2M is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified α2M involves the formation of stable soluble complexes with misfolded client proteins, including heat-denatured enzymes, oxidized fibrinogen, oxidized LDL, and native or oxidized amyloid β-peptide (Aβ1?42). Here, we show that hypochlorite-modified α2M delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces Aβ1?42 neurotoxicity. Our results support the conclusion that α2M is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity.

exaggerated Ca2+ signaling

Role of calcium in familial Alzheimer's disease clarified, pointing to new therapeutics

Published: Wednesday, May 14, 2014 - 05:44 in Health & Medicine

In 2008 researchers at the Perelman School of Medicine at the University of Pennsylvania showed that mutations in two proteins associated with familial Alzheimer's disease (FAD) disrupt the flow of calcium ions within neurons. The two proteins interact with a calcium release channel in an intracellular compartment. Mutant forms of these proteins that cause FAD, but not the normal proteins, result in exaggerated calcium signaling in the cell. Now, the same team, led by J. Kevin Foskett, PhD, chair of Physiology, and a graduate student, Dustin Shilling, has found that suppressing the hyperactivity of the calcium channels alleviated FAD-like symptoms in mice models of the disease. Their findings appear this week in the Journal of Neuroscience.

Current therapies for Alzheimer's include drugs that treat the symptoms of cognitive loss and dementia, and drugs that address the pathology of Alzheimer's are experimental. These new observations suggest that approaches based on modulating calcium signaling could be explored, says Foskett.

The two proteins, called PS1 and PS2 (presenilin 1 and 2), interact with a calcium release channel, the inositol trisphosphate receptor (IP3R), in the endoplasmic reticulum. Mutant PS1 and PS2 increase the activity of the IP3R, in turn increasing calcium levels in the cell. "We set out to answer the question: Is increased calcium signaling, as a result of the presenilin-IP3R interaction, involved in the development of familial Alzheimer's disease symptoms, including dementia and cognitive deficits?" says Foskett. "And looking at the findings of these experiments, the answer is a resounding 'yes.'"

Robust Phenomenon

Exaggerated intracellular calcium signaling is a robust phenomenon seen in cells expressing FAD-causing mutant presenilins, in both human cells in culture and in mice. The team used two FAD mouse models to look for these connections. Specifically, they found that reducing the expression of IP3R1, the dominant form of this receptor in the brain, by 50 percent, normalized the exaggerated calcium signaling observed in neurons of the cortex and hippocampus in both mouse models.

In addition, using 3xTg mice -- animals that contain presenilin 1 with an FAD mutation, as well as expressed mutant human tau protein and APP genes -- the team observed that the reduced expression of IP3R1 profoundly decreased amyloid plaque accumulation in brain tissue and the hyperphosphorylation of tau protein, a biochemical hallmark of advanced Alzheimer's disease. Reduced expression of IP3R1 also rescued defective electrical signaling in the hippocampus, as well and memory deficits in the 3xTg mice, as measured by behavioral tests.

"Our results indicate that exaggerated calcium signaling, which is associated with presenilin mutations in familial Alzheimer's disease, is mediated by the IP3R and contributes to disease symptoms in animals," says Foskett. "Knowing this now, the IP3 signaling pathway could be considered a potential therapeutic target for patients harboring mutations in presenilins linked to AD."

The 'calcium dysregulation' hypothesis

"The 'calcium dysregulation' hypothesis for inherited, early-onset familial Alzheimer's disease has been suggested by previous research findings in the Foskett lab. Alzheimer's disease affects as many as 5 million Americans, 5 percent of whom have the familial form. The hallmark of the disease is the accumulation of tangles and plaques of amyloid beta protein in the brain.

"The 'amyloid hypothesis' that postulates that the primary defect is an accumulation of toxic amyloid in the brain has long been used to explain the cause of Alzheimer's," says Foskett. In his lab's 2008 Neuron study, cells that carried the disease-causing mutated form of PS1 showed increased processing of amyloid beta that depended on the interaction of the PS proteins with the IP3R. This observation links dysregulation of calcium inside cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer's disease.

Clinical trials for AD have largely been directed at reducing the amyloid burden in the brain. So far, says Foskett, these trials have failed to demonstrate therapeutic benefits. One idea is that the interventions started too late in the disease process. Accordingly, anti-amyloid clinical trials are now underway using asymptomatic FAD patients because it is known that they will eventually develop the disease, whereas predicting who will develop the common form of AD is much less certain.

"There has been an assumption that FAD is simply AD with an earlier, more aggressive onset," says Foskett. "However, we don't know if the etiology of FAD pathology is the same as that for common AD. So the relevance of our findings for understanding common AD is not clear. What's important, in my opinion, is to recognize that AD could be a spectrum of diseases that result in common end-stage pathologies. FAD might therefore be considered an orphan-disease, and it's important to find effective treatments, specifically for these patients -- ones that target the IP3R and calcium signaling."

Source: University of Pennsylvania School of Medicine

The Journal of Neuroscience, 14 May 2014, 34(20): 6910-6923; doi: 10.1523/JNEUROSCI.5441-13.2014

Suppression of InsP3 Receptor-Mediated Ca2+ Signaling Alleviates Mutant Presenilin-Linked Familial Alzheimer's Disease Pathogenesis


Exaggerated intracellular Ca2+ signaling is a robust proximal phenotype observed in cells expressing familial Alzheimer's disease (FAD)-causing mutant presenilins (PSs). The mechanisms that underlie this phenotype are controversial and their in vivo relevance for AD pathogenesis is unknown. Here, we used a genetic approach to identify the mechanisms involved and to evaluate their role in the etiology of AD in two FAD mouse models. Genetic reduction of the type 1 inositol trisphosphate receptor (InsP3R1) by 50% normalized exaggerated Ca2+ signaling observed in cortical and hippocampal neurons in both animal models. In PS1M146V knock-in mice, reduced InsP3R1 expression restored normal ryanodine receptor and cAMP response element-binding protein (CREB)-dependent gene expression and rescued aberrant hippocampal long-term potentiation (LTP). In 3xTg mice, reduced InsP3R1 expression profoundly attenuated amyloid β accumulation and tau hyperphosphorylation and rescued hippocampal LTP and memory deficits. These results indicate that exaggerated Ca2+ signaling, which is associated with FAD PS, is mediated by InsP3R and contributes to disease pathogenesis in vivo. Targeting the InsP3 signaling pathway could be considered a potential therapeutic strategy for patients harboring mutations in PS linked to AD.

Amyloid precursor protein

Researchers uncover novel function of Amyloid Precursor Protein linked to Alzheimer's disease

April 22, 2014

A research team led by the National Neuroscience Institute (NNI) has uncovered a novel function of the Amyloid Precursor Protein (APP), one of the main pathogenic culprits of Alzheimer's disease. This discovery may help researchers understand how the protein goes awry in the brains of Alzheimer's disease patients, and potentially paves the way for the development of innovative therapeutics to improve the brain function of dementia patients.

The findings were published in the prestigious scientific research journal Nature Communications last month. The study, which is led by Dr Zeng Li and her team from NNI, involved investigators from Duke-NUS Graduate Medical School and the Agency for Science and Technology (A*STAR).

Alzheimer's disease is the most common form of dementia, which is set to rise significantly from the current 28,000 cases to 80,000 cases in 2030 among Singaporeans aged 60 and above. With a rapidly aging population, the burden of the disease will be profound affecting not just the person afflicted, but also the caregiver and family. While the exact cause of Alzheimer's disease remains unknown, one of its pathological hallmarks is clear - the clumping of APP product in the brain when the protein is abnormally processed.

Finding out more about APP can help researchers gain a better understanding of the disease, and potentially identify biomarkers and therapeutic targets for it. However up till this point, little was known about the APP's primary function in the brain.

The discovery - APP controls growth and maturation of brain cells

During this study, Dr Zeng and her team discovered that APP can control the growth and maturation of newborn brain cells, which are critical for the maintenance of a healthy brain function. APP does this by regulating a target known as microRNA-574-5-p. MicroRNAs are small molecules that influence the expression of human genes. The human body has many microRNAs to regulate the expression of different genes for proper cellular functions.

This study identified that microRNA-574-5p normally promotes the production of newborn neurons in the brain. In turn, the APP antagonises it to ensure the timely birth of new neurons to support normal brain function. In other words, the APP controls the growth and maturation of brain cells, without which neuron expression can go unregulated and cause brain activities to go haywire.

"Our findings highlight that microRNA-574-5p may be a potentially useful new target for drug development against Alzheimer's disease," said Dr Zeng Li, the principal investigator of the study. "We are just starting to understand how misregulated microRNA-574-5p expression can cause our brain activities to go wrong, and much more work needs to be done."

With this discovery, the research team intends to further their research by investigating the mechanisms of how the APP regulates microRNA-574-5p in association with the impairment of newborn neurons as seen in Alzheimer's disease. Eventually, they hope to develop the microRNA into a biomarker for the disease. And it does not just stop there - the finding also boosts the team's work on other neurodevelopmental conditions and brain disorders.

"Brain-specific microRNAs control neurogenesis during brain development, and their misregulation is implicated in other devastating psychiatric disorders like autism and schizophrenia," said Assistant Professor Shawn Je from Duke-NUS, a collaborator for this study. "So, this discovery also sheds light on ongoing collaboration work between our team and Dr Zeng's group to elucidate genetic and cellular mechanisms of autism."

Professor Stephen Cohen from A*STAR's Institute of Molecular and Cellular Biology, a world expert on microRNA biology, affirmed this discovery. He said, "This important study suggests a link between a key neurodegenerative disease gene and regulation of microRNAs in the brain. We are at an early stage of understanding how this microRNA might impact disease progression and associated behavior, but the prospects are exciting."

Source: SingHealth

Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex

Nature Communications 5, Article number: 3330 doi:10.1038/ncomms4330 Received 19 September 2013 Accepted 27 January 2014 Published 03 March 2014

Wei Zhang,
Selvaratnam Thevapriya,
Paul J. Kim,
Wei-Ping Yu,
H. Shawn Je,
Eng King Tan
& Li Zeng

Amyloid precursor protein (APP) is a transmembrane glycoprotein proteolytically processed to release amyloid beta, a pathological hallmark of Alzheimer’s disease. APP is expressed throughout the developing and mature brain; however, the primary function of this protein is unknown. We previously demonstrated that APP deficiency enhances neurogenesis, but the mechanisms underlying this process are not known. Here we show that APP regulates the expression of microRNAs in the cortex and in neural progenitors, specifically repressing miR-574-5p. We also show that overexpression of miR-574-5p promotes neurogenesis, but reduces the neural progenitor pool. In contrast, the reduced expression of miR-574-5p inhibits neurogenesis and stimulates proliferation in vitro and in utero. We further demonstrate that the inhibition of miR-574-5p in APP-knockout mice rescues the phenotypes associated with APP deficiency in neurogenesis. Taken together, these results reveal a mechanism in which APP regulates the neurogenesis through miRNA-mediated post-transcriptional regulation.


April 20, 2014

'Chaperone' compounds offer new approach to Alzheimer's treatment

Researchers have identified a new class of compounds -- pharmacologic chaperones -- that can stabilize the retromer protein complex (the blue and orange structure shows part of the complex). Retromer plays a vital role in keeping amyloid …more

A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer's disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer's.

Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.

"Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology," said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer's Disease Research Center in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC, and a senior author of the paper. "This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins."

In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer's disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer's-like symptoms. Retromer abnormalities have also been observed in Parkinson's disease.

In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer's Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. "The idea that it would be beneficial to protect a protein's structure is one that nature figured out a long time ago," said Dr. Petsko. "We're just learning how to do that pharmacologically."

Other researchers had already determined retromer's three-dimensional structure. "Our challenge was to find small molecules?or pharmacologic chaperones?that could bind to retromer's weak point and stabilize the whole protein complex," said Dr. Ringe.

This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.

The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. "One concern was that this compound would be toxic," said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. "But R55 was found to be relatively non-toxic in mouse neurons in cell culture."

More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer's. The researchers are currently testing the clinical effects of R55 in the actual mouse model .

"The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones," said Dr. Petsko. "While we're testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective."

Explore further: Faulty internal recycling by brain's trash collectors may contribute to Alzheimer's

More information: "Pharmacological chaperones stabilize retromer to limit APP processing," Nature Chemical Biology, 2014. DOI: 10.1038/nchembio.1508

Journal reference: Nature Chemical Biology search and more info website

Provided by Columbia University Medical Center search and more info website

Pharmacological chaperones stabilize retromer to limit APP processing

Vincent J Mecozzi,
Diego E Berman,
Sabrina Simoes,
Chris Vetanovetz,
Mehraj R Awal,
Vivek M Patel,
Remy T Schneider,
Gregory A Petsko,
Dagmar Ringe
& Scott A Small

Nature Chemical Biology (2014) doi:10.1038/nchembio.1508 Received 06 March 2013 Accepted 21 March 2014 Published online 20 April 2014

Retromer is a multiprotein complex that trafficks cargo out of endosomes. The neuronal retromer traffics the amyloid-precursor protein (APP) away from endosomes, a site where APP is cleaved into pathogenic fragments in Alzheimer's disease. Here we determined whether pharmacological chaperones can enhance retromer stability and function. First, we relied on the crystal structures of retromer proteins to help identify the 'weak link' of the complex and to complete an in silico screen of small molecules predicted to enhance retromer stability. Among the hits, an in vitro assay identified one molecule that stabilized retromer against thermal denaturation. Second, we turned to cultured hippocampal neurons, showing that this small molecule increases the levels of retromer proteins, shifts APP away from the endosome, and decreases the pathogenic processing of APP. These findings show that pharmacological chaperones can enhance the function of a multiprotein complex and may have potential therapeutic implications for neurodegenerative diseases.

co-aggregation of ferric iron

March 26, 2014

'Big Science' uncovers another piece in the Alzheimer's puzzle

In a paper published today, British scientists have found evidence that biological material contributing to lesions in the brain, characteristic in Alzheimer's patients, may also cause the build-up of brain-cell-damaging toxic iron. Scientists have made the discovery using advanced imaging techniques at giant X-ray facilities - the Diamond Light Source synchrotron in Oxfordshire and other synchrotrons in Switzerland and the US.

Iron occurs naturally in the human body, including the brain. The conversion of this iron between two chemical forms is essential for normal function. However, one of these forms of iron, known as ferrous iron, can be highly toxic if it is overproduced or builds up in tissues where it can't be processed and removed properly. Scientists have known for some time that this toxic iron builds up in the same location as the brain lesions caused by Alzheimer's disease.

Researchers have been studying the protein fragment that makes up the Alzheimer's lesions, a peptide known as beta-amyloid, to try to understand how and why the build-up of toxic iron is occurring; and whether it's a cause or a symptom of the brain cell damage in Alzheimer's patients.

At the UK's national synchrotron, Diamond Light Source, beams of light 10 billion times brighter than the sun, were used to shine a light on the problem, to study the chemical and magnetic makeup of the iron after it had interacted with the beta-amyloid peptide. By using these techniques along with electron microscopy they witnessed predominant biological form of iron changing into the more toxic ferrous form. As well as Diamond Light Source, studies were also carried out at the Swiss Light Source and the Advanced Light Source in the USA, using applied advanced x-ray techniques, more commonly used to study the latest hi-tech materials.

The experiments revealed that the peptide that makes up Alzheimer's lesions is capable of converting iron into the form which could be causing damage to brain cells. This means that the lesions caused by Alzheimer's could be causing a subtle disruption in how the brain manages iron, confronting brain cells with a level of toxicity that they simply cannot manage.

This discovery paves the way for future medical research into treatments that could halt or manage the conversion of iron into this toxic form, potentially slowing or limiting the damage to the brain. It could also lead to developments in using magnetic resonance imaging (MRI) to detect early stages of the disease by mapping altered patterns of iron in the brain.

Dr Neil Telling from the University of Keele, who lead the research in collaboration with colleagues at the University of Warwick and the University of Florida, commented: "Alzheimer's is a sensitive and emotive area of research. The disease involves progressive brain cell failure, the reasons for which are still not fully understood. When findings showed increased levels of toxic iron within Alzheimer's disease tissues, we realised that techniques we had used to study other iron based materials could be applied to understand where this toxic iron came from. Our observations suggest an origin for the toxic iron; that it may well be made toxic by the lesions themselves. This could open up new avenues of research into treatments to stop the build-up of this neurotoxic substance, potentially limiting the damage done by Alzheimer's. Understanding how this toxic iron forms could also tell us where to look for early stages of the disease in MRI scans, perhaps even before irreversible brain damage occurs. It's at an early stage but these promising results seem to be another piece of the jigsaw to fully understand Alzheimer's."

Dr Doug Brown, Director of Research and Development at Alzheimer's Society, commented: "Clumps of amyloid beta are a hallmark of Alzheimer's disease although why they accumulate in this way or cause brain cells to die is still being understood. This study suggests that the protein may cause iron to turn into its toxic form, leading to damage to brain cells. Why this might happen and how it can be stopped are important future avenues for research.

"There will be a million people with dementia in the UK by 2021 yet we still don't know what causes the condition and there are only limited treatments available. We desperately need more research aimed at unravelling the underlying causes of dementia to help us in our quest to find better treatments and ultimately a cure."

Andrew Harrison, CEO of Diamond Light Source, commented: "It is always wonderful to see a piece of research come out of Diamond Light Source which has the potential to have a positive impact on people's lives. Research done at Diamond is leading step changes in our understanding of diseases like this, and supporting technological innovation and new drug designs for a range of different diseases. We put an enormous amount of work into maintaining Diamond as a centre of cutting edge research and making our light source available to 3,000 scientists every year; these groups rely on our advanced facilities to further their research and make crucial steps forward."

Explore further: Study suggests iron is at core of Alzheimer's disease

More information: The full research paper "Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide β-amyloid (1-42)" was published in Journal of the Royal Society Interface on Wednesday, 26th March 2014 DOI: 10.1098/rsif.2014.0165.

A related paper was published recently online by the same research team in the journal ACS Inorganic Chemistry entitled "Evidence of Redox-Active Iron Formation Following Aggregation of Ferrihydrite and the Alzheimer's Disease Peptide β?Amyloid" DOI: 10.1021/ic402406g.

Journal reference: Journal of the Royal Society Interface search and more info website Inorganic Chemistry search and more info website

Diamond Light Source search and more info website

Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide β-amyloid (1-42)

J. Everett1,
E. C?spedes1,
L. R. Shelford2,
C. Exley3,
J. F. Collingwood4,
J. Dobson5,6,
G. van der Laan7,
C. A. Jenkins8,
E. Arenholz8 and
N. D. Telling1?

Author Affiliations
1Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, Staffordshire ST4 7QB, UK
2College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter EX4 4QL, UK
3The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire ST5 5BG, UK
4School of Engineering, University of Warwick, Coventry CV4 7AL, UK
5J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
6Department of Materials Science and Engineering, University of Florida, Gainesville, FL 32611, USA
7Magnetic Spectroscopy Group, Diamond Light Source, Didcot, Oxfordshire OX11 ODE, UK
8Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
e-mail: n.d.telling@keele.ac.uk


For decades, a link between increased levels of iron and areas of Alzheimer's disease (AD) pathology has been recognized, including AD lesions comprised of the peptide β-amyloid (Aβ). Despite many observations of this association, the relationship between Aβ and iron is poorly understood. Using X-ray microspectroscopy, X-ray absorption spectroscopy, electron microscopy and spectrophotometric iron(II) quantification techniques, we examine the interaction between Aβ(1?42) and synthetic iron(III), reminiscent of ferric iron stores in the brain. We report Aβ to be capable of accumulating iron(III) within amyloid aggregates, with this process resulting in Aβ-mediated reduction of iron(III) to a redox-active iron(II) phase. Additionally, we show that the presence of aluminium increases the reductive capacity of Aβ, enabling the redox cycling of the iron. These results demonstrate the ability of Aβ to accumulate iron, offering an explanation for previously observed local increases in iron concentration associated with AD lesions. Furthermore, the ability of iron to form redox-active iron phases from ferric precursors provides an origin both for the redox-active iron previously witnessed in AD tissue, and the increased levels of oxidative stress characteristic of AD. These interactions between Aβ and iron deliver valuable insights into the process of AD progression, which may ultimately provide targets for disease therapies.


REST and stress resistance in ageing and Alzheimer’s disease

Nature (2014) doi:10.1038/nature13163 Received 27 June 2013 Accepted 21 February 2014 Published online 19 March 2014


Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer’s disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer’s disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer’s disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

New Clues to Alzheimer’s

MARCH 24, 2014

Two studies of Alzheimer’s disease published in respected scientific journals this month offered glimmers of hope for progress against this devastating neurological disorder. Neither advance is guaranteed to produce important clinical benefits anytime soon, but they may point the way toward new pathways to treat and diagnose a condition that impairs the thinking and memories of its victims and ultimately kills many of them.

One promising study, led by researchers at Harvard Medical School, was published online Wednesday in the journal Nature. It identified a protein that typically increases in old age and appears to protect brain cells from dying. In patients who develop Alzheimer’s, the protein, called REST, is in short supply and out of position. In patients who have yet to suffer cognitive losses, the protective protein is still present and in the right spot (the nucleus of a neuron) to be effective even if those patients have the brain tangles and plaques long associated with Alzheimer’s.

Further research is clearly needed, but if the importance of REST is confirmed, the hope is that drugs can be found that will boost its functioning in the brain without causing other harm in the brain’s complicated circuitry.

The other promising study, led by researchers at Georgetown University Medical Center, was published online in Nature Medicine on March 9. The scientists developed a test that looks for 10 substances in the blood that they believe can predict with greater than 90 percent accuracy whether a healthy older adult will develop mild cognitive impairment or Alzheimer’s disease within three years.

It was a small study whose clinical value needs further validation. But if an accurate blood test can make it easier to identify at-risk patients, the hope is that science will also be able to offer them effective treatment.

A version of this editorial appears in print on March 25, 2014, in The International New York Times. Order Reprints|Today's Paper|Subscribe

Golgi fragmentation

March 17, 2014

Scientists slow development of Alzheimer's trademark cell-killing plaques

University of Michigan researchers have learned how to fix a cellular structure called the Golgi that mysteriously becomes fragmented in all Alzheimer's patients and appears to be a major cause of the disease.

They say that understanding this mechanism helps decode amyloid plaque formation in the brains of Alzheimer's patients?plaques that kills cells and contributes to memory loss and other Alzheimer's symptoms.

The researchers discovered the molecular process behind Golgi fragmentation, and also developed two techniques to 'rescue' the Golgi structure.

"We plan to use this as a strategy to delay the disease development," said Yanzhuang Wang, U-M associate professor of molecular, cellular and developmental biology. "We have a better understanding of why plaque forms fast in Alzheimer's and found a way to slow down plaque formation."

The paper appears in an upcoming edition of the Proceedings of the National Academy of Sciences. Gunjan Joshi, a research fellow in Wang's lab, is the lead author.

Wang said scientists have long recognized that the Golgi becomes fragmented in the neurons of Alzheimer's patients, but until now they didn't know how or why this fragmentation occurred.

The Golgi structure has the important role of sending molecules to the right places in order to make functional cells, Wang said. The Golgi is analogous to a post office of the cell, and when the Golgi becomes fragmented, it's like a post office gone haywire, sending packages to the wrong places or not sending them at all.

U-M researchers found that the accumulation of the Abeta peptide?the primary culprit in forming plaques that kill cells in Alzheimer's brains?triggers Golgi fragmentation by activating an enzyme called cdk5 that modifies Golgi structural proteins such as GRASP65.

Wang and colleagues rescued the Golgi structure in two ways: they either inhibited cdk5 or expressed a mutant of GRASP65 that cannot be modified by cdk5. Both rescue measures decreased the harmful Abeta secretion by about 80 percent.

The next step is to see if Golgi fragmentation can be delayed or reversed in mice, Wang said. This involves a collaboration with the Michigan Alzheimer's Disease Center at the U-M Health System, directed by Dr. Henry Paulson, professor of neurology, and Geoffrey Murphy, assistant professor of physiology and research professor at the U-M Molecular and Behavioral Neuroscience Institute.

The collaboration was made possible by MCubed, a two-year seed funding program to fuel interdisciplinary teams of U-M faculty to pursue research with major societal impact.

Provided by University of Michigan search and more info website

Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production

Gunjan Joshi,
Youjian Chi,
Zheping Huang, and
Yanzhuang Wang1

Edited by Graham B. Warren, Max F. Perutz Laboratories, Vienna, Austria and accepted by the Editorial Board February 24, 2014 (received for review October 25, 2013)


In Alzheimer’s disease (AD), formation of the Aβ aggregates occurs by the cleavage of the amyloid precursor protein (APP) during its trafficking inside the nerve cells. The Golgi apparatus plays a critical role in APP trafficking; fragmentation of the normally highly ordered Golgi structure occurs in nerve cells of AD patients. Here we report that Aβ accumulation triggers Golgi fragmentation by activating cyclin-dependent kinase-5 (cdk5), which phosphorylates Golgi structural proteins such as GRASP65. Rescue of Golgi structure by inhibiting cdk5 or by expressing nonphosphorylatable GRASP65 mutants reduced Aβ secretion. Our study provides a molecular mechanism for Golgi fragmentation and its effects on APP trafficking and processing, suggesting Golgi as a potential drug target for AD treatment.


Golgi fragmentation occurs in neurons of patients with Alzheimer’s disease (AD), but the underlying molecular mechanism causing the defects and the subsequent effects on disease development remain unknown. In this study, we examined the Golgi structure in APPswe/PS1?E9 transgenic mouse and tissue culture models. Our results show that accumulation of amyloid beta peptides (Aβ) leads to Golgi fragmentation. Further biochemistry and cell biology studies revealed that Golgi fragmentation in AD is caused by phosphorylation of Golgi structural proteins, such as GRASP65, which is induced by Aβ-triggered cyclin-dependent kinase-5 activation. Significantly, both inhibition of cyclin-dependent kinase-5 and expression of nonphosphorylatable GRASP65 mutants rescued the Golgi structure and reduced Aβ secretion by elevating α-cleavage of the amyloid precursor protein. Our study demonstrates a molecular mechanism for Golgi fragmentation and its effects on amyloid precursor protein trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment.

Microscopic images after the researchers restored the Golgi structure (red). Credit: Yanzhuang Wang

Microscope images of the Golgi structure (red) when fragmented under disease conditions. Credit: Yanzhuang Wang

loss of SORLA’s Aβ sorting function

Sci Transl Med 12 February 2014:
Vol. 6, Issue 223, p. 223ra20
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3007747
Research Article

Lysosomal Sorting of Amyloid-β by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation

Safak Caglayan1,
Shizuka Takagi-Niidome2,
Fan Liao3,4,
Anne-Sophie Carlo1,
Vanessa Schmidt1,
Tilman Burgert1,
Yu Kitago2,
Ernst-Martin F?chtbauer5,
Annette F?chtbauer5,
David M. Holtzman3,4,
Junichi Takagi2,* and
Thomas E. Willnow1,*

Author Affiliations
1Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
2Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
3Department of Neurology, Washington University, St. Louis, MO 63110, USA.
4Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.
5Department of Molecular Biology, Aarhus University, 8000 Aarhus, Denmark.
?*Corresponding author. E-mail: willnow@mdc-berlin.de (T.E.W.); takagi@protein.osaka-u.ac.jp (J.T.)


SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer’s disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-β (Aβ) in mouse models and AD patients, suggesting that increasing expression of this receptor could be a therapeutic option for decreasing the amount of amyloidogenic products in affected individuals. We characterize a new mouse model in which SORLA is overexpressed, and show a decrease in Aβ concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent Aβ peptides. Aβ binds to the amino-terminal VPS10P domain of SORLA, and this binding is impaired by a familial AD mutation in SORL1. Thus, loss of SORLA’s Aβ sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development.
Copyright ? 2014, American Association for the Advancement of Science

lateral entorhinal cortex dysfunction

Scientists discover Alzheimer's origin

7:00 AM Tuesday Dec 24, 2013
    New Zealand Herald

Scientists have pinpointed a specific part of the brain where Alzheimer's begins and traced how the disease spreads.

High-resolution brain scans of 96 healthy adults over the age of 65 revealed the first footprint of Alzheimer's in a dozen individuals who went on to develop symptoms.

Reduced metabolic activity was seen in the lateral entorhinal cortex (LEC), a small region linked to the hippocampus where long-term memories are stored.

The change, associated with declining memory, occurred at a time when all 12 volunteers were free of dementia and was not seen in the 84 participants who did not develop Alzheimer's.

The study also showed how the effects of Alzheimer's spread from the LEC to other areas of the brain's cerebral cortex.

One region especially affected was the parietal cortex, which is involved in functions including spatial orientation and navigation.

Professor Scott Small, director of the Alzheimer's Disease Research Center at Columbia University in New York, said: "It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex. But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC.

"The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected."

The scientists suspect that Alzheimer's spreads by a domino effect: neurons are compromised in the LEC, which in turn reduces the integrity of their neighbours.

Two of the hallmarks of Alzheimer's disease are sticky protein deposits in the brain called beta amyloid plaques, and "tangles" of tau protein.

A first step to accumulating beta amyloid is the production of amyloid precursor protein (APP).

Professor Karen Duff, also of Columbia University and co-author of the report, said: "The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitises the LEC to the accumulation of APP.

"Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's."

Prof Small said: "Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable ... we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions."

Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease

Usman A Khan,
Li Liu,
Frank A Provenzano,
Diego E Berman,
Caterina P Profaci,
Richard Sloan,
Richard Mayeux,
Karen E Duff
& Scott A Small

Nature Neuroscience (2013) doi:10.1038/nn.3606
Published online 22 December 2013

The entorhinal cortex has been implicated in the early stages of Alzheimer's disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer's disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.

jugular venous reflux

Pilot Study Links Alzheimer’s with Vascular Changes in Neck

Published December 5, 2013
School of Medicine and Biomedical Sciences
? 2013 University at Buffalo

Dementia and Alzheimer’s disease may be related to a vascular abnormality in the internal jugular veins, according to a revealing pilot study by an international research team, including University at Buffalo scientists.

The researchers believe their study is the first to associate jugular venous reflux (JVR) ? a hemodynamic abnormality in these veins ? with a higher frequency of white matter changes in the brain, says senior author Robert Zivadinov, MD, PhD, professor of neurology.

Using Doppler ultrasound and magnetic resonance imaging, the researchers assessed 12 patients with Alzheimer’s disease, 24 with mild cognitive impairment and 17 elderly controls.

White Matter Changes Signal Dementia, Alzheimer’s

Although results must be validated through larger studies, this research could potentially lead to a better understanding of Alzheimer’s and other aging-related neurological disorders.

Age-related white matter changes have long been associated with dementia and faster cognitive decline, and Alzheimer’s patients have more white matter lesions than healthy people, Zivadinov explains.

If validated, the observed JVR-white matter association “also could be significant for the development of new diagnostic tools and treatments for pathological white matter lesions,” notes first author Ching-Ping Chung, assistant professor of neurology at National Yang-Ming University in Taiwan.

JVR May Be Linked to Dirty-Appearing White Matter

Another finding suggests that JVR is associated with dirty-appearing white matter, which is thought to represent early-stage lesion formation.

The researchers believe this is one of the first studies to explore the impact of dirty-appearing white matter in the elderly, says second author Clive Beggs, professor of medical engineering at the University of Bradford in the United Kingdom, adding that the significance of this research requires additional study.

Path to Damaged Brains: Cerebral Venous Drainage

White matter changes have a direct relationship to the buildup of amyloid plaque, long seen as central to the development of Alzheimer’s disease.

“The accumulation of amyloid plaque may result from the inability of cerebrospinal fluid to be properly cleared from the brain,” says Beggs.

JVR, which is more common in the elderly, may be the culprit leading to impaired cerebral venous drainage.

The process begins as the internal jugular vein valves do not open and close properly, causing the pressure gradient to reverse the direction of blood flow in the veins, in turn causing blood to leak backwards into the brain.

Venous System Changes Accumulate Over Time

JVR’s accumulated effects on cerebral circulation may take many years to develop, Zivadinov says, noting that “patients are likely to be asymptomatic for a long time.”

This would explain why Zivadinov’s team previously found structural and hemodynamic changes of the extracranial venous system in both healthy controls and people with a variety of neurological diseases.

Study Published in Journal of Alzheimer’s Disease

The research, “Jugular Venous Reflux and White Matter Abnormalities in Alzheimer's Disease: A Pilot Study,” has been published in the Journal of Alzheimer’s Disease.
Other UB co-authors, all with the Department of Neurology’s Buffalo Neuroimaging Analysis Center, include Deepa P. Ramasamy, MD, clinical trial neuroimager and senior clinical trial research assistant; Niels Bergsland, integration director; and Michael G. Dwyer, director of technical imaging.

Additional colleagues from the University of Bradford, the Taipei Veterans General Hospital and the National Yang-Ming University School of Medicine also contributed.

IChih-Ping Chung, Clive Beggs, Pei-Ning Wang*, Niels Bergsland, Simon Shepherd, Chun-Yu Cheng, Deepa P. Ramasamy, Michael G. Dwyer, Han-Hwa Hu, Robert Zivadinov* *These authors contributed equally to this manuscript.

Jugular Venous Reflux and White Matter Abnormalities in Alzheimer’s Disease: A Pilot Study

Abstract: To determine whether jugular venous reflux (JVR) is associated with cerebral white matter changes (WMCs) in individuals with Alzheimer’s disease (AD), we studied 12 AD patients 24 mild cognitive impairment (MCI) patients, and 17 elderly age- and gender-matched controls. Duplex ultrasonography and 1.5T MRI scanning was applied to quantify cerebral WMCs [T2 white matter (WM) lesion and dirty-appearing-white-matter (DAWM)]. Subjects with severe JVR had more frequently hypertension (p=0.044), more severe WMC, including increased total (p =0.047) and periventricular DAWM volumes (p = 0.008), and a trend for increased cerebrospinal fluid volumes (p=0.067) compared with the other groups. A significantly decreased (65.8%) periventricular DAWM volume (p=0.01) in the JVR-positive AD individuals compared with their JVR-negative counterparts was detected. There was a trend for increased periventricular and subcortical T2 WMC lesion volumes in the JVR-positive AD individuals compared with their JVR-negative counterparts (p=0.073). This phenomenon was not observed in either the control or MCI groups. In multiple regression analysis, the increased periventricular WMC lesion volume and decreased DAWM volume resulted in 85.7% sensitivity and 80% specificity for distinguishing between JVR-positive and JVR-negative AD patients. These JVR-WMC association patterns were not seen in the control and MCI groups. Therefore, this pilot study suggests that there may be an association between JVR and WMCs in AD patients, implying that cerebral venous outflow impairment might play a role in the dynamics of WMCs formation in AD patients, particularly in the periventricular regions. Further longitudinal studies are needed to confirm and validate our findings.

E280A gene mutation

December 4, 2013

Study finds origin of inherited gene mutation causing early-onset Alzheimer's

The age and origin of the E280A gene mutation responsible for early-onset Alzheimer's in a Colombian family with an unusually high incidence of the disease has been traced to a single founder dating from the 16th century.

Kenneth S. Kosik, Harriman Professor in Neuroscience at UC Santa Barbara and co-director of the campus's Neuroscience Research Institute (NRI), conducted the study. The findings appear in the journal Alzheimer's & Dementia.

"Some mutations just increase your risk, but this mutation is not a risk," Kosik said. "This mutation is highly penetrant, which means that if you carry the mutation, you will get early-onset Alzheimer's disease."

Kosik's team sequenced the genomes of more than 100 family members and applied identity-by-descent analysis to identify regions of common ancestry. DNA is inherited from both the parents and recombined in chunks. From these pieces, scientists can identify which parent ?and sometimes which grandparent or great-grandparent?is the source of the DNA. As time goes by, sections of DNA recombine into smaller and smaller segments, each representing a history of its ancestry.

Sequencing the genomes came about because the researchers knew that while most family members with the mutation develop early-onset Alzheimer's at age 45, there were a small number of outliers. "A few people got it a decade later, a few got it a decade earlier and we wondered if there was a gene that was protecting those who got the disease later," Kosik explained. "That protective gene?even though this mutation exists only in this Colombian family ?might be useful for all of us. That research is still ongoing."

UCSB researcher finds origin of inherited gene mutation causing early-onset Alzheimer's
Out of the genome sequencing came the idea of determining where the gene mutation originated. In addition to DNA analysis, the researchers conducted interviews with the older healthy individuals of each affected family and spoke to genealogists and historians in Colombia's Antioquian region. Kosik's co-author Francisco Lopera examined local historical and genealogical books, last wills and ecclesiastical records dating as far back as 1540.

When the scientists examined the DNA patterns around the gene mutation site, they found markers from the Iberian peninsula. They estimated the age and geographic origin of E280A to be consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century.

"This doesn't have big medical implications, but it shows that genetics is a very powerful tool and can be used to reconstruct history," Kosik said. "What we've done here might be called 'neuroarchaeology.' "

Explore further: New risk gene discovery gives hope to early-onset breast cancer sufferers

Provided by University of California - Santa Barbara search and more info

Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease
Alzheimer's & Dementia
published online 18 November 2013



A mutation in presenilin 1 (E280A) causes early-onset Alzheimer's disease. Understanding the origin of this mutation will inform medical genetics.


We sequenced the genomes of 102 individuals from Antioquia, Colombia. We applied identity-by-descent analysis to identify regions of common ancestry. We estimated the age of the E280A mutation and the local ancestry of the haplotype harboring this mutation.


All affected individuals share a minimal haplotype of 1.8 Mb containing E280A. We estimate a time to most recent common ancestor of E280A of 10 (95% credible interval, 7.2?12.6) generations. We date the de novo mutation event to 15 (95% credible interval, 11?25) generations ago. We infer a western European geographic origin of the shared haplotype.


The age and geographic origin of E280A are consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century.

(A-D) This shows geographic origin of the haplotype spanning E280 A. Credit: UCSB

All carriers of E280 A share a minimal common haplotype spanning 1.8 Mb surrounding presenilin 1 E280 A from rs2158987 to rs10135303 (chromosome 14). Positions are given in GRCh37 coordinates. Credit: UCSB

Lysosomal NEU1 deficiency

Enzyme Can Halt Plaque Build-up in Mice with Alzheimer's

Wed, 12/04/2013 - 12:30pm

St. Jude Children’s Research Hospital scientists have identified an enzyme that can halt or possibly even reverse the build-up of toxic protein fragments known as plaques in the brains of mice with Alzheimer’s disease. The research appeared in a recent edition of the scientific journal Nature Communications.

Plaques decreased substantially in mice treated with gene therapy to increase activity of the enzyme neuraminidase 1 (NEU1) in a region of the brain involved in learning and memory. Plaques accumulate between neurons in the brains of Alzheimer’s patients and are a hallmark of the disease.

The results raise hopes the enzyme could lead to new methods of diagnosing and treating Alzheimer’s disease, a neurodegenerative disorder that causes problems with memory, thinking and behavior. More than 5 million Americans are currently living with the problem. The number is expected to rise as the population ages.

“The findings suggest that down-regulation of NEU1 and a reduced supply of the enzyme may contribute to the development of Alzheimer’s disease or similar neurodegenerative disorders in some patients,” said the study’s corresponding author Alessandra d’Azzo, a member in the St. Jude Department of Genetics. “Among the questions we are asking is whether a therapeutic window exists when the enzyme could be used to halt or even reverse the disease.”

NEU1 belongs to a family of enzymes in cells whose job is to dismantle and recycle unneeded proteins and other components. The work is done inside cell structures called lysosomes.

The enzyme is missing or reduced in a rare inherited disorder called sialidosis that can affect children and adolescents. This is the first report linking NEU1 to age-related neurodegenerative disorders like Alzheimer’s. In collaboration with the University of California, Davis, D’Azzo and her colleagues have begun checking NEU1 levels in brain tissue of Alzheimer’s patients at different stages of the disease.

D’Azzo’s long-standing interest in sialidosis and related disorders known as lysosomal storage diseases led to the discovery. The findings include evidence of how the protein fragments that make up the Alzheimer’s plaque are deposited outside neurons and how loss of NEU1 possibly contributes to disease progression and spread.

The work was done in a mouse developed in d’Azzo’s laboratory that lacked the NEU1 gene. These studies revealed that loss of NEU1 activity was associated with a build-up in lysosomes of the amyloid precursor protein (APP), which they identified as a natural target of the enzyme. Improperly processed, APP is broken into the toxic peptides that form Alzheimer’s plaques. Those fragments include amyloid beta peptide 42 (Aβ-42), which researchers suspect play a major role in the Alzheimer’s disease process.

Not only did APP accumulate in lysosomes of mice lacking NEU1 but researchers found evidence that the build-up promoted the production of Aβ-42 and other toxic peptides tied to Alzheimer’s disease. Aβ-42 was detected in the spinal fluid and hippocampus of mice that lacked NEU1, but not in mice with a functional NEU1 gene. The hippocampus plays a critical role in learning and memory and is the brain region that is often an early casualty of Alzheimer’s disease.

Previously, d’Azzo’s laboratory discovered that NEU1 directs a process called lysosomal exocytosis. Cells use this process to repair the outer membrane of cells and to selectively expel material in lysosomes. Working with nerve cells growing in culture, investigators reported that the absence of NEU1 was accompanied by an increase in a protein named LAMP1. The protein is a key regulator of lysosomal exocytosis. Increased LAMP1 levels were followed by excessive lysosomal exocytosis in nerve cells, resulting in increased release of Alzheimer-linked peptides from neurons.

Loss of NEU1 also accelerated the disease process in mice bred to mimic early-onset Alzheimer’s in humans. Without the enzyme, both APP and the protein fragments that make up plaques accumulated faster in these mice.

But within weeks of using gene therapy to bolster NEU1 activity, d’Azzo’s group reported that plaques declined dramatically in the hippocampus of treated mice. Scientists used an altered cold virus as the vector to deliver both the NEU1 and PPCA genes to mouse brain cells. The PPCA protein is required for NEU1 to function properly. The gene therapy vector was developed at St. Jude.

“These results suggest that not only is NEU1 deficiency a risk factor for developing Alzheimer’s disease, but that this enzyme could be used to slow or even reverse the disease process,” d’Azzo said.

The study’s first author is Ida Annunziata, a postdoctoral fellow in d’Azzo’s laboratory. The other authors are Annette Patterson, Danielle Helton, Huimin Hu, Simon Moshiach and Elida Gomero, all of St. Jude, and Ralph Nixon, of the Nathan S. Kline Institute, Orangeburg, N.Y.

Source: St. Jude Children's Research Hospital

Nature Communications | Article

Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis

Ida Annunziata,
Annette Patterson,
Danielle Helton,
Huimin Hu,
Simon Moshiach,
Elida Gomero,
Ralph Nixon
& Alessandra d’Azzo

Nature Communications 4, Article number: 2734 doi:10.1038/ncomms3734 Received 18 July 2013 Accepted 09 October 2013 Published 14 November 2013

Alzheimer’s disease (AD) belongs to a category of adult neurodegenerative conditions, which are associated with intracellular and extracellular accumulation of neurotoxic protein aggregates. Understanding how these aggregates are formed, secreted and propagated by neurons has been the subject of intensive research, but so far no preventive or curative therapy for AD is available, and clinical trials have been largely unsuccessful. Here we show that deficiency of the lysosomal sialidase NEU1 leads to the spontaneous occurrence of an AD-like amyloidogenic process in mice. This involves two consecutive events linked to NEU1 loss-of-function?accumulation and amyloidogenic processing of an oversialylated amyloid precursor protein in lysosomes, and extracellular release of Aβ peptides by excessive lysosomal exocytosis. Furthermore, cerebral injection of NEU1 in an established AD mouse model substantially reduces β-amyloid plaques. Our findings identify an additional pathway for the secretion of Aβ and define NEU1 as a potential therapeutic molecule for AD.

receptor CD36

November 6, 2013
Alzheimer's Weekly

Amyloid Causes Alzheimer's in More Ways Than One

Most researchers think amyloid plaque is the culprit behind Alzheimer's. They know it damages brain cells. Now they are finding it also accumulates in blood vessels. Learn how it accumulates, about the damage it causes and what to do to prevent it.

NEW YORK ? A team of researchers at Weill Cornell Medical College has discovered that amyloid peptides are harmful to the blood vessels that supply the brain with blood in Alzheimer's disease ? thus accelerating cognitive decline by limiting oxygen-rich blood and nutrients. In their animal studies, the investigators reveal how amyloid-? (also known as plaque, amyloid or amyloid-beta) accumulates in blood vessels and how such accumulation and damage might be ultimately prevented.

Their study, published in the Feb. 4 online edition of the Proceedings of the National Academy of Sciences (PNAS), is the first to identify the role that the innate immunity receptor CD36 plays in damaging cerebral blood vessels and promoting the accumulation of amyloid deposits in these vessels, a condition known as cerebral amyloid angiopathy (CAA).

Importantly, the study provides the rational bases for targeting CD36 to slow or reverse some of the cognitive deficits in Alzheimer's disease by preventing CAA.

"Our findings strongly suggest that amyloid, in addition to damaging neurons, also threatens the cerebral blood supply and increases the brain's susceptibility to damage through oxygen deprivation," says the study's senior investigator, Dr. Costantino Iadecola, the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medical College and director of the Brain and Mind Research Institute at Weill Cornell Medical College and NewYork-Presbyterian Hospital. "If we can stop accumulation of amyloid in these blood vessels, we might be able to significantly improve cognitive function in Alzheimer's disease patients. Furthermore, we might be able to improve the effectiveness of amyloid immunotherapy, which is in clinical trials but has been hampered by the accumulation of amyloid in cerebral blood vessels."

Mounting scientific evidence shows that changes in the structure and function of cerebral blood vessels contribute to brain dysfunction underlying Alzheimer's disease, but no one has truly understood how this happens until now.

In the study, the research team ? which also includes investigators from the Mayo Clinic in Florida, the McLaughlin Research Institute in Montana and The Rockefeller University ? used mice that were genetically modified to develop amyloid in their brain and blood vessels, but in which the CD36 receptor was eliminated. They demonstrated that mice lacking CD36 have less buildup of amyloid in cerebral arteries (CAA) even if they have massive amyloid buildup in their brain tissue (amyloid plaques).

"Remarkably, mice lacking CD36, in which only CAA is reduced, perform significantly better in cognitive tests than do mice with intact CD36," says the study's first author, Dr. Laibaik Park, an assistant professor of neuroscience in the Brain and Mind Research Institute.

"In essence, reduced amyloid burden in cerebral blood vessels, or CAA, was able to preserve cognitive function despite the buildup of amyloid plaques in the brain tissue," says Dr. Iadecola, who is also a neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "These findings indicate that clearing the amyloid from cerebral blood vessels might be of tremendous benefit to patients with Alzheimer's disease. These conclusions are based on mice studies, and mice are not humans, of course, but we have a very exciting new direction to explore in our search for Alzheimer's disease therapies."

Scavenger Molecule Response Damages Blood Vessels

CAA is already known to be a major cause of brain dysfunction and hemorrhage from weak, damaged brain arteries in some elderly patients, but no one has identified how it occurs. It is also not clear how many older adults suffer from CAA because there is no way to make a clear diagnosis of the condition, unless sophisticated brain imaging studies are performed. But it is believed that this condition is widespread and that CAA, either in association with Alzheimer's disease or independent of it, is a major cause of cognitive decline in the elderly.

The human brain normally produces the amyloid-β peptide as part of neuronal function, but these peptides are routinely cleared from the brain, in large part, through the blood vessels. However, in most Alzheimer's patients, the brain's ability to clear amyloid-β is impaired and, consequently, one type of amyloid-β (Aβ42) accumulates in amyloid plaques and another type (Aβ40) collects in brain arteries, resulting in CAA.

The research team found that CD36, a protein located on the surface of immune cells and in blood vessels, is key to the buildup of Aβ40 in blood vessels. The protein is part of the innate immune system; its function is to act as a sensor to detect molecules that represent a danger to the host. Some of these molecules are derived from invading organisms, such as infectious agents, but some are produced by the body, such as amyloid peptides that, in excess amounts, could become toxic.

"CD36 is a scavenger protein that binds threatening molecules and activates a host of cellular responses designed to get rid of the threat," Dr. Iadecola says. "Such responses include ramping up inflammation and producing free radicals, both aimed at neutralizing the offenders. However, in the case of amyloid-β, inflammation and free radicals damage brain blood vessels and prevent the efficient clearance of the peptide through these vessels. This, in turn, sets up a vicious circle that favors the vascular accumulation of the amyloid-β peptide and promotes CAA."

Dr. Iadecola and his colleagues say it may be possible to design new drugs that bind to CD36 on the precise site on the protein's structure that amyloid-β sticks to, thus blocking the deleterious effects of receptor activation. "We now know how it occurs, and so now we have a new target," he says.


This research study was funded by grants from the National Institutes of Health, the American Heart Association, and the Alzheimer's Association.

Study co-authors include, Dr. Laibaik Park, Joan Zhou, Dr. Ping Zhou, Dr. Sleiman El Jamal, Dr. Joseph Pierce, Andrea Arreguin, and Dr. Josef Anrather from Weill Cornell Medical College; Rose Pistick and Dr. George A. Carlson from McLaughlin Research Institute in Great Falls, Montana; Linda Younkin and Dr. Steven G. Younkin from the Mayo Clinic in Jacksonville, Florida; and Dr. Bruce S. McEwen from The Rockefeller University.

Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances ? including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.

vol. 108 no. 12

Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β

Laibaik Parka,
Gang Wanga,
Ping Zhoua,
Joan Zhoua,
Rose Pitstickb,
Mary Lou Previtic,
Linda Younkind,
Steven G. Younkind,
William E. Van Nostrandc,
Sunghee Choe,
Josef Anrathera,
George A. Carlsonb, and
Costantino Iadecolaa,1


Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-β (Aβ), a peptide central to the pathogenesis of AD, has profound vascular effects mediated, for the most part, by reactive oxygen species produced by the enzyme NADPH oxidase. The mechanisms linking Aβ to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds Aβ, is essential for the vascular oxidative stress and neurovascular dysfunction induced by Aβ1?40. Thus, topical application of Aβ1?40 onto the somatosensory cortex attenuates the increase in cerebral blood flow elicited by neural activity or by endothelium-dependent vasodilators in WT mice but not in CD36-null mice (CD360/0). The cerebrovascular effects of infusion of Aβ1?40 into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD360/0 mice. Furthermore, CD36 deficiency prevents the neurovascular dysfunction observed in transgenic mice overexpressing the Swedish mutation of the amyloid precursor protein Tg2576 despite elevated levels of brain Aβ1?40. CD36 is also required for the vascular oxidative stress induced by exogenous Aβ1?40 or observed in Tg2576 mice. These observations establish CD36 as a key link between Aβ1?40 and the NADPH oxidase-dependent vascular oxidative stress underlying the neurovascular dysfunction and suggest that CD36 is a potential therapeutical target to counteract the cerebrovascular dysfunction associated with Aβ.

C9orf72 homozygosity

RNA Build-Up Linked to Dementia, Motor Neuron Disease

Oct. 30, 2013 ? A new toxic entity associated with genetically inherited forms of dementia and motor neuron disease has been identified by scientists at the UCL Institute of Neurology. The toxin is the result of a genetic mutation that leads to the production of RNA molecules which could be responsible for the diseases. The findings are published in the journal Acta Neuropathologica.

Frontotemporal dementia and motor neuron disease are related neurodegenerative diseases that affect approximately 15,000 people in the UK. Frontotemporal dementia causes profound personality and behaviour changes. Motor neuron disease leads to muscle weakness and eventual paralysis.

The most common known cause for both frontotemporal dementia and motor neuron disease is an unusual genetic mutation in the C9orf72 gene. The mutation involves a small string of DNA letters at the beginning of the gene, which expand massively to produce thousands of copies.

The new research, funded by Alzheimer's Research UK and the Medical Research Council, has shown that this DNA expansion acts in a peculiar way, leading to the generation of unexpected RNA molecules that could cause the disease.

When a gene is turned on, an RNA copy of the gene's DNA is generated. The gene's DNA code has directionality, so that it is normally turned on in only one direction, termed the 'sense direction'. The new research shows that the DNA expansion is turned on in both directions.

This leads to the normal sense RNA being produced, as well as RNA in the opposite direction, termed 'antisense RNA'. Both RNA types accumulate into aggregates in the neurons of people with frontotemporal dementia.

Intriguingly, the research showed that people with more of these aggregates in their brains developed the disease earlier than people with less RNA aggregates. This correlation suggests that the build-up may be important in causing frontotemporal dementia and motor neuron disease, making the C9orf72 DNA expansion a potential target for therapy.

Dr Adrian Isaacs, lead researcher at the UCL Institute of Neurology, said: ""These findings identify new, potentially toxic molecules in diseases caused by DNA expansions. The next steps will be to determine how they might kill neurons and how to stop them building up."

Dr Simon Ridley, Head of Research at Alzheimer's Research UK, the UK's leading dementia research charity, said: "The discovery of the C9ORF72 gene was a major step forward for research into frontotemporal dementia and motor neuron disease, and it's positive to see researchers beginning to untangle how this gene may cause these diseases in some people. Alzheimer's Research UK is delighted to have supported this promising study. By unravelling some of the biological mechanisms at play, this research could take us further on the road to new treatments that are so desperately needed by the thousands of people with these devastating diseases. For these results to reach their full potential it's vital that we continue to invest in research."

Acta NeuropathologicaPathology and Mechanisms of Neurological Disease? The Author(s) 201310.1007/s00401-013-1147-0

Original Paper

Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia

Pietro Fratta1 , Mark Poulter4, Tammaryn Lashley2, Jonathan D. Rohrer3, James M. Polke5, Jon Beck4, Natalie Ryan3, Davina Hensman1, Sarah Mizielinska1, Adrian J. Waite6, Mang-Ching Lai1, Tania F. Gendron7, Leonard Petrucelli7, Elizabeth M. C. Fisher1, Tamas Revesz2, Jason D. Warren3, John Collinge4, Adrian M. Isaacs1 and Simon Mead4
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK

Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK

Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA
Pietro Fratta

Email: p.fratta@prion.ucl.ac.uk

Simon Mead (Corresponding author)

Email: s.mead@prion.ucl.ac.uk

Received: 11 May 2013Revised: 16 June 2013Accepted: 18 June 2013Published online: 2 July 2013


An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity.

Electronic supplementary material

The online version of this article (doi:10.1007/s00401-013-1147-0) contains supplementary material, which is available to authorized users.

C9orf72 ? ALS ? FTD

11 new Alzheimer's genes

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

Nature Genetics (2013) doi:10.1038/ng.2802 Received 13 March 2013
Accepted 27 September 2013
Published online 27 October 2013

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10?8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

International group finds 11 new Alzheimer's genes to target for drug discovery



Contact: Kim Menard
University of Pennsylvania School of Medicine

Global collaboration including Penn Medicine experts yields fresh look at role of immune system in Alzheimer's

PHILADELPHIA - The largest international Alzheimer's disease genetics collaboration to date has found 11 new genetic areas of interest that contribute to late onset Alzheimer's Disease (LOAD), doubling the number of potential genetics-based therapeutic targets to interrogate. The study, published in Nature Genetics, provides a broader view of genetic factors contributing to the disease and expands the scope of disease understanding to include new areas including the immune system, where a genetic overlap with other neurodegenerative diseases such as multiple sclerosis and Parkinson's disease was identified.

"Human genetic studies are being used with increased frequency to validate new drug targets in many diseases. Here we greatly increased the list of possible drug target candidates for Alzheimer's disease, finding as many new significant genes in this one study as have been found in the last 15 years combined," said co-senior author Gerard Schellenberg, PhD, director of the Alzheimer's Disease Genetics Consortium (ADGC) and professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. "This international effort has given us new clues into the steps leading to and accelerating Alzheimer's disease. We can add these new genetic clues to what we already know and try to piece together the mechanism of this complex disease."

Pooling resources through the International Genomics of Alzheimer's Project (IGAP), the collaborative team collected 74,076 patients and controls from 15 countries. After a two stage meta-analysis, the group found some genes which confirmed known biological pathway of Alzheimer's disease, including the role of the amyloid pathway (SORL1 , CASS4) and tau (CASS4, FERMT2). Newly discovered genes involved in the immune response and inflammation (HLA-DRB5/DRB1, INPP5D, MEF2C) reinforced a pathway implied by previous work (on CR1, TREM2). Additional genes related to cell migration (PTK2B), lipid transport and endocytosis (SORL1) were also confirmed. And new hypotheses emerged related to hippocampal synaptic function (MEF2C , PTK2B), the cytoskeleton and axonal transport (CELF1, NME8, CASS4) as well as myeloid and microglial cell functions (INPP5D).

One of the more significant new associations was found in the HLA-DRB5 - DRB1 region, one of the most complex parts of the genome, which plays a role in the immune system and inflammatory response. It has also been associated with multiple sclerosis and Parkinson's disease, suggesting that the diseases where abnormal proteins accumulate in the brain may have a common mechanism involved, and possibly have a common drug target, Dr. Schellenberg noted.

"We know that healthy cells are very good at clearing out debris, thanks in part to the immune response system, but in these neurodegenerative diseases where the brain has an inflammatory response to bad proteins and starts forming plaques and tangle clumps, perhaps the immune response can get out of hand and do damage," said Dr. Schellenberg. "Through this powerful international group as well as our own US collaborations, we'll expand the data set even further to look for rare variants and continue our analysis to find more opportunities to better understand the disease and find viable therapeutic targets. Large-scale sequencing will certainly play a part in the next phase of our genetics studies."


Started in 2011, IGAP includes the contributions from the European Alzheimer's Disease Initiative (EADI) in France led by Philippe Amouyel, MD, PhD, at the Institute Pasteur de Lille and Lille University; the Genetic and Environmental Risk in Alzheimer's Disease (GERAD) from the United Kingdom led by Julie Williams, PhD, at Cardiff University; the neurology subgroup of the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) led by Sudha Seshadri, MD, at Boston University School of Medicine; the Alzheimer's Disease Genetics Consortium (ADGC) from the United States led by Gerard Schellenberg, PhD, Perelman School of Medicine at the University of Pennsylvania; as well as ADGC teams from the University of Miami, Vanderbilt University, Boston University and Columbia University in the United States, among others.

The National Institute on Aging provided funding for the ADGC (U01 AG032984, R01 AG033193), and the Alzheimer's Association provided crucial support to make this international collaboration possible.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.

自食(autophagy in Aβ metabolism)





理化学研究所(理研、野依良治理事長)は、細胞の自食に新たな機能があることを発見し、この新機能がアルツハイマー病の発症に関与している可能性を示しました。これは、理研脳科学総合研究センター(利根川進センター長)神経蛋白制御研究チームのニルソン パー研究員、津吹聡専門職研究員、西道隆臣チームリーダーらの研究チームの成果です。





本研究成果は、米国の科学雑誌『Cell Reports』に掲載されるに先立ち、オンライン版(10月3日付け:日本時間10月4日)に掲載されます。










?Per Nilsson, Krishnapriya Loganathan, Misaki Sekiguchi, Yukio Matsuba, Kelvin Hui, Satoshi Tsubuki, Motomasa Tanaka, Nobuhisa Iwata, Takashi Saito and Takaomi C. Saido. "Aβ Secretion and Plaque Formation Depend on Autophagy."
Cell Reports 2013, doi: org/10.1016/j.celrep.2013.08.042


脳科学総合研究センター 神経蛋白制御研究チーム
チームリーダー 西道 隆臣 (さいどう たかおみ)
専門職研究員 津吹 聡 (つぶき さとし)


脳科学総合研究センター 脳科学研究推進室
Tel: 048-467-9757 / Fax: 048-462-4914

独立行政法人理化学研究所 広報室 報道担当
Tel: 048-467-9272 / Fax: 048-462-4715
独立行政法人理化学研究所 社会知創成事業 連携推進部

5.モ-リス水迷路試験水を入れた大きな円形プールの中に設置してある逃避台までマウスを泳がせて、空間学習の効果を測定する課題。1981年にリチャード G.モーリスによって考案された。

Aβ Secretion and Plaque Formation Depend on Autophagy

Cell Reports, 03 October 2013
Copyright 2013 The Authors

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.


Per Nilssonsend email, Krishnapriya Loganathan, Misaki Sekiguchi, Yukio Matsuba, Kelvin Hui, Satoshi Tsubuki, Motomasa Tanaka, Nobuhisa Iwata, Takashi Saito, Takaomi C. Saidosend emailSee Affiliations

?Aβ secretion is dependent on autophagy
?Autophagy defect decreases extracellular Aβ deposition
?Aβ accumulates intracellularly upon autophagy deficiency, causing neurodegeneration
?Autophagy defect causes cognitive dysfunction in a mouse model of Alzheimers disease


Alzheimers disease (AD) is a neurodegenerative disease biochemically characterized by aberrant protein aggregation, including amyloid beta (Aβ) peptide accumulation. Protein aggregates in the cell are cleared by autophagy, a mechanism impaired in AD. To investigate the role of autophagy in Aβ pathology in vivo, we crossed amyloid precursor protein (APP) transgenic mice with mice lacking autophagy in excitatory forebrain neurons obtained by conditional knockout of autophagy-related protein 7. Remarkably, autophagy deficiency drastically reduced extracellular Aβ plaque burden. This reduction of Aβ plaque load was due to inhibition of Aβ secretion, which led to aberrant intraneuronal Aβ accumulation in the perinuclear region. Moreover, autophagy-deficiency-induced neurodegeneration was exacerbated by amyloidosis, which together severely impaired memory. Our results establish a function for autophagy in Aβ metabolism: autophagy influences secretion of Aβ to the extracellular space and thereby directly affects Aβ plaque formation, a pathological hallmark of AD.

LilrB2 (leukocyte immunoglobulin-like receptor B2)
Scientists Reveal What May Cause Alzheimer's: Beta-Amyloid
Catherine Griffin
Sep 20, 2013 12:22 PM EDT

Alzheimer's disease continues to remain a major health concern across the U.S. and the world. Now, though, scientists have learned a little bit more about this disease. They've shown how a protein fragment known as beta-amyloid, strongly implicated in Alzheimer's disease, begins destroying synapses before it clumps into plaques that lead to nerve cell death. The findings could help researchers better understand exactly how Alzheimer's develops in patients.

In order to better understand Alzheimer's, the researchers used experimental mice that are highly susceptible to the synaptic and cognitive impairments of the disease. The scientists found that if the mice lacked a surface protein ordinarily situated very close to synapses, they were resistant to the memory breakdown and synapse loss associated with the disorder. In fact, the researchers discovered that this protein, called PirB, is a high-affinity receptor for beta-amyloid in its soluble cluster form. In other works, the soluble beta-amyloid clusters stuck to PirB quite strongly.

Beta-amyloid begins life as a solitary molecule but eventually begins to bunch up. At first, it forms small clusters that are still soluble and can travel freely in the brain. Eventually, though, they create the plaques that are so well-known in Alzheimer's.

When the soluble clusters stick to PirB, though, something interesting happens. It trips off a cascade of biochemical activities that culminate in the destruction of synapses. Synapses are the connections between nerve cells and are essential for storing memories, processing thoughts and emotions and planning and ordering how we move our bodies.

The next step was to eliminate PirB from the Alzheimer's mouse strain. Researchers wanted to see whether eliminating this protein would restore the brain's flexibility. In the end, they found that the brains of young "Alzheimer's mice" in which PirB was absent retained as much synaptic-strength-shifting flexibility as normal mice.

"The PirB-lacking Alzheimer's mice were protected from the beta-amyloid-generating consequences of their mutations," said Carla Shatz, one of the researchers, in a news release.

After further experimentation, the researchers found that PirB and beta-amyloid were binding. This caused PirB to stomp on the brakes even more than it usually does, weakening synapses so much that they could disappear altogether, taking memories with them.

The findings are important for better understanding the development of Alzheimer's in patients. This, in turn, could allow researchers to develop better treatments. For example, soluble PirB fragments containing portions of the molecule that could act as a decoy might be able to exert a therapeutic effect.

The findings are published in the journal Science.

Science 20 September 2013:
Vol. 341 no. 6152 pp. 1399-1404
DOI: 10.1126/science.1242077

Human LilrB2 Is a β-Amyloid Receptor and Its Murine Homolog PirB Regulates Synaptic Plasticity in an Alzheimer’s Model

Taeho Kim1,*,
George S. Vidal1,
Maja Djurisic1,
Christopher M. William2,
Michael E. Birnbaum3,
K. Christopher Garcia3,
Bradley T. Hyman2,
Carla J. Shatz1,*

Corresponding author. E-mail: cshatz@stanford.edu (C.J.S.); tkim808@stanford.edu (T.K.)

Soluble β-amyloid (Aβ) oligomers impair synaptic plasticity and cause synaptic loss associated with Alzheimer’s disease (AD). We report that murine PirB (paired immunoglobulin-like receptor B) and its human ortholog LilrB2 (leukocyte immunoglobulin-like receptor B2), present in human brain, are receptors for Aβ oligomers, with nanomolar affinity. The first two extracellular immunoglobulin (Ig) domains of PirB and LilrB2 mediate this interaction, leading to enhanced cofilin signaling, also seen in human AD brains. In mice, the deleterious effect of Aβ oligomers on hippocampal long-term potentiation required PirB, and in a transgenic model of AD, PirB not only contributed to memory deficits present in adult mice, but also mediated loss of synaptic plasticity in juvenile visual cortex. These findings imply that LilrB2 contributes to human AD neuropathology and suggest therapeutic uses of blocking
LilrB2 function.

U1 snRNP

Alzheimer's: Newly identified protein pathology impairs RNA splicing

by Quinn Eastman
September 10, 2013

Researchers at Emory University School of Medicine's Alzheimer's Disease Research Center have identified a previously unrecognized type of pathology in the brains of patients with Alzheimer's disease.

These tangle-like structures appear at early stages of Alzheimer's and are not found in other neurodegenerative diseases such as Parkinson's disease.

What makes these tangles distinct is that they sequester proteins involved in RNA splicing, the process by which instructional messages from genes are cut and pasted together. The researchers show that the appearance of these tangles is linked to widespread changes in RNA splicing in Alzheimer's brains compared to healthy brains.

The finding could change scientists' understanding of how the disease develops and progresses, by explaining how genes that have been linked to Alzheimer's contribute their effects, and could lead to new biomarkers, diagnostic approaches, and therapies.

The results are published in the Proceedings of the National Academy of Sciences, Early Edition.

"We were very surprised to find alterations in proteins that are responsible for RNA splicing in Alzheimer's, which could have major implications for the disease mechanism," says Allan Levey, MD, PhD, chair of neurology at Emory University School of Medicine and director of the Emory ADRC.

"This is a brand new arena," says James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Many Alzheimer's investigators have looked at how the disease affects alternative splicing of individual genes. Our results suggest a global distortion of RNA processing is taking place."

This research was led by Drs. Levey, Lah, and Junmin Peng, PhD, who was previously associate professor of genetics at Emory and is now a faculty member at St Jude Children's Research Hospital. They were aided by collaborators at University of Kentucky, Rush University, and University of Washington as well as colleagues at Emory.

Accumulations of plaques and tangles in the brains of patients with Alzheimer's disease were first observed more than a century ago. Investigating the proteins in these pathological structures has been central to the study of the disease.

Most experimental treatments for Alzheimer's have aimed at curbing beta-amyloid, an apparently toxic protein fragment that is the dominant component of amyloid plaques. Other approaches target the abnormal accumulation of the protein tau in neurofibrillary tangles. Yet the development of Alzheimer's is not solely explained by amyloid and tau pathologies, Lah says.

"Two individuals may harbor similar amounts of amyloid plaques and tau tangles in their brains, but one may be completely healthy while the other may have severe memory loss and dementia," he says.

These discrepancies led Emory investigators to take a "back to basics" proteomics approach, cataloguing the proteins that make up insoluble deposits in the brains of Alzheimer's patients.

"The Alzheimer's field has been very focused on amyloid and tau, and we wanted to use today's proteomics technologies to take a comprehensive, unbiased approach," Levey says.

The team identified 36 proteins that were much more abundant in the detergent-resistant deposits in brain tissue from Alzheimer's patients. This list included the usual suspects: tau and beta-amyloid. Also on the list were several "U1 snRNP" proteins, which are involved in RNA splicing.

These U1 proteins are normally seen in the nucleus of normal cells, but in Alzheimer's brains they accumulated in tangle-like structures. Accumulation of insoluble U1 protein was seen in samples from patients with mild cognitive impairment (MCI), a precursor stage to Alzheimer's, but the U1 pathology was not seen in any other brain diseases that were examined.

According to Chad Hales, MD, PhD, one of the study's lead authors, "U1 aggregation is occurring early in the disease, and U1 tangles can be seen independently of tau pathology. In some cases, we see accumulation of insoluble U1 proteins before the appearance of insoluble tau, suggesting that it is a very early event."

For most genes, after RNA is read out from the DNA (transcription), some of the RNA must be spliced out. When brain cells accumulate clumps of U1 proteins, that could mean the process of splicing is impaired. To test this, the Emory team examined RNA from the brains of Alzheimer's patients. In comparison to RNA from healthy brains, more of the RNA from Alzheimer's brain samples was unspliced.

The finding could explain how many genes that have been linked to Alzheimer's are having their effects. In cells, U1 snRNP plays multiple roles in processing RNA including the process of alternative splicing, by which one gene can make instructions for two or more proteins.

"U1 dysfunction might produce changes in RNA processing affecting many genes or specific changes affecting a few key genes that are important in Alzheimer's," Lah says. "Understanding the disruption of such a fundamental process will almost certainly identify new ways to understand Alzheimer's and new approaches to treating patients."

Explore further: New Alzheimer's research suggests possible cause: The interaction of proteins in the brain

More information: B. Bai et al. U1 Small Nuclear Ribonucleoprotein Complex and RNA Splicing Alterations in Alzheimer's Disease. PNAS Early Edition (2013).

Journal reference: Proceedings of the National Academy of Sciences search and more info website

Provided by Emory University search and more info website

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease

Bing Baia,1,
Chadwick M. Halesb,c,1,
Ping-Chung Chena,1,
Yair Gozalb,c,1,
Eric B. Dammerc,
Jason J. Fritzb,c,
Xusheng Wangd,
Qiangwei Xiac,
Duc M. Duongc,
Craig Streete,
Gloria Canterof,g,
Dongmei Chengc,
Drew R. Jonesa,
Zhiping Wua,
Yuxin Lia,
Ian Dinerc,
Craig J. Heilmanb,c,
Howard D. Reesb,c,
Hao Wuh,
Li Line,
Keith E. Szulwache,
Marla Gearingc,i,
Elliott J. Mufsonj,
David A. Bennettj,
Thomas J. Montinek,
Nicholas T. Seyfriedc,l,
Thomas S. Wingob,c,
Yi E. Sunf,
Peng Jinc,e,
John Hanfeltc,h,
Donna M. Willcockm,
Allan Leveyb,c,2,
James J. Lahb,c,2, and
Junmin Penga,d,2

Edited by Gideon Dreyfuss, University of Pennsylvania, Philadelphia, PA, and approved August 12, 2013 (received for review May 30, 2013)


Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer’s disease (AD) has facilitated advancement of the amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc box-dependent-interacting protein 1, clusterin, and presenilin-1. U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein. Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.
liquid chromatography-tandem mass spectrometry
premature cleavage and polyadenylation

Metabotropic Glutamate Receptor 5( mGluR5)

"Missing Link" found in cure for Alzheimer's

SCIENTISTS have moved a step closer to finding a cure for Alzheimer’s after identifying the “missing link” that triggers the harrowing disease.

By: Giles Sheldrick
Published: Wed, September 4, 2013

In a medical first, researchers believe they have isolated a protein that plays a crucial role in the complicated chain of events leading to Alzheimer’s.

The breakthrough offers fresh hope of developing drugs to slow, or even halt, the degenerative and incurable illness.

The offending protein is thought to be one of a number that build up in the brain, eventually causing a breakdown in cognitive function.

In findings that have been cautiously welcomed by British campaigners, scientists at the respected Yale School of Medicine found blocking the protein with an existing drug can restore memory in mice with brain damage.

Study leader and Professor of Neurology Stephen Strittmatter said: “What is very exciting is that of all the links in this molecular chain, this is the protein that may be most easily targeted by drugs.

“This gives us strong hope that we can find a drug that will work to lessen the burden of Alzheimer’s.”

Years of painstaking research has enabled researchers to build a partial molecular map of how Alzheimer’s destroys brain cells.

Findings published in the journal Neuron show that when a protein known to scientists as mGluR5 is blocked by a drug in development for Fragile X syndrome, memory is restored in mice.

The protein is believed to be one of a number that build up in the brain eventually causing a cognitive breakdown.

It is hoped new drugs may be able to specifically target mGluR5 to break the chain of events leading to Alzheimer’s.

Shocking statistics show 800,000 people in the UK have some form of dementia with more than half suffering with Alzheimer’s.

In less than ten years one million people will be living with dementia, a figure that will soar to 1.7million people by 2051.

This afternoon Alzheimer’s Society research officer Jess Smith said: “This study helps us to understand more about the processes that lead to the development of Alzheimer’s disease.

“Although it is promising this process can be blocked in a mouse model of Alzheimer’s disease, more research is needed to understand why this is the case, and whether the same benefits would be seen in humans.

"One in three people over the age of 65 will develop dementia before they die and yet dementia research is hugely underfunded. We need to fund more research to better understand the causes of dementia and work to develop better treatments.”

Meanwhile, a separate study showed too much clean living may be contributing to a surge in cases of Alzheimer’s.

Scientists have linked the “hygiene hypothesis” - the idea that lack of exposure to germs, viruses and parasites harms the immune system - to rising rates of the condition in richer nations.

Evidence shows countries where the risk of infection is relatively low more people are suffering from Alzheimer’s.

Likewise, better sanitation and the expansion of cities go hand in hand with higher incidence of the disease, the most common form of dementia.

Taken together, infection levels, sanitation and urbanisation account for 42.5 per cent of the variation in rates of Alzheimer’s between different countries.

Dr Molly Fox, of Cambridge University who led the research, said: “The ‘hygiene hypothesis’, which suggests a relationship between cleaner environments and a higher risk of certain allergies and autoimmune diseases, is well established.

“We believe we can now add Alzheimer’s to this list of diseases. There are important implications for forecasting future global disease burden, especially in developing countries as they increase in sanitation."

Access to clean drinking water was one area said to have a high impact on Alzheimer’s rates. Countries like Britain and France had a nine per cent higher incidence of Alzheimer’s than countries such as Kenya and Cambodia where less than half the population can access clean water.

A similar pattern emerged from comparisons between countries with low and high rates of infectious disease.

Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein

Neuron, Volume 79, Issue 5, 887-902, 4 September 2013
Copyright 2013 Elsevier Inc. All rights reserved.


Ji Won Um, Adam C. Kaufman, Mikhail Kostylev, Jacqueline K. Heiss, Massimiliano Stagi, Hideyuki Takahashi, Meghan E. Kerrisk, Alexander Vortmeyer, Thomas Wisniewski, Anthony J. Koleske, Erik C. Gunther, Haakon B. Nygaard, Stephen M. Strittmattersend emailSee Affiliations


Soluble amyloid-β oligomers (Aβo) trigger Alzheimers disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrPC). At the postsynaptic density (PSD), extracellular Aβo bound to lipid-anchored PrPC activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Aβo-PrPC with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrPC-bound Aβo to activate Fyn. PrPC and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Aβo-PrPC generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by Aβo-PrPC-mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory, and synapse density. Thus, Aβo-PrPC complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.


September 4, 2013

Stress-related protein speeds progression of Alzheimer's disease

A stress-related protein genetically linked to depression, anxiety and other psychiatric disorders contributes to the acceleration of Alzheimer's disease, a new study led by researchers at the University of South Florida has found.

The study is published online today in the Journal of Clinical Investigation.

When the stress-related protein FKBP51 partners with another protein known as Hsp90, this formidable chaperone protein complex prevents the clearance from the brain of the toxic tau protein associated with Alzheimer's disease.

Under normal circumstances, tau helps make up the skeleton of our brain cells. The USF study was done using test tube experiments, mice genetically engineered to produce abnormal tau protein like that accumulated in the brains of people with Alzheimer's disease, and post-mortem human Alzheimer's brain tissue.

The researchers report that FKBP51 levels increase with age in the brain, and then the stress-related protein partners with Hsp90 to make tau more deadly to the brain cells involved in memory formation.

Hsp90 is a chaperone protein, which supervises the activity of tau inside nerve cells. Chaperone proteins typically help ensure that tau proteins are properly folded to maintain the healthy structure of nerve cells.

However, as FKBP51 levels rise with age, they usurp Hsp90's beneficial effect to promote tau toxicity.

"We found that FKB51 commandeers Hsp90 to create an environment that prevents the removal of tau and makes it more toxic," said the study's principal investigator Chad Dickey, PhD, associate professor of molecular medicine at the USF Health Byrd Alzheimer's Institute. "Basically, it uses Hsp90 to produce and preserve the bad tau."

The researchers conclude that developing drugs or other ways to reduce FKB51 or block its interaction with Hsp90 may be highly effective in treating the tau pathology featured in Alzheimer's disease, Parkinson's disease dementia and several other disorders associated with memory loss.

A previous study by Dr. Dickey and colleagues found that a lack of FKBP51 in old mice improved resilience to depressive behavior.

Explore further: New Alzheimer's research suggests possible cause: The interaction of proteins in the brain

More information: Blair, L. et al. Accelerated neurodegeneration through chaperone-mediated oligomerization of tau, Journal of Clinical Investigation, Vol. 123, No. 10. DOI: 10.1172/JCI69003.

Journal reference: Journal of Clinical Investigation search and more info website

Provided by University of South Florida search and more info website

J Clin Invest. doi:10.1172/JCI69003.
Copyright ? 2013, The American Society for Clinical Investigation.

Research Article

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

Laura J. Blair1, Bryce A. Nordhues1, Shannon E. Hill2, K. Matthew Scaglione3, John C. O’Leary, III1, Sarah N. Fontaine1, Leonid Breydo1, Bo Zhang1, Pengfei Li1, Li Wang1, Carl Cotman4, Henry L. Paulson3, Martin Muschol2, Vladimir N. Uversky1,5, Torsten Klengel6, Elisabeth B. Binder6, Rakez Kayed7, Todd E. Golde8, Nicole Berchtold4 and Chad A. Dickey1

1Department of Molecular Medicine, Byrd Institute, and
2Department of Physics, University of South Florida, Tampa, Florida, USA.
3Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
4Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, USA.
5Institute for Biological Instrumentation, Russian Academy of Sciences, Moscow, Russia.
6Max Planck Institute of Psychiatry, Munich, Germany.
7Department of Neurology and Department of Neuroscience and Cell Biology, George P. and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas, USA.
8Department of Neuroscience, University of Florida, Gainesville, Florida, USA.

Address correspondence to: Chad Dickey, University of South Florida, 4001 E. Fletcher Ave., MDC 36, Tampa, Florida 33613, USA. Phone: 813.396.0639; Fax: 813.974.3081; E-mail: cdickey@health.usf.edu.

Published September 3, 2013
Received for publication January 30, 2013, and accepted in revised form June 27, 2013.

Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5?/? mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer’s disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

Microglial Beclin 1

September 4, 2013

Faulty internal recycling by brain's trash collectors may contribute to Alzheimer's

A defective trash-disposal system in the brain's resident immune cells may be a major contributor to neurodegenerative disease, a scientific team from the Stanford University School of Medicine has found.

Preliminary observations show that this defect appears in the brains of patients who died of Alzheimer's disease, so correcting it may someday prove to be an effective way of preventing or slowing the course of the disease.

"We were fortunate in being able to compare microglia?the brain's own immune cells?from five patients who died of Alzheimer's disease with five who died of other causes," said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences at the medical school and senior research career scientist at the Veterans Affairs Palo Alto Health Care System. "And we discovered that in Alzheimer's disease, the microglia are defective. One of these cells' main functions, removing garbage, is impaired."

Wyss-Coray is the senior author of the study, which will be published Sept. 4 in Neuron. The lead author was postdoctoral scholar Kurt Lucin, PhD.

Microglia, one of several important cell types in the brain, serve as both cops and trash collectors. These immune cells continuously police the brain, making sure everything is running smoothly. When they sense a pathogen, they pull out the molecular equivalent of a pistol. If they spot a dead cell or a clump of protein detritus, they don a pair of overalls and hasten to remove it.

They do this by engulfing and ingesting the target in a process called phagocytosis. Many cells can do this, but microglia are the pros?and they'd better be, said Wyss-Coray. "If they don't clear up all the detritus in the brain efficiently, debris left lying around can trigger inflammation and consequent injury to neurons," he said.

Proteins called phagocytic receptors on the surface of microglia look out for characteristic earmarks of detritus, dead cells and potentially toxic substances such as A-beta, a protein widely implicated in Alzheimer's disease. A-beta is prone to clump into plaques that abound in the brains of people with Alzheimer's and, to a lesser extent, in the rest of us as we grow older.

When a targeted protein or piece of cellular debris is bound by a phagocytic receptor, part of the microglial cell's outer membrane forms a bubble that encloses the target, migrates inward and fuses with the cell's high-powered digestive machinery, which breaks down the ingested contents.

The phagocytic receptors, which have come along for the ride on the membranes engulfing the ingested materials, aren't digested, though. They are recycled, Wyss-Coray said. "Microglia don't constantly make brand-new receptors. Instead, existing ones are returned to the cell membrane by a very sophisticated multiprotein complex called the retromer, which effectively grabs the internalized receptors and shuttles them back to the cell surface."

But a defect in microglia's internal recycling program, the new study shows, can result in faulty phagocytosis, which in turn could allow A-beta to accumulate in aging brains. For example, it was recently discovered that a rare mutation in a key phagocytic receptor that binds to A-beta confers a three- to four-fold additional risk for Alzheimer's disease.

The researchers believe they have determined a culprit: beclin, a protein expressed in every cell in the body and known to be crucial to survival. They found that deficiencies in this protein impair the retromer's ability to steward phagocytic receptors back to microglial cell surfaces, with nasty consequences for neurons in the brain.

Beclin and the retromer apparatus are similar in mice and humans. So Wyss-Coray and his colleagues first looked at mouse microglia that had been altered to reduce beclin levels by more than half. These beclin-deficient microglia turned out to be less efficient at gobbling up latex beads, a proxy for cellular debris, than microglia with normal levels.

When the scientists injected A-beta into the brains of normal mice, their microglia cleared up this substance quickly, said Wyss-Coray. But in beclin-deficient mice, the microglia took much longer to get the job done.

The researchers also showed that in beclin-deficient cells, the recycling of a phagocytic receptor that binds A-beta was severely impaired.

Apparently beclin is required for adequate retromer function, Wyss-Coray said. "To our surprise, if beclin levels were low, all key components of the retromer were quite dramatically reduced. So, the receptor can't get back because the retromers aren't there."

When his team compared autopsied brains from five Alzheimer's patients and five people who had died of other causes, they saw that levels of both beclin and at least one of the retromer's protein components were diminished by as much as 80 percent in Alzheimer's brains.

"We didn't expect to see such dramatic differences in these proteins in human tissue. This has not been previously shown for any proteins in human microglia," Wyss-Coray said. "We have to take our findings about microglia in human brains with a grain of salt because we looked at only 10 brains in all. But the findings are exciting. If they're accurate, they show one way that microglia can become dysfunctional, and what the consequences can be."

Wyss-Coray said he still doesn't know what initially causes the drop in beclin levels. But other experiments suggested that beclin deficits in Alzheimer's brains are likely not resulting from the accumulation of A-beta deposits but preceding it, and may be contributing to it.

"Most research has focused on neurons," he said. "Our findings suggest that we should also be looking at other cell types that may be malfunctioning in the brain. If microglia don't work the way they're designed to work, a lot of problems may result."

These findings may also be relevant not just for Alzheimer's but for other age-related brain diseases. A mutation in one retromer protein has been implicated in Parkinson's, Wyss-Coray said. "If beclin decline turns out to be a part of normal aging, eventually A-beta or other protein aggregates, such as those that occur in Parkinson's disease, could arise."

Explore further: Lack of immune cell receptor impairs clearance of amyloid beta protein from the brain

Journal reference: Neuron search and more info website

Provided by Stanford University Medical Center search and more info website

Microglial Beclin 1 Regulates Retromer Trafficking and Phagocytosis and Is Impaired in Alzheimers Disease

Neuron, Volume 79, Issue 5, 873-886, 4 September 2013

Kurt M. Lucin, Caitlin E. OBrien, Gregor Bieri, Eva Czirr, Kira I. Mosher, Rachelle J. Abbey, Diego F. Mastroeni, Joseph Rogers, Brian Spencer, Eliezer Masliah, Tony Wyss-Coray


Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimers disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.


Study suggests iron is at core of Alzheimer's disease

August 20, 2013

Alzheimer's disease has proven to be a difficult enemy to defeat. After all, aging is the No. 1 risk factor for the disorder, and there's no stopping that.

Most researchers believe the disease is caused by one of two proteins, one called tau, the other beta-amyloid. As we age, most scientists say, these proteins either disrupt signaling between neurons or simply kill them.

Now, a new UCLA study suggests a third possible cause: iron accumulation.

Dr. George Bartzokis, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and senior author of the study, and his colleagues looked at two areas of the brain in patients with Alzheimer's. They compared the hippocampus, which is known to be damaged early in the disease, and the thalamus, an area that is generally not affected until the late stages. Using sophisticated brain-imaging techniques, they found that iron is increased in the hippocampus and is associated with tissue damage in that area. But increased iron was not found in the thalamus.

The research appears in the August edition of the Journal of Alzheimer's Disease.

While most Alzheimer's researchers focus on the buildup of tau or beta-amyloid that results in the signature plaques associated with the disease, Bartzokis has long argued that the breakdown begins much further "upstream." The destruction of myelin, the fatty tissue that coats nerve fibers in the brain, he says, disrupts communication between neurons and promotes the buildup of the plaques. These amyloid plaques in turn destroy more and more myelin, disrupting brain signaling and leading to cell death and the classic clinical signs of Alzheimer's.

Myelin is produced by cells called oligodendrocytes. These cells, along with myelin, have the highest levels of iron of any cells in the brain, Bartzokis says, and circumstantial evidence has long supported the possibility that brain iron levels might be a risk factor for age-related diseases like Alzheimer's. Although iron is essential for cell function, too much of it can promote oxidative damage, to which the brain is especially vulnerable.

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In the current study, Bartzokis and his colleagues tested their hypothesis that elevated tissue iron caused the tissue breakdown associated with Alzheimer's disease. They targeted the vulnerable hippocampus, a key area of the brain involved in the formation of memories, and compared it to the thalamus, which is relatively spared by Alzheimer's until the very late stages of disease.

The researchers used an MRI technique that can measure the amount of brain iron in ferritin, a protein that stores iron, in 31 patients with Alzheimer's and 68 healthy control subjects.

In the presence of diseases like Alzheimer's, as the structure of cells breaks down, the amount of water increases in the brain, which can mask the detection of iron, according to Bartzokis.

"It is difficult to measure iron in tissue when the tissue is already damaged," he said. "But the MRI technology we used in this study allowed us to determine that the increase in iron is occurring together with the tissue damage. We found that the amount of iron is increased in the hippocampus and is associated with tissue damage in patients with Alzheimer's but not in the healthy older individuals?or in the thalamus. So the results suggest that iron accumulation may indeed contribute to the cause of Alzheimer's disease."

But it's not all bad news from this study, Bartzokis noted.

"The accumulation of iron in the brain may be influenced by modifying environmental factors, such as how much red meat and iron dietary supplements we consume and, in women, having hysterectomies before menopause," he said.

In addition, he noted, medications that chelate and remove iron from tissue are being developed by several pharmaceutical companies as treatments for the disorder. This MRI technology may allow doctors to determine who is most in need of such treatments.

Journal of Alzheimer's Disease.
Volume 37, Number 1, IN PRESS

Erika P. Raven, Po H. Lu, Todd A. Tishler, Panthea Heydari, George Bartzokis
Increased Iron Levels and Decreased Tissue Integrity in Hippocampus of Alzheimer’s Disease Detected in vivo with Magnetic Resonance Imaging
Abstract:Background: Iron can catalyze damaging free radical reactions. With age, iron accumulates in brain gray matter regions and may contribute to the risk of developing age-related diseases such as Alzheimer’s disease (AD). Prior MRI studies demonstrated increased iron deposits in basal ganglia regions; however, the hippocampus (Hipp), which is heavily damaged in AD, and comparator regions that are resistant to AD damage, such as thalamus (Th), have rarely been examined. Objective: To assess iron levels and evidence of tissue damage in Hipp and Th of AD subjects and healthy controls. Methods: Thirty-one AD and sixty-eight healthy control subjects participated in this study. High- and low-field strength MRI instruments were used in combination to quantify iron content of ferritin molecules (ferritin iron) using the field dependent relaxation rate increase (FDRI) method. Decreased transverse relaxation rate (R2) was used as an index of tissue damage. Results: Compared with healthy controls, AD subjects had increased ferritin iron in Hipp (p=0.019) but not Th (p=0.637), and significantly decreased R2 in Hipp (p<0.001) but not Th (p=0.37). In the entire sample, FDRI and R2 were negatively correlated. Conclusion: The data shows that in AD, Hipp damage occurs in conjunction with ferritin iron accumulation. Prospective studies are needed to evaluate how increasing iron levels may influence the trajectory of tissue damage and cognitive and pathologic manifestations of AD.

C1q protein

A potential cure for Alzheimer’s? Scientists discover new culprit behind brain-wasting disease

By Loren Grush
Published August 14, 2013

The accumulation of a specific protein in the aging brain may be the cause of numerous devastating neurodegenerative diseases ? most notably Alzheimer’s disease.

But it’s not amyloids ? the proteins that most health experts blame for the brain-wasting condition. It’s an entirely new culprit.

In a groundbreaking study from Stanford University School of Medicine, researchers detailed the significance of a protein called C1q, which was previously known as the initiator of the immune system response. After analyzing brain tissue in mice of varying ages, as well as postmortem samples of a 2-month-old infant and an elderly person, they discovered that C1q exponentially increases in the aging brain ? creating as much as a 300-fold buildup. Comparatively, most age-associated increases of proteins in the brain are only three- or four-fold.

The research team revealed that as the brain ages, C1q accumulates around the brain’s synapses ? contact points that connect the brain’s nerve cells to one another. Rather than being naturally cleared by the brain, the C1q sticks, making these synapses vulnerable to destruction from the brain’s immune cells.

According to study author Dr. Ben Barres, the findings could fundamentally change the way scientists and doctors perceive neurodegenerative diseases, as well as lead to treatments that could alleviate the devastating effects of age-related brain disorders. Classic symptoms of neurodegneration range anywhere from severe memory loss to problems with motor function and complete loss of limb movement.

“We’re suggesting the reason the old brain is so vulnerable to Alzheimer’s disease is because of this massive buildup of C1q,” Barres, professor and chair of neurobiology at Stanford, told FoxNews.com. “One of the things that’s very interesting about this pattern is that the earliest accumulation of C1q starts in regions of the brain that are well-known to be most vulnerable to neurodegenerative disease ? the hippocampus and substantia nigra.”

The complement system

C1q is a well-established component of what is known as the complement system ? a group of 20 proteins that help antibodies and macrophages clear pathogens from the body. Considered the initiator of the system, C1q is responsible for recognizing the body’s “garbage,” such as bacteria, dying cells, and other harmful agents.

After locating these potentially dangerous cells, C1q binds to them and triggers a molecular reaction known as the amplifying cascade, in which the remaining 19 complement proteins bind to and coat the debris. This allows the macrophages (immune cells) to recognize the complement-tagged junk and eliminate it from the body.

“In the body, this system makes a lot of sense,” Barres said. “All the cells in the body contain inhibitors to the complement, so normal cells aren’t targeted and destroyed. For example, a normal liver cell will be fine, so it doesn’t have to worry about showers of complement protein.”

It was previously thought that the complement system did not exist in the brain, but in 2007, Barres’ group discovered that this system is actually hard at work in the brains of infants. As a young brain grows, it generates an excess of synapses that will potentially form new neural circuits. However, since too many synapses are created, the brain had to develop a mechanism for eliminating the ones deemed unnecessary.

“The mystery was nobody knew how the extra synapses were removed,” Barres explained.

Through their research, they found that this synaptic pruning was done by the complement system. The microglia ? the brain’s version of immune cells ? were secreting C1q, while other brain cells called astrocytes were responsible for secreting the rest of the complement proteins. As a result, the microglia would then attack the complement coated synapses, eliminating the excess from the brain.

“This is what really got us interested,” Barres said. “Neurodegenerative disorders are well described as unwanted synapse degeneration. So there is massive synapse loss, but no one knows why. We thought maybe the complement system is way overactive in Alzheimer’s. It’s not normally active in the typical adult brain, but in Alzheimer’s, it turns on like a switch.”

Complement gone wrong

Barres explained that when the complement system gets reactivated in the aging brain, an overabundance of C1q is created by the microglia, while the other complement proteins are somehow not activated. The C1q then targets the synapses but does not get cleared from the brain, so the protein remains on the neural connectors ? causing more and more damage.

Barres’ explanation for this is that the synapses in the aging brain are different from those in the developing brain.

“We infer the existence of aging synapses that aren’t present in young brains ? what we call senescent synapses,” Barres said. “We don’t know why they become this way. We infer that the old synapses are changing with age. One of the things about the brain that makes it different from most other tissues is the cells don’t turnover. The neurons you’re born with you’ll have your entire life.”

It’s possible that the senescent synapses become “sticky,” Barres theorized, which allows for this accumulation of C1q. This leaves the synapses on the brink of catastrophe, since a traumatic brain event such as a trauma or a stroke could trigger an activation of the remaining complement proteins, leading to massive synapse destruction.

According to Barres, his findings stand in contrast to current ways of thinking, as most scientists believe the pathology of Alzheimer’s begins with the buildup of amyloid plaque, which causes the loss of brain synapses and subsequent inflammation. Instead, he believes the amyloid buildup is a symptom of the disease rather than the cause.

“We think people have the ordering backwards,” Barres said. “We believe the complement turns on first and starts to kill synapses. If that’s true, the implication is we just need to block this complement cascade to treat Alzheimer’s.”

Barres is so confident about his findings that he is already developing a drug to target the complement system in the brain. In 2011, he co-founded a company, Annexon, which has been working on creating a drug that binds and inhibits the C1q protein. While their main focus has been on alleviating the effects of Alzheimer’s, Barres said this kind of drug could potentially help those suffering from a full range of neurodegenerative disease.

“One thing is clear is that the compliment mechanism is activated very highly in all neurodegenerative diseases ? Parkinson’s, multiple sclerosis, Alzheimer’s, Huntington’s, etc.,” Barres said. “If we can block this pathway, we should be able to block the neurodegeneration process in many, many people.”

The research was published in the Journal of Neuroscience.

A Dramatic Increase of C1q Protein in the CNS during Normal Aging

Alexander H. Stephan1,
Daniel V. Madison2,
Jos? Mar?a Mateos3,
Deborah A. Fraser4,
Emilie A. Lovelett1,
Laurence Coutellier5,
Leo Kim5,
Hui-Hsin Tsai6,7,8,
Eric J. Huang9,
David H. Rowitch6,7,8,
Dominic S. Berns1,
Andrea J. Tenner4,
Mehrdad Shamloo5, and
Ben A. Barres1

1Stanford University School of Medicine, Departments of Neurobiology and
2Molecular and Cellular Physiology, Stanford, California 94305-5345,
3Center for Microscopy and Image Analysis, University of Zurich, 8057 Zurich, Switzerland,
4Departments of Molecular Biology and Biochemistry, Neurobiology and Behavior, and Pathology and Laboratory Medicine, University of California, Irvine, California 92697-3900,
5Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, California 94305-5345,
6Howard Hughes Medical Institute,
7Department of Pediatrics,
8Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and
9Department of Pathology, University of California San Francisco, San Francisco, California 94143-0734

D. A. Fraser's present address: Department of Biological Sciences, California State University at Long Beach, 1250 Bellflower Boulevard, Long Beach, CA 90840-9502.

Author contributions: A.H.S., D.V.M., J.M.M., L.C., and B.A.B. designed research; A.H.S., D.V.M., J.M.M., E.A.L., L.K., H.-H.T., E.J.H., D.H.R., and D.S.B. performed research; D.A.F. and A.J.T. contributed unpublished reagents/analytic tools; A.H.S., D.V.M., J.M.M., E.A.L., L.C., L.K., and M.S. analyzed data; A.H.S. and B.A.B. wrote the paper.


The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.
Received March 29, 2013.
Revision received May 26, 2013.
Accepted July 15, 2013.
Copyright ? 2013 the authors 0270-6474/13/3313460-15$15.00/0