Posts tagged amyloid plaques
Articles and news from the latest research reports.
Caffeine against Alzheimer’s disease
A team of researchers working with Prof. Dr. Christa E. Müller from the University of Bonn demonstrates a positive effect on tau deposits
As part of a German-French research project, a team led by Dr. Christa E. Müller from the University of Bonn and Dr. David Blum from the University of Lille was able to demonstrate for the first time that caffeine has a positive effect on tau deposits in Alzheimer’s disease. The two-years project was supported with 30,000 Euro from the non-profit Alzheimer Forschung Initiative e.V. (AFI) and with 50,000 Euro from the French Partner organization LECMA. The initial results were published in the online edition of the journal “Neurobiology of Aging”
Tau deposits, along with beta-amyloid plaques, are among the characteristic features of Alzheimer’s disease. These protein deposits disrupt the communication of the nerve cells in the brain and contribute to their degeneration. Despite intensive research there is no drug available to date which can prevent this detrimental process. Based on the results of Prof. Dr. Christa Müller from the University of Bonn, Dr. David Blum and their team, a new class of drugs may now be developed for the treatment of Alzheimer’s disease.
Caffeine, an adenosine receptor antagonist, blocks various receptors in the brain which are activated by adenosine. Initial results of the team of researchers had already indicated that the blockade of the adenosine receptor subtype A2A in particular could play an important role. Initially, Prof. Müller and her colleagues developed an A2A antagonist in ultrapure and water-soluble form (designated MSX-3). This compound had fewer adverse effects than caffeine since it only blocks only the A2A adenosine receptor subtype, and at the same time it is significantly more effective. Over several weeks, the researchers then treated genetically altered mice with the A2A antagonist. The mice had an altered tau protein which, without therapy, leads to the early development of Alzheimer’s symptoms.
In comparison to a control group which only received a placebo, the treated animals achieved significantly better results on memory tests. The A2A antagonist displayed positive effects in particular on spatial memory. Also, an amelioration of the pathogenic processes was demonstrated in the hippocampus, which is the site of memory in rodents.
"We have taken a good step forward," says Prof. Müller. "The results of the study are truly promising, since we were able to show for the first time that A2A adenosine receptor antagonists actually have very positive effects in an animal model simulating hallmark characteristics and progression of the disease. And the adverse effects are minor."
The researchers now want to test the A2A antagonist in additional animal models. If the results are positive, a clinical study may follow. “Patience is required until A2A adenosine receptor antagonists are approved as new therapeutic agents for Alzheimer’s disease. But I am optimistic that clinical studies will be performed,” says Prof. Müller.
(Image: Shutterstock)
High good and low bad cholesterol levels are healthy for the brain, too
High levels of “good” cholesterol and low levels of “bad” cholesterol are correlated with lower levels of the amyloid plaque deposition in the brain that is a hallmark of Alzheimer’s disease, in a pattern that mirrors the relationship between good and bad cholesterol in cardiovascular disease, UC Davis researchers have found.
“Our study shows that both higher levels of HDL — good — and lower levels of LDL — bad — cholesterol in the bloodstream are associated with lower levels of amyloid plaque deposits in the brain,” said Bruce Reed, lead study author and associate director of the UC Davis Alzheimer’s Disease Center.
“Unhealthy patterns of cholesterol could be directly causing the higher levels of amyloid known to contribute to Alzheimer’s, in the same way that such patterns promote heart disease,” he said.
The relationship between elevated cholesterol and increased risk of Alzheimer’s disease has been known for some time, but the current study is the first to specifically link cholesterol to amyloid deposits in living human study participants, Reed said.
The study, “Associations Between Serum Cholesterol Levels and Cerebral Amyloidosis,” is published online today in JAMA Neurology.
In the United States, cholesterol levels are measured in milligrams (mg) of cholesterol per deciliter (dL) of blood. For HDL cholesterol, a level of 60 mg/dl or higher is best. For LDL cholesterol, a level of 70 mg/dL or lower is recommended for people at very high risk of heart disease.
Charles DeCarli, director of the Alzheimer’s Disease Center and an author of the study, said it is a wake-up call that, just as people can influence their late-life brain health by limiting vascular brain injury through controlling their blood pressure, the same is true of getting a handle on their serum cholesterol levels.
“If you have an LDL above 100 or an HDL that is less than 40, even if you’re taking a statin drug, you want to make sure that you are getting those numbers into alignment,” DeCarli said. “You have to get the HDL up and the LDL down.”
The study was conducted in 74 diverse male and female individuals 70 years and older who were recruited from California stroke clinics, support groups, senior facilities and the Alzheimer’s Disease Center. They included three individuals with mild dementia, 33 who were cognitively normal and 38 who had mild cognitive impairment.
The participants’ amyloid levels were obtained using a tracer that binds with amyloid plaques and imaging their brains using PET scans. Higher fasting levels of LDL and lower levels of HDL both were associated with greater brain amyloid — a first-time finding linking cholesterol fractions in the blood and amyloid deposition in the brain. The researchers did not study the mechanism for how cholesterol promotes amyloid deposits.
Recent guidelines instituted by the American College of Cardiology, the American Heart Association and the National Heart, Lung, and Blood Institute have suggested abandoning guidelines for LDL targets. Reed said that recommendation may be an instance in which the adage that “what’s good for the heart is good for the brain” does not apply.
“This study provides a reason to certainly continue cholesterol treatment in people who are developing memory loss, regardless of concerns regarding their cardiovascular health,” said Reed, a professor in the UC Davis Department of Neurology.
“It also suggests a method of lowering amyloid levels in people who are middle aged, when such build-up is just starting,” he said. “If modifying cholesterol levels in the brain early in life turns out to reduce amyloid deposits late in life, we could potentially make a significant difference in reducing the prevalence of Alzheimer’s, a goal of an enormous amount of research and drug development effort.”
Copper Identified as Culprit in Alzheimer’s Disease
Copper appears to be one of the main environmental factors that trigger the onset and enhance the progression of Alzheimer’s disease by preventing the clearance and accelerating the accumulation of toxic proteins in the brain. That is the conclusion of a study appearing today in the journal Proceedings of the National Academy of Sciences.
“It is clear that, over time, copper’s cumulative effect is to impair the systems by which amyloid beta is removed from the brain,” said Rashid Deane, Ph.D., a research professor in the University of Rochester Medical Center (URMC) Department of Neurosurgery, member of the Center for Translational Neuromedicine, and the lead author of the study. “This impairment is one of the key factors that cause the protein to accumulate in the brain and form the plaques that are the hallmark of Alzheimer’s disease.”
Copper’s presence in the food supply is ubiquitous. It is found in drinking water carried by copper pipes, nutritional supplements, and in certain foods such as red meats, shellfish, nuts, and many fruits and vegetables. The mineral plays an important and beneficial role in nerve conduction, bone growth, the formation of connective tissue, and hormone secretion.
However, the new study shows that copper can also accumulate in the brain and cause the blood brain barrier – the system that controls what enters and exits the brain – to break down, resulting in the toxic accumulation of the protein amyloid beta, a by-product of cellular activity. Using both mice and human brain cells Deane and his colleagues conducted a series of experiments that have pinpointed the molecular mechanisms by which copper accelerates the pathology of Alzheimer’s disease.
Under normal circumstances, amyloid beta is removed from the brain by a protein called lipoprotein receptor-related protein 1 (LRP1). These proteins – which line the capillaries that supply the brain with blood – bind with the amyloid beta found in the brain tissue and escort them into the blood vessels where they are removed from the brain.
The research team“dosed” normal mice with copper over a three month period. The exposure consisted of trace amounts of the metal in drinking water and was one-tenth of the water quality standards for copper established by the Environmental Protection Agency.
“These are very low levels of copper, equivalent to what people would consume in a normal diet.” said Deane.
The researchers found that the copper made its way into the blood system and accumulated in the vessels that feed blood to the brain, specifically in the cellular “walls” of the capillaries. These cells are a critical part of the brain’s defense system and help regulate the passage of molecules to and from brain tissue. In this instance, the capillary cells prevent the copper from entering the brain. However, over time the metal can accumulate in these cells with toxic effect.
The researchers observed that the copper disrupted the function of LRP1 through a process called oxidation which, in turn, inhibited the removal of amyloid beta from the brain. They observed this phenomenon in both mouse and human brain cells.
The researchers then looked at the impact of copper exposure on mouse models of Alzheimer’s disease. In these mice, the cells that form the blood brain barrier have broken down and become “leaky” – a likely combination of aging and the cumulative effect of toxic assaults – allowing elements such as copper to pass unimpeded into the brain tissue. They observed that the copper stimulated activity in neurons that increased the production of amyloid beta. The copper also interacted with amyloid beta in a manner that caused the proteins to bind together in larger complexes creating logjams of the protein that the brain’s waste disposal system cannot clear.
This one-two punch, inhibiting the clearance and stimulating the production of amyloid beta, provides strong evidence that copper is a key player in Alzheimer’s disease. In addition, the researchers observed that copper provoked inflammation of brain tissue which may further promote the breakdown of the blood brain barrier and the accumulation of Alzheimer’s-related toxins.
However, because metal is essential to so many other functions in the body, the researchers say that these results must be interpreted with caution.
“Copper is an essential metal and it is clear that these effects are due to exposure over a long period of time,” said Deane. “The key will be striking the right balance between too little and too much copper consumption. Right now we cannot say what the right level will be, but diet may ultimately play an important role in regulating this process.”
(Source: urmc.rochester.edu)
New drugs to find the right target to fight Alzheimer’s disease
Next-generation drugs designed to fight Alzheimer’s disease look very promising. Scientists have unveiled the mechanisms behind two classes of compound currently being tested in clinical trials. They have also identified a likely cause of early-onset hereditary forms of the disease.
The future is looking good for drugs designed to combat Alzheimer’s disease. EPFL scientists have unveiled how two classes of drug compounds currently in clinical trials work to fight the disease. Their research suggests that these compounds target the disease-causing peptides with high precision and with minimal side-effects. At the same time, the scientists offer a molecular explanation for early-onset hereditary forms of Alzheimer’s, which can strike as early as thirty years of age. The conclusions of their research, which has been published in the journal Nature Communications, are very encouraging regarding the future of therapeutic means that could keep Alzheimer’s disease in check.
Alzheimer’s disease is characterized by an aggregation of small biological molecules known as amyloid peptides. We all produce these molecules; they play an essential antioxidant role. But in people with Alzheimer’s disease, these peptides aggregate in the brain into toxic plaques – called “amyloid plaques” – that destroy the surrounding neurons.
The process starts with a long protein, “APP”, which is located across the neuron’s membrane. This protein is cut into several pieces by an enzyme, much like a ribbon is cut by scissors. The initial cut generates a smaller intracellular protein that plays a useful role in the neuron. Another cut releases the rest of APP outside the cell – this part is the amyloid peptide.
For reasons not yet well understood, APP protein can be cut in several different places, producing amyloid peptides that are of varying lengths. Only the longer forms of the amyloid peptide carry the risk of aggregating into plaques, and people with Alzheimer’s disease produce an abnormally high number of these.
A favorite Alzheimer’s target: gamma secretase
The two next-generation classes of compound that are currently in clinical trials target an enzyme that cuts APP, known as gamma secretase. Until now, our understanding of the mechanism involved has been lacking. But with this work, the EPFL researchers were able to shed some more light on it by determining how the drug compounds affect gamma secretase and its cutting activity.
In most forms of Alzheimer’s, abnormally large quantities of the long amyloid peptide 42 – named like that because it contains 42 amino acids – are formed. The drug compounds change the location where gamma secretase cuts the APP protein, thus producing amyloid peptide 38 instead of 42, which is shorter and does not aggregate into neurotoxic plaques.
Compared to previous therapeutic efforts, this is considerable progress. In 2010, Phase III clinical trials had to be abandoned, because the compound being tested inhibited gamma-secretase’s function across the board, meaning that the enzyme was also deactivated in essential cellular differentiation processes, resulting to side-effects like in gastrointestinal bleeding and skin cancer.
“Scientists have been trying to target gamma secretase to treat Alzheimer’s for over a decade,” explains Patrick Fraering, senior author on the study and Merck Serono Chair of Neurosciences at EPFL. “Our work suggests that next-generation molecules, by modulating rather than inhibiting the enzyme, could have few, if any, side-effects. It is tremendously encouraging.”
New insights into hereditary forms of the disease
During their investigation, the scientists also identified possible causes behind some hereditary forms of Alzheimer’s disease. Early-onset Alzheimer’s can appear as early as thirty years of age, with a life expectancy of only a few years. In vitro experiments and numerical simulations show that in early-onset patients, mutations in the APP protein gene modify the way by which APP is cut by the gamma-secretase enzyme. This results in overproduction of amyloid peptide 42, which then aggregates into amyloid plaques.
This research illuminates much that is unknown about Alzheimer’s disease. “We have obtained extraordinary knowledge about how gamma secretase can be modulated,” explains co-author Dirk Beher, scientific chief officer of Asceneuron, a spin-off of Merck Serono, the biopharmaceutical division of Merck KGaA, Darmstadt, Germany. “This knowledge will be invaluable for developing even better targeted drugs to fight the disease.”
(Source: actu.epfl.ch)
Path of Plaque Buildup in Brain Shows Promise as Early Biomarker for Alzheimer’s Disease
The trajectory of amyloid plaque buildup—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study published online July 15 in the Journal of Neurobiology of Aging.
Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. “Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,” said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.
Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.
Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.
“It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,” Dr. Davatzikos said. “This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.”
The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analyzed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analyzing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.
Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).
Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.
A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.
“This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,” said Dr Davatzikos. “The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.”
(Source: uphs.upenn.edu)
Alzheimer’s brain change measured in humans
Scientists at Washington University School of Medicine in St. Louis have measured a significant and potentially pivotal difference between the brains of patients with an inherited form of Alzheimer’s disease and healthy family members who do not carry a mutation for the disease.
Researchers have known that amyloid beta, a protein fragment, builds up into plaques in the brains of Alzheimer’s patients. They believe the plaques cause the memory loss and other cognitive problems that characterize the disease. Normal brain metabolism produces different forms of amyloid beta.
The new study shows that research participants with genetic mutations that cause early-onset Alzheimer’s make about 20 percent more of a specific form of amyloid beta – known as amyloid beta 42 – than family members who do not have the Alzheimer’s mutation.
Scientists found another, more surprising difference linked to amyloid beta 42 in mutation carriers: signs that amyloid beta 42 drops out of the cerebrospinal fluid much more quickly than other forms of amyloid beta. This may be because amyloid beta 42 is being deposited on brain amyloid plaques.
“These results indicate how much we should target amyloid beta 42 with Alzheimer’s drugs,” said Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology. “We are hopeful that this and other research will lead to preventive therapies to delay or even possibly prevent Alzheimer’s disease.”
The study appears June 12 in Science Translational Medicine.
In addition to helping develop treatments for inherited Alzheimer’s, investigations of these conditions have helped scientists lay the groundwork for advances in treatment of the much more common sporadic forms of the disease.
Three forms account for most of the amyloid beta found in the cerebrospinal fluid: amyloid beta 38, 40 and 42. Earlier studies of the human brain after death and using animal research had suggested that amyloid beta 42 was the most important contributor to Alzheimer’s. The new study not only confirms this connection but also quantifies overproduction of amyloid beta 42 for the first time in living human brains.
Bateman, who co-developed a technique that measures the rate at which amyloid beta is produced and cleared from the cerebrospinal fluid, contacted several Washington University colleagues to see if they could develop a way to analyze the types of amyloid beta being produced in the brain.
Bateman, metabolism expert Bruce Patterson, PhD, and biomedical engineer Donald Elbert, PhD, created a new mathematical model to describe the production and clearance of amyloid beta.
The scientists applied the model to data from 11 research participants with Alzheimer’s mutations and 12 related family members who did not have the genetic errors that cause Alzheimer’s. The model let the scientists compare the production rates of the protein’s different forms, revealing an increase in amyloid beta 42 production in subjects with an Alzheimer’s gene.
“Working in isolation, any one of us would likely have gotten the wrong answer, or no answer,” Elbert said. “Bringing our different skill sets together let us tackle a very complex physiological problem.”
Scientists are testing the new model on data from approximately 100 Alzheimer’s patients.
“We hope that our new insights about the production and clearance of amyloid beta proteins will pave the way for future studies aimed at understanding and altering the metabolic processes that underlie this devastating disease,” Patterson said.
Exposure to general anaesthesia could increase the risk of dementia in elderly by 35 percent
Exposure to general anaesthesia increases the risk of dementia in the elderly by 35%, says new research presented at Euroanaesthesia, the annual congress of the European Society of Anaesthesiology (ESA). The research is by Dr Francois Sztark, INSERM and University of Bordeaux, France, and colleagues.
Postoperative cognitive dysfunction, or POCD, could be associated with dementia several years later. POCD is a common complication in elderly patients after major surgery. It has been proposed that there is an association between POCD and the development of dementia due to a common pathological mechanism through the amyloid β peptide. Several experimental studies suggest that some anaesthetics could promote inflammation of neural tissues leading to POCD and/or Alzheimer’s disease (AD) precursors including β-amyloid plaques and neurofibrillary tangles. But it remains uncertain whether POCD can be a precursor of dementia.
In this new study, the researchers analysed the risk of dementia associated with anaesthesia within a prospective population-based cohort of elderly patients (aged 65 years and over). The team used data from the Three-City study, designed to assess the risk of dementia and cognitive decline due to vascular risk factors. Between 1999 and 2001, the 3C study included 9294 community-dwelling French people aged 65 years and over in three French cities (Bordeaux, Dijon and Montpellier).
Participants aged 65 years and over were interviewed at baseline and subsequently 2, 4, 7 and 10 years after. Each examination included a complete cognitive evaluation with systematic screening of dementia. From the 2-year follow-up, 7008 non-demented participants were asked at each follow-up whether they have had a history of anaesthesia (general anaesthesia (GA) or local/locoregional anaesthesia (LRA)) since the last follow-up. The data were adjusted to take account of potential confounders such as socioeconomic status and comorbidities.
The mean age of participants was 75 years and 62% were women. At the 2-year follow-up, 33% of the participants (n=2309) reported an anaesthesia over the 2 previous years, with 19% (n=1333) reporting a GA and 14% (n=948) a LRA. A total of 632 (9%) participants developed dementia over the 8 subsequent years of follow-up, among them 284 probable AD and 228 possible AD, and the remaining 120 non-Alzheimer’s dementia. The researchers found that demented patients were more likely to have received anaesthesia (37%) than non-demented patients (32%). This difference in anaesthesia was due to difference in numbers receiving general anaesthetics, with 22% of demented patients reporting a GA compared with 19% of non-demented patients. After adjustment, participants with at least one GA over the follow-up had a 35% increased risk of developing a dementia compared with participants without anaesthesia.
Dr Sztark concludes: “These results are in favour of an increased risk for dementia several years after general anaesthesia. Recognition of POCD is essential in the perioperative management of elderly patients. A long-term follow-up of these patients should be planned.”
(Source: eurekalert.org)
Anti-cancer drug viewed as possible Alzheimer’s treatment doesn’t work in UF study
An anti-cancer drug about to be tested in a clinical trial by a biomedical company in Ohio as a possible treatment for Alzheimer’s disease has failed to work with the same type of brain plaques that plague Alzheimer’s patients, according to results of a study by University of Florida researchers.
David Borchelt, Ph.D., a professor of neuroscience affiliated with the Evelyn F. and William L. McKnight Brain Institute of the University of Florida, emphasized the importance of verifying promising research results before investing in clinical studies or testing potential therapies in people. Bexarotene has known side effects that include effects on the liver, blood and other metabolic systems.
“We wanted to repeat the study to see if we could build on it, and we couldn’t,” he said. “We thought it was important that something like this, which got a lot of publicity and patients were immediately looking to try to get access to this drug, that it was important to publish the fact that we couldn’t reproduce the most exciting part of the study. Maybe there should be some caution going forward in regard to patients.”
Borchelt and Kevin Felsenstein, Ph.D., an associate professor of neuroscience, said a drug called bexarotene that their team orally administered to mice did not reduce amyloid plaques, waxy buildups on the brain that are a key culprit in Alzheimer’s disease. Their findings will be published in the May 24, 2013 issue of the journal Science magazine, with two additional articles (1, 2) detailing similar results from other researchers.
The research follows up on a 2012 Science article that claimed bexarotene had reversed Alzheimer’s-like symptoms in mice afflicted with the plaques. Authors of that study also administered the drug orally.
The paper “indicated that with as little as three days of treatment, they basically cleared the amyloid deposits from these animals, as well as restored cognitive abilities,” Felsenstein said of the 2012 paper.He said the results of the original study were surprising, given decades of research that had failed to find a therapy successful in dismantling amyloid plaques.
“We can shut down the production of amyloid in these animal models and the deposits in these animal models don’t disappear,” Felsenstein said. “These deposits have been described by some as cement, and it will take a lot to get rid of them. The fact that something could actually make them disappear in literally a couple of days is — again — very remarkable.”
Interested to see how bexarotene might work to break down amyloid plaques, Felsenstein and Borchelt selected mice approximately the same age as those used in the 2012 study and orally administered the drug to the mice. Tests confirmed the drug had reached its target genes in the mice, and that it elevated levels of a protein called apolipoprotein E. Some scientists believe one of the forms of this protein may prevent the buildup of amyloid brain plaques in people who don’t have Alzheimer’s disease.
But elevated levels of the protein in the mice studied by UF researchers seemed to have no effect on the animals’ amyloid plaques. Samples taken after seven days of treatment with bexarotene showed no significant difference in the number or size of plaques in the animals’ brains. Two teams of researchers from other institutions also were unable to replicate the breakdown of amyloid plaques.
Felsenstein emphasized that his team does not claim the previous study indicating bexarotene’s effectiveness is “totally wrong.”
“We’re just saying right now it’s extremely difficult to replicate and there may be little nuances, that there’s something that we don’t quite understand,” he added. Felsenstein and Borchelt both work at UF’s Center for Translational Research in Neurodegenerative Disease.
(Source: ufhealth.org)
Scientists identify molecular trigger for Alzheimer’s disease
Researchers have pinpointed a catalytic trigger for the onset of Alzheimer’s disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons in the brain.
For the first time, scientists at Cambridge’s Department of Chemistry, led by Dr Tuomas Knowles, Professor Michele Vendruscolo and Professor Chris Dobson working with Professor Sara Linse and colleagues at Lund University in Sweden have been able to map in detail the pathway that generates “aberrant” forms of proteins which are at the root of neurodegenerative conditions such as Alzheimer’s.
They believe the breakthrough is a vital step closer to increased capabilities for earlier diagnosis of neurological disorders such as Alzheimer’s and Parkinson’s, and opens up possibilities for a new generation of targeted drugs, as scientists say they have uncovered the earliest stages of the development of Alzheimer’s that drugs could possibly target.
The study, published today in the Proceedings of the US National Academy of Sciences, is a milestone in the long-term research established in Cambridge by Professor Christopher Dobson and his colleagues, following the realisation by Dobson of the underlying nature of protein ‘misfolding’ and its connection with disease over 15 years ago.
The research is likely to have a central role to play in diagnostic and drug development for dementia-related diseases, which are increasingly prevalent and damaging as populations live longer.
In 2010, the Alzheimer’s Research UK showed that dementia costs the UK economy over £23 billion, more than cancer and heart disease combined. Just last week, PM David Cameron urged scientists and clinicians to work together to “improve treatments and find scientific breakthroughs” to address “one of the biggest social and healthcare challenges we face.”
The neurodegenerative process giving rise to diseases such as Alzheimer’s is triggered when the normal structures of protein molecules within cells become corrupted.
Protein molecules are made in cellular ‘assembly lines’ that join together chemical building blocks called amino acids in an order encoded in our DNA. New proteins emerge as long, thin chains that normally need to be folded into compact and intricate structures to carry out their biological function.
Under some conditions, however, proteins can ‘misfold’ and snag surrounding normal proteins, which then tangle and stick together in clumps which build to masses, frequently millions, of malfunctioning molecules that shape themselves into unwieldy protein tendrils.
The abnormal tendril structures, called ‘amyloid fibrils’, grow outwards around the location where the focal point, or ‘nucleation’ of these abnormal “species” occurs.
Amyloid fibrils can form the foundations of huge protein deposits – or plaques – long-seen in the brains of Alzheimer’s sufferers, and once believed to be the cause of the disease, before the discovery of ‘toxic oligomers’ by Dobson and others a decade or so ago.
A plaque’s size and density renders it insoluble, and consequently unable to move. Whereas the oligomers, which give rise to Alzheimer’s disease, are small enough to spread easily around the brain - killing neurons and interacting harmfully with other molecules - but how they were formed was until now a mystery.
The new work, in large part carried out by researcher Samuel Cohen, shows that once a small but critical level of malfunctioning protein ‘clumps’ have formed, a runaway chain reaction is triggered that multiplies exponentially the number of these protein composites, activating new focal points through ‘nucleation’.
It is this secondary nucleation process that forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules. Small and highly diffusible, these are the ‘toxic oligomers’ that careen dangerously around the brain cells, killing neurons and ultimately causing loss of memory and other symptoms of dementia.
“There are no disease modifying therapies for Alzheimer’s and dementia at the moment, only limited treatment for symptoms. We have to solve what happens at the molecular level before we can progress and have real impact,” said Dr Tuomas Knowles from Cambridge’s Department of Chemistry, lead author of the study and long-time collaborator of Professor Dobson and Professor Michele Vendruscolo.
“We’ve now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed. This is the key pathway to detect, target and intervene – the molecular catalyst that underlies the pathology.”
The researchers brought together kinetic experiments with a theoretical framework based on master equations, tools commonly used in other areas of chemistry and physics but had not been exploited to their full potential in the study of protein malfunction before.
The latest research follows hard on the heels of another ground breaking study, published in April of this year again in PNAS, in which the Cambridge group, in Collaboration with Colleagues in London and at MIT, worked out the first atomic structure of one of the damaging amyloid fibril protein tendrils. They say the years spent developing research techniques are really paying off now, and they are starting to solve “some of the key mysteries” of these neurodegenerative diseases.
“We are essentially using a physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to ‘recreate the crime scene’ at the molecular root of Alzheimer’s disease,” explained Knowles.
“Increasingly, using quantitative experimental tools and rigorous theoretical analysis to understand complex biological processes are leading to exciting and game-changing results. With a disease like Alzheimer’s, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we’ve found how the oligomers are created, we know what process we need to turn off.”
Alzheimer’s markers predict start of mental decline
Scientists at Washington University School of Medicine in St. Louis have helped identify many of the biomarkers for Alzheimer’s disease that could potentially predict which patients will develop the disorder later in life. Now, studying spinal fluid samples and health data from 201 research participants at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center, the researchers have shown the markers are accurate predictors of Alzheimer’s years before symptoms develop.
“We wanted to see if one marker was better than the other in predicting which of our participants would get cognitive impairment and when they would get it,” said Catherine Roe, PhD, research assistant professor of neurology. “We found no differences in the accuracy of the biomarkers.”
The study, supported in part by the National Institute on Aging, appears in Neurology.
The researchers evaluated markers such as the buildup of amyloid plaques in the brain, newly visible thanks to an imaging agent developed in the last decade; levels of various proteins in the cerebrospinal fluid, such as the amyloid fragments that are the principal ingredient of brain plaques; and the ratios of one protein to another in the cerebrospinal fluid, such as different forms of the brain cell structural protein tau.
The markers were studied in volunteers whose ages ranged from 45 to 88. On average, the data available on study participants spanned four years, with the longest recorded over 7.5 years.
The researchers found that all of the markers were equally good at identifying subjects who were likely to develop cognitive problems and at predicting how soon they would become noticeably impaired.
Next, the scientists paired the biomarkers data with demographic information, testing to see if sex, age, race, education and other factors could improve their predictions.
“Sex, age and race all helped to predict who would develop cognitive impairment,” Roe said. “Older participants, men and African Americans were more likely to become cognitively impaired than those who were younger, female and Caucasian.”
Roe described the findings as providing more evidence that scientists can detect Alzheimer’s disease years before memory loss and cognitive decline become apparent.
“We can better predict future cognitive impairment when we combine biomarkers with patient characteristics,” she said. “Knowing how accurate biomarkers are is important if we are going to some day be able to treat Alzheimer’s before symptoms and slow or prevent the disease.”
Clinical trials are already underway at Washington University and elsewhere to determine if treatments prior to symptoms can prevent or delay inherited forms of Alzheimer’s disease. Reliable biomarkers for Alzheimer’s should one day make it possible to test the most successful treatments in the much more common sporadic forms of Alzheimer’s.
(Source: news.wustl.edu)