‘Critical Insights’ for Treating, Preventing Alzheimer’s Disease

(Northeastern University) New research led by Northeastern University suggests that Alzheimer’s disease may not progress like falling dominoes, as conventional wisdom holds, with one molecular event sparking the formation of plaques throughout the brain. Instead, it may progress like a fireworks display, with a unique flare launching each plaque, one by one.

The study, headed by Lee Makowski, professor and chair of the Department of Bioengineering, was published Thursday in the journal Scientific Reports.

“I believe the findings will provide us with a new way of thinking about the molecular basis for Alzheimer’s ,” says Makowski.

“Once you do that, you can start asking the right questions about how to prevent it.”

More than 5 million Americans are living with Alzheimer’s disease, according to the Alzheimer’s Association. It is the sixth leading cause of death in the U.S., the association reports, killing more people than breast and prostate cancers combined.

Yet much about its cause and the mechanisms driving its progression remain unknown. Alzheimer’s disease typically starts with the death of brain cells, or “neurons,” in one part of the brain and then, over time, slowly spreads to other regions. Amyloid fibrils—thin rigid strands of protein aggregates—accumulate in these areas of neuronal death, packing together to form dense plaques.

“Just as there are different strains of a virus, there appear to be different strains of fibrils,” explains Makowski.

“Remarkably, the different strains have the same chemical makeup but different three-dimensional structures.”

Insight into Therapies

It was the structures that Makowski’s team zeroed in on.

In collaboration with researchers from Massachusetts General Hospital and Argonne National Laboratory’s Advanced Photon Source, Makowski and former research associate Jiliang Liu, PhD’15, scanned slices of brain tissue retrieved at autopsy from four people with Alzheimer’s and one with no history of dementia using an X-ray beam just five microns across. They then built images of the fibrous structures within the plaques from the thousands of diffraction patterns they collected.

Because fibrils self-propagate, researchers have speculated that all fibrils in a given brain are of the same strain and hence have the same structure. That led to the assumption that a single molecular event initiated their accumulation into plaques and the subsequent cascading progression of the disease.

“Our data wasn’t consistent with that,” says Makowski.

“We found that fibrils with distinctly different structures can accumulate in the same brain, even in plaques quite close to one another.

This strongly suggests that there is not one event that initiates fibril formation throughout the brain but many.

Our research indicates that it is the condition under which fibrils form that slowly propagates through the brain and triggers a distinct initiation event for each plaque.”

Think of a cold front traveling south from Massachusetts to Virginia. It’s raining up and down the East Coast. When conditions are right in Massachusetts—that is, when the temperature drops to 32 degrees—the rain turns to snow (the initiation event). Virginia, however, doesn’t get any snow until a week later when its temperature drops to the freezing point. As in the , the conditions drive the event.

“The findings are important because they change the way we think about disease progression,” says Makowski.

“It gives us a new point of view from which to develop hypotheses about the conditions that lead to the formation of fibrils and plaques.”

The researchers also showed that the structure of the fibrils may vary based on a person’s clinical history. For example, the fibrils of one woman who had exhibited no signs of dementia prior to death were distinctly different from those found in the others, who had Alzheimer’s disease.

“This may mean that some strains of are associated with disease whereas others are not,” says Makowski.

“Distinguishing between them may provide critical insights for developing therapies to slow, halt, or reverse the neurodegeneration associated with Alzheimer’s disease.”



By Thea Singer

© 2016 Northeastern University



Elevating Brain Protein Allays Symptoms of Alzheimer’s and Improves Memory

(MedicalNewsToday) Boosting levels of a specific protein in the brain alleviates hallmark features of Alzheimer’s disease in a mouse model of the disorder, according to new research published online in Scientific Reports.

The protein, called neuregulin-1, has many forms and functions across the brain and is already a potential target for brain disorders such as Parkinson’s disease, amyotrophic lateral sclerosis and schizophrenia.

“Neuregulin-1 has broad therapeutic potential, but mechanistically, we are still learning about how it works,”

says the study’s senior investigator Kuo-Fen Lee, a professor in the Salk Institute’s Clayton Foundation Laboratories for Peptide Biology and holder of the Helen McLoraine Chair in Molecular Neurobiology.

“We’ve shown that it promotes metabolism of the brain plaques that are characteristic of Alzheimer’s disease.”

Previously, researchers have shown that treating cells with neuregulin-1, for example, dampens levels of amyloid precursor protein, a molecule that generates amyloid beta, which aggregate and form plaques in the brains of Alzheimer’s patients. Other studies suggest that neuregulin-1 could protect neurons from damage caused by blockage of blood flow.

In the new study, Lee’s team tested this idea in a mouse model of Alzheimer’s disease by raising the levels of one of two forms of neuregulin-1 in the hippocampus, an area of the brain responsible for learning and memory. Both forms of the protein seemed to improve performance on a test of spatial memory in the models.

What’s more, the levels of cellular markers of disease – including the levels of amyloid beta and plaques – were noticeably lower in mice with more neuregulin-1 compared to controls.

The group’s experiments suggest that neuregulin-1 breaks up plaques by raising levels of an enzyme called neprilysin, shown to degrade amyloid-beta. But that is probably not the only route through which neuregulin-1 confers its benefits, and the group is exploring other possible mechanisms – such as whether the protein improves signaling between neurons, which is impaired in Alzheimer’s – says the study’s first author Jiqing Xu, a research associate in Lee’s group.

A neuregulin-1 treatment is not available on the market, though it is being explored in clinical trials as a potential treatment for chronic heart failure and Parkinson’s disease. One advantage of neuregulin-1 as a potential drug is that it can cross the blood brain barrier, which means that it could be administered relatively noninvasively even though the efficiency is not clear.

On the other hand, other research suggests too much of the protein impairs brain function. Working with chemists at Salk, Lee’s team has come up with a small molecule that can raise levels of existing neuregulin-1 (rather than administering it directly) and are testing it in cells. This alternative therapy could be a better way to prevent plaques from forming because small molecules more readily cross the blood brain barrier.

The group is also interested in neuregulin-1 for its ties to schizophrenia. An alteration in the neuregulin-1 gene – a single change in one letter of the DNA code for the protein – has been found in families with schizophrenia and linked to late-onset Alzheimer’s disease with psychosis. The protein may be a way to understand the overlap between Alzheimer’s and other brain disorders, Lee says.

An important caveat is that the new research was conducted in a single type of mouse model of Alzheimer’s. Lee’s group is testing neuregulin-1’s affects across other models.

“There’s much more work ahead before neuregulin-1 could become a treatment, but we are excited about its potential, possibly in combination with other therapeutics for Alzheimer’s disease,” Lee says.

The research was supported by the National Institutes of Health, the Clayton Foundation, The Albert G. and Olive H. Schlink Foundation, the Gemcon Family Foundation and the Brown Foundation.



Article: Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer’s disease model, Jiqing Xu, Fred de Winter, Catherine Farrokhi, Edward Rockenstein, Michael Mante, Anthony Adame, Jonathan Cook, Xin Jin, Eliezer Masliah & Kuo-Fen Lee, Scientific Reports, doi:10.1038/srep31692, published online 25 August 2016.

MediLexicon International Ltd, Bexhill-on-Sea, UK

© 2004-2016 All rights reserved.


Midlife Physical Activity Associated with Better Cognition in Old Age

(University of Helsinki) A new study of 3050 twins finds moderately vigorous physical activity – i.e., more strenuous than walking – to be associated with better cognition in a 25-year follow-up.

A long-term follow-up study of 3050 twins from the Finnish Twin Cohort has shown that midlife, moderately vigorous physical activity is associated with better cognition at old age. The association was statistically independent of midlife hypertension, smoking, education level, sex, obesity and binge drinking.

“This suggests that the beneficial influence of physical activity on the brain and cognition is not solely based on decreasing vascular risk factors”, says researcher Paula Iso-Markku from the University of Helsinki.

The association was studied first in all individuals of the cohort, and then by comparing later cognition in pairs where one twin was more physically active than the other.

Increasing the volume of physical activity was not, however, associated with increased memory-protecting benefits. Instead, quite a moderate amount of physical activity was found to be sufficient for memory-protecting benefits, and only the most inactive group of twins stood out with a significantly higher risk for cognitive impairment.

“Overall, the study shows that moderately vigorous physical activity, meaning more strenuous than walking, is associated with better cognition after an average of 25 years”, states Professor Urho Kujala from the University of Jyväskylä.

“This finding is in accordance with earlier animal model studies, which have shown that physical activity increases the amount of growth factors in the brain and improves synaptic plasticity.”

The prevalence of dementia has increased with aging populations both in Finland and globally. Although the incidence of dementia seems to have decreased in less senior generations, the total prevalence of dementia is still expected to rise. No cure for dementia exists, but during the last decade research has produced an abundance of new information on dementia prevention. The traditional vascular risk factors (elevated blood pressure, hypercholesterolemia, obesity, diabetes and lack of exercise) have also been associated with dementia risk.

“However, few long-term, high-quality, follow-up studies on physical activity and cognition have been published, and it has remained unclear what type and amount of exercise is needed to safeguard cognition”, Iso-Markku says.

The study, published in the Journal of Alzheimer’s Disease, was conducted by scientists at the universities of Helsinki, Jyväskylä and Turku. The twins provided information on physical activity through questionnaire surveys from 1975 and 1981 (mean age in 1981: 49 years), while cognition was assessed by validated telephone interviews conducted between 1999 and 2015.



Reference: Iso-Markku P, Waller K, Vuoksimaa E, Heikkilä K, Rinne J, Kaprio J, Kujala UM. Midlife Physical Activity and Cognition Later in Life: A Prospective Twin Study. J Alzheimers Dis. 2016 Sep 2 (Epub ahead of print). DOI 10.3233/JAD-160377 

© University of Helsinki 2016


How “Super Aging” Older Adults Retain Youthful Memory Abilities

(Massachusetts General Hospital) Some loss of memory is often considered an inevitable part of aging, but new research reveals how some people appear to escape that fate. A study by Massachusetts General Hospital (MGH) investigators examines a remarkable group of older adults whose memory performance is equivalent to that of younger individuals and finds that certain key areas of their brains resemble those of young people.

The study published in The Journal of Neuroscience is the first step in a research program aimed at understanding how some older adults retain youthful thinking abilities and the brain circuits that support those abilities. The program is led by Bradford Dickerson, MD, director of the Frontotemporal Disorders Unit in the MGH Department of Neurology and Lisa Feldman Barrett, PhD, MGH Department of Psychiatry, who are co-senior authors of the new study.

While most older adults experience a gradual decline in memory ability, some researchers have described older adults – sometimes called “super agers” – with unusually resilient memories. For the current study, the MGH team enrolled 40 adults ages 60 to 80 – 17 of whom performed as well as adults four to five decades younger on memory tests, and 23 with normal results for their age group – and 41 young adults ages 18 to 35.

“Previous research on super aging has compared people over age 85 to those who are middle aged,” says Alexandra Touroutoglou, PhD, MGH Neurology, co-senior author with Dickerson and Barrett.

“Our study is exciting because we focused on people around or just after typical retirement age – mostly in their 60s and 70s – and investigated those who could remember as well as people in their 20s.

Imaging studies revealed that these super agers had brains with youthful characteristics. While the cortex – the outermost sheet of brain cells that is critical for many thinking abilities – and other parts of the brain typically shrink with aging, in the brains of super-agers a number of those regions were comparable in size to those of young adults.

“We looked at a set of brain areas known as the default mode network, which has been associated with the ability to learn and remember new information, and found that those areas, particularly the hippocampus and medial prefrontal cortex, were thicker in super agers than in other older adults.

In some cases, there was no difference in thickness between super agers and young adults,” Touroutoglou says.

Barrett, who is also University Distinguished Professor at Northeastern University, adds,

“We also examined a group of regions known as the salience network, which is involved in identifying information that is important and needs attention for specific situations, and found preserved thickness among super-agers in several regions, including the anterior insula and orbitofrontal cortex.”

Critically, the researchers showed not only that super-agers had no shrinkage in these brain networks but also that the size of these regions was correlated with memory ability. One of the strongest correlations between brain size and memory was found in an area at the intersection of the salience and default mode networks.

Previous research has shown that this region – the para-midcingulate cortex – is an important hub that allows different brain networks to communicate efficiently.

“We believe that effective communication between these networks is very important for healthy cognitive aging,” says Touroutoglou, who is an instructor in Neurology at Harvard Medical School (HMS).

Understanding which factors protect against memory decline could lead to important advances in preventing and treating age-related memory loss and possibly even various forms of dementia, says Dickerson, who is an associate professor of Neurology at HMS.

“We desperately need to understand how some older adults are able to function very well into their seventh, eight, and ninth decades. This could provide important clues about how to prevent the decline in memory and thinking that accompanies aging in most of us.”

Dickerson is part of the newly launched Institute for Brain Health, a joint effort between the MGH Departments of Neurology and Psychiatry aiming find new ways to promote healthy brain function over the lifespan. Felica Sun, of the Martinos Center for Biomedical Imaging at MGH, and Michael Stepanovic, MGH Neurology, are co-lead authors of the Journal of Neuroscience paper; and Joseph Andreano, PhD, MGH Psychiatry, is also a co-author. The study was supported by National Institute of Aging grant R01 AG030311.



Copyright © 2007-2016. The General Hospital Corporation. All Rights Reserved.


An Alzheimer’s Drug Shows Serious Promise

(Time) Experts are excited about a drug that, at high doses, seems to chip away at Alzheimer’s damage in the brain.

Treating Alzheimer’s likely won’t ever be an easy or simple thing. Researchers think that managing the disease will require a combination of treatments, possibly tailored to each person. But in a paper published Wednesday in the journal Nature, scientists from a biotech company report the most encouraging results so far for one drug that could play a key role.

Researchers at Biogen say that the antibody they have been testing can bind to and break down the amyloid protein that builds up in abnormal amounts in the brains of Alzheimer’s patients. Even more encouraging, they report that for a small number of people in the study, that reduction in amyloid plaques was linked to a slowing in the cognitive decline associated with Alzheimer’s.

“We are pretty certain of the fact that the antibody reduces the amyloid plaques and in some ways gets rid of the majority of it,” says Alfred Sandrock, senior author of the paper from Massachusetts-based Biogen.

“That’s important because if we really want to treat Alzheimer’s at even the very earliest stages, then we felt it was important for our antibody to remove the plaque that’s already there.”

The results of the trial, which Biogen has revealed in pieces at previous scientific conferences, shows that the higher the dose of the antibody, called aducanumab, the more amyloid is removed.

In the trial of 165 people with mild to moderate Alzheimer’s, participants were randomly assigned to receive either placebo or one of three different doses of the drug. After a year of monthly infusions, those receiving the highest doses showed the most reduction in amyloid compared to the start of the study.

The small number of people who were tested on cognitive function showed promising signs that reducing the amount of amyloid in the brain might translate into improved function, but that’s just an early hint. The company is recruiting people for two other ongoing trials that aim to answer that question. So far, though, the drug seems to slow the cognitive decline; whether this decline can return brains to their pre-amyloid, pre-Alzheimer’s function won’t be known until the additional studies are completed.

What happens when amyloid builds up in the brain is a complex process that involves damage, some of it permanent, to nerves and neural networks. But animal work showed that some nerves surrounding amyloid plaques were restored to close to their original function, providing hope that it might be possible to recover at least some cognitive function if amyloid plaques are removed.

It’s not clear yet exactly how the antibody is melting away the plaque, but studies in animals may provide a clue. In earlier trials, researchers think the aducanumab is breaking down the amyloid and attracting the body’s immune system to dispatch the remnants — specifically a class of cells known as microglia, which can digest biological residue.

Aducanumab is one of several anti-amyloid strategies that companies are pursuing to treat Alzheimer’s. Biogen believes its compound has an advantage in that it doesn’t bind to amyloid that most people have circulating in the blood; instead it preferentially targets the amyloid that is aggregated in plaques in the brain, which Alzheimer’s experts believe is the most toxic form of the protein and responsible for the disease’s symptoms of memory problems and cognitive decline.

The drug is not without side effects. The people getting the highest dose showed higher rates of a brain swelling that’s been linked with aducanumab and other drugs in earlier trials. About 41% of those receiving the drug at any dose showed this side effect.

Stephen Salloway, professor of neurology and psychiatry at Brown University and one of the co-authors of the paper, says that swelling could be monitored with more frequent brain scans. The researches also learned that people with a genetic predisposition to developing Alzheimer’s are also at higher risk of developing the side effect.

Salloway says that more studies will be needed to understand what is causing the swelling, but it’s possible that the dramatic change in amyloid could be the major factor. Most of the swelling occurs soon after people start taking the drug, and it subsides if they stop the treatment.

“At this point, I would not be so concerned that I would advise people not to participate in the trials of the drug,” says James Hendrix, director of global science initiatives at the Alzheimer’s Association.

“It’s something the company is keenly aware of, that the Food and Drug Administration is keenly aware of, and the we just need to see if we can manage the risk. I’m very excited by these results.”

If the additional studies confirm these early results, it’s possible that aducanumab could be used as a preventive therapy doctors prescribe to people who might be at higher risk of developing Alzheimer’s. Routine screening for amyloid could also become more common if treatments like these become available, so that doctors can find those who might benefit most from these medications and stop the disease before it really takes hold.


http://time.com/4473174/ most-promising-results-yet-for-alzheimers-treatment/

By Alice Park

© 2016 Time Inc. All rights reserved.


Memory Loss Not Enough to Diagnose Alzheimer’s

(Northwestern University) Alzheimer’s disease can have symptoms other than memory loss.

Relying on clinical symptoms of memory loss to diagnose Alzheimer’s disease may miss other forms of dementia caused by Alzheimer’s that don’t initially affect memory, reports a new Northwestern Medicine study.

“These individuals are often overlooked in clinical trial designs and are missing out on opportunities to participate in clinical trials to treat Alzheimer’s,” said first study author Emily Rogalski, associate professor at Northwestern’s Cognitive Neurology and Alzheimer’s Disease Center.

There is more than one kind of Alzheimer’s disease. Alzheimer’s can cause language problems, disrupt an individual’s behavior, personality and judgment or even affect someone’s concept of where objects are in space.

If it affects personality, it may cause lack of inhibition.

“Someone who was very shy may go up to grocery store clerk — who is a stranger — and try to give her a hug or kiss,” Rogalski said.

This all depends on what part of the brain it attacks. A definitive diagnosis can only be achieved with an autopsy. Emerging evidence suggests an amyloid PET scan, an imaging test that tracks the presence of amyloid — an abnormal protein whose accumulation in the brain is a hallmark of Alzheimer’s — may be used during life to determine the likelihood of Alzheimer’s disease pathology.

In the study, the authors identify the clinical features of individuals with primary progressive aphasia (PPA), a rare dementia that causes progressive declines in language abilities due to Alzheimer’s disease.  Early on in PPA, memory and other thinking abilities are relatively intact.

PPA can be caused either by Alzheimer’s disease or another neurodegenerative disease family called frontotemporal lobar degeneration. The presence of Alzheimer’s disease was assessed in this study by amyloid PET imaging or confirmed by autopsy.

The study demonstrates that knowing an individual’s clinical symptoms isn’t sufficient to determine whether someone has PPA due to Alzheimer’s disease or another type of neurodegenerative disease. Therefore, biomarkers, such as amyloid PET imaging, are necessary to identify the neuropathological cause, the authors said.

Northwestern scientists looked at individuals in mild stages of language loss caused by Alzheimer’s disease and described their brain atrophy based on MRI scans and their results on cognitive tests.

“We wanted to describe these individuals to raise awareness about the early clinical and brain features of PPA to develop metrics which would advocate for their inclusion in clinical trials targeting Alzheimer’s disease,” Rogalski said.

“These individuals are often excluded because they don’t have memory deficits, but they share the same disease [Alzheimer’s] that’s causing their symptoms.”

The study was published online in the journal Neurology Aug. 26.

Dr. Marsel Mesulam, director of the Cognitive Neurology and Alzheimer’s Disease Center and the Ruth Dunbar Davee Professor of Neuroscience at Northwestern University Feinberg School of Medicine, is senior author of the paper.

The study was funded by grants DC008552 from the National Institute on Deafness and Other Communication Disorders, AG13854 from the National Institute on Aging,  NS075075 from the National Institute of Neurological Disorders and Stroke, all of the National Institutes of Health.



by Marla Paul

Copyright Northwestern University


Alzheimer’s Beginnings Prove to be a Sticky Situation

(Michigan State University) Laser technology has revealed a common trait of Alzheimer’s disease – a sticky situation that could lead to new targets for medicinal treatments.

Alzheimer’s statistics are always staggering. The neurodegenerative disease affects an estimated 5 million Americans, one in three seniors dies with Alzheimer’s or a form of dementia, it claims more lives than breast and prostate cancers combined, and its incidence is rising.

To help fight this deadly disease, Lisa Lapidus, Michigan State University professor of physics and astronomy, has found that peptides, or strings of amino acids, related to Alzheimer’s wiggle at dangerous speeds prior to clumping or forming the plaques commonly associated with Alzheimer’s.

“Strings of 40 amino acids are the ones most-commonly found in healthy individuals, but strings of 42 are much more likely to clump,” said Lapidus, who published the results in the current issue of ChemPhysChem.

“We found that the peptides’ wiggle speeds, the step before aggregation, was five times slower for the longer strings, which leaves plenty of time to stick together rather than wiggle out of the way.”

This so-called “wiggle” precedes clumping, or aggregating, which is the first step of neurological disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Lapidus pioneered the use of lasers to study the speed of protein reconfiguration before aggregation.

If reconfiguration is much faster or slower than the speed at which proteins bump into each other, aggregation is slow. If reconfiguration is the same speed, however, aggregation is fast. She calls the telltale wiggle that she discovered the “dangerous middle.”

“The dangerous middle is the speed in which clumping happens fastest,” Lapidus said.

“But we were able to identify some ways that we can bump that speed into a safer zone.”

Lapidus and her team of MSU scientists, including Srabasti Acharya (now a biotechnology researcher in the San Francisico Bay area), Kinshuk Srivastava and Suresh Babu Nagarajan, found that increasing pH levels kept the amino acids wiggling at fast, safe speeds. Also, a naturally occurring molecule, curcumin (from the spice turmeric), kept the peptide out of the dangerous middle.

While this is not a viable drug candidate because it does not easily cross the blood-brain barrier, the filter that controls what chemicals reach the brain, they do provide strong leads that could lead to medicinal breakthroughs.

Along with new drug targets, Lapidus’ research provides a potential model of early detection. By the time patients show symptoms and go to a doctor, aggregation already has a stronghold in their brains. Policing amino acids for wiggling at dangerous speeds could tip off doctors long before the patient begins to suffer from the disease.

This research was funded by the National Institutes of Health.


Journal Reference:

Srabasti Acharya, Kinshuk Raj Srivastava, Sureshbabu Nagarajan, Lisa Jill Lapidus. Monomer dynamics of the Alzheimer peptides and Kinetic Control of Early Aggregation in Alzheimer’s Disease. ChemPhysChem, 2016; DOI: 10.1002/cphc.201600706

© Michigan State University

Specific Herbicides Induce Amyloid-β42 Production

(Journal of Alzheimer’s Disease) A new study led by Laurent Meijer, at ManRos Therapeutics, and collaborators shows that some herbicides (triazines) trigger enhanced in vitro production of the Aβ42 over Aβ40 amyloid peptides in various cell lines.

This suggests that some products from the ‘human chemical exposome’ (HCE) (estimated to be over 85,000 products) may contribute to the increased production of Aβ42 over Aβ40 characteristic of Alzheimer’s disease (AD).

In addition, some of these products might be turned into pharmacological tools to develop a chemically-induced animal model of AD (in contrast with the currently used genetic, recombinant mice models). Publication of these findings is scheduled in the Journal of Alzheimer’s Disease, vol. 54(4) issue. This work is now continuing with special focus on (1) Persistent Organic Pollutants (POPs) and (2) defining conditions under which such products could trigger in vivo Aβ42 production in mice.

Identifying products able to induce Aβ42 production may be a key to understand some of the initiating causes of sporadic AD and to generate non-recombinant, chemically-induced AD animal models. A cell model was used to screen HCE libraries for Aβ42 inducers. Out of 3500+ compounds tested, six triazine herbicides were found that induced a β- and γ-secretases -dependent, 2-10 fold increase in the production of extracellular Aβ42 in various cell lines, primary neuronal cells and neurons differentiated from human induced pluripotent stem cells (iPSCs from a healthy or a familial AD patient (APP K724N)).

Immunoprecipitation/mass spectrometry analyses show enhanced production of Aβ peptides cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and lower, a characteristic of AD. Triazines also shifted the cleavage pattern of alcadeinα, another γ-secretase substrate, suggesting a direct effect of triazines on γ-secretase activity.

In conclusion, several widely used triazines enhance the production of toxic, aggregation prone Aβ42/Aβ43 amyloids, suggesting the possible existence of environmental “Alzheimerogens” (by analogy with carcinogens) which may contribute to the initiation and propagation of the amyloidogenic process in late-onset AD.