Blood test for a dementia protein

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Nature

Scientists in Japan and Australia have developed a blood test that can identify people who have high levels of a protein associated with Alzheimer's disease. If confirmed by further research, this long-sought test could help in the increasingly desperate search for therapies that halt the progression of dementia, which affects tens of millions of people worldwide.

The test identifies people whose brains have high levels of amyloid-β, a protein that is a key player in Alzheimer’s disease, and which may either cause dementia or be a symptom of it. The researchers hope that drug developers could use the test to recruit individuals with dementia into clinical trials before irreversible damage to their brains has occurred — thus making the trials more reliable.

Molecular biologist Katsuhiko Yanagisawa at the Center for Development of Advanced Medicine for Dementia in Obu, Japan, and his colleagues developed the prototype biomarker test. They published their work online on 31 January in Nature1.

Scientists around the world have been searching for a simple blood test for dementia for the past 15 years. “At first it wasn’t obvious that it would be possible for brain pathology to be measurable in the blood, but we have been getting ever closer,” says neuroscientist Simon Lovestone at the University of Oxford, UK, who has led other studies to find blood biomarkers for Alzheimer’s disease. “This paper provides the best results I’ve seen so far.”

High failure rate

All candidate drugs designed to halt Alzheimer’s disease have failed in clinical trials so far, and many pharmaceutical companies have abandoned the field. Scientists suspect that the design of such trials might be the problem, rather than the drugs being tested. Until now, there has been no reliable way to identify people with the early stages of dementia, so most clinical trials have recruited people whose clinical symptoms are already apparent. At this point, brain damage associated with amyloid-β has already occurred and it may be too late to reverse it, says Yanagisawa.

Until now, the only way to identify amyloid-β in the brain — short of an autopsy — has been to image the brain using positron-emission tomography, or to measure levels of the protein directly in cerebrospinal fluid from the spinal cord. Both of these procedures have been used to help recruit patients into recent trials, but the tests are expensive and uncomfortable.

To measure the levels of several amyloid-β fragments in blood samples, as well as a fragment of a larger protein from which amyloid-β derives, Yanagisawa and his colleagues combined two existing techniques — immunoprecipitation and mass spectroscopy. Their results matched those achieved through brain imaging and the analysis of spinal-cord fluid in two separate cohorts involving 121 people in Japan and 252 people in Australia. Each cohort included individuals aged between 60 and 90. Some of the participants were healthy; some showed mild impairment in their cognitive skills; and some had Alzheimer’s disease.

The authors say that larger and more long-term studies are needed to confirm how accurate the blood test is at identifying high levels of amyloid-β in human brains. If it is highly accurate, then the test could help recruitment for clinical trials, because it is relatively easy and cheap to do.

Stabilizing amyloid

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The Dementia Caregiver's Little Book of Hope [Kindle Edition]

Lund University

Incredible images taken by the world's largest synchrotron exposed a missing link in the early-Alzheimer's cascade. They imply new drugs may do better stabilizing amyloid than eliminating it. Learn more about this course-changing discovery. 

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Researchers at Lund University in Sweden have used the MAX IV synchrotron in Lund - the strongest of its kind in the world - to produce images that predate the formation of toxic clumps of beta-amyloid, the protein believed to be at the root of Alzheimer's disease. 

The unique images appear to contradict a previously unchallenged consensus. Instead of attempting to eliminate beta-amyloid, or so-called plaques, the researchers now suggest stabilizing the protein. 

It is a long-held belief in the scientific community that the beta-amyloid plaques appear almost instantaneously. Hence the term "popcorn plaques". The infrared spectroscopy images, however, revealed something entirely different. 

The researchers could now see structural, molecular changes in the brain. 

"No one has used this method to look at Alzheimer's development before. The images tell us that the progression is slower than we thought and that there are steps in the development of Alzheimer's disease that we know little about. This, of course, sparked our curiosity," says Gunnar Gouras, professor in experimental neurology at Lund University and senior author of the study. 

What was happening at this previously unknown phase? Through biochemical identification the first author of the study, Oxana Klementieva, was able to look closer at these early brain changes. 

The results revealed another discovery. Namely, that the beta-amyloid did not appear as a single peptide, a widely held belief in the field, but as a unit of four peptides sticking together, a tetramer. 

This breakthrough offers a new hypothesis to the cause of the disease. The abnormal separation of these four peptides could be the start of the beta-amyloid aggregation that later turns into plaques. 

"This is very, very exciting. In another amyloid disease, transthyretin amyloidosis, the breaking up of the tetramer has been identified as key in disease development. For this disease, there is already a drug in the clinic that stabilizes the tetramers, consequently slowing down disease progression. We hope that stabilizing beta-amyloid in a similar fashion may be the way forward in developing future therapies" says Gunnar Gouras. 

The discovery could therefore alter the direction of therapy development for the disease. The aim of most clinical trials today is to eliminate plaques. 

Researchers at Lund University will now try to understand the interaction patterns of beta-amyloid preceding the aggregation process. Finding the antidote to whatever breaks the beta-amyloid protein apart could open doors towards a major shift in­ the development of therapies for Alzheimer's disease. 

Alzheimer's Cause Found In Trigger Of Brain Protein Malfunction

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

Medical News Today

 

In a new breakthrough to find the cause of Alzheimer's disease, scientists have pinpointed a molecule that appears to trigger a chain reaction of protein malfunction that eventually clogs up and kills brain cells.
The teams, from the University of Cambridge in the UK and Lund University in Sweden, write about their findings in a paper due to be published online first this week in the Proceedings of the National Academy of Sciences.

Tuomas Knowles, one of the study leaders, runs a group based at Cambridge that studies the physical aspects of protein molecule self-assembly. In a statement about the study, he says current therapies for Alzheimer's and dementia are limited, they don't address the disease, only the symptoms:

"We have to solve what happens at the molecular level before we can progress and have real impact," he adds.

And that is what the researchers on this study did: they dug deep into molecular behavior and produced a detailed map of the pathway that produces the malformed proteins that are at the root of neurodegenerative disorders like Alzheimer's.

They believe their breakthrough is an important step toward earlier diagnosis of neurological disorders like Alzheimer's and Parkinson's.

And by revealing molecular clues about the earliest stages of Alzheimer's, they say the findings also open new avenues for developing drugs that target these pathways in the early stages of the disease.

Misfolding Proteins and Amyloid Fibrils

When proteins made in brain cells start to misfold and take on structures that cause them to malfunction, the end result is neurodegenerative diseases like Alzheimer's.

Proteins are important molecules for carrying out essential jobs in and around cells. To make a protein, the cell assembles amino acids according to patterns encoded in its DNA. The assembled protein is a long thin chain that is then folded into a complex, tightly packed and precise structure so it can carry out its tasks correctly.

Things start to go wrong when proteins misfold. These can then snag surrounding proteins, even if they are normal, producing clumps that can build up to millions of protein molecules, forming unwieldy tendrils called "amyloid fibrils".

Amyloid fibrils are what produce the large protein deposits or "plaques" found in the brains of people with Alzheimer's. These were thought to be the primary cause of the disease, until another senior author of this latest study, Christopher Dobson, a professor of Chemistry at Cambridge, and his team discovered "toxic oligomers" about ten years ago.

Toxic Oligomers and Juvenile Tendrils

When the abnormal amyloid fibrils that lead to plaques start to grow, the tendrils grow outwards around the starting or focal point. This is known as "nucleation".

When these were first discovered, it was thought that the key to the cause of Alzheimer's was this nucleation process. But that is only part of the story.

What this study shows is that once a small but critical amount of malfunctioning protein clumps together, it triggers a runaway chain reaction that leads to rapid formation of new clumps, activating new focal points through "nucleation".

And it appears it is these secondary nucleations that create juvenile tendrils that at first have just a few clusters containing a handful of protein molecules, or "toxic oligomers". (An oligomer, comprising only a few molecular units, is a much shorter version of a polymer, a repeating chain of units that can almost go on for ever).

These "toxic oligomers" are soluble and small enough, unlike the bigger, insoluble and denser plaques (which have more of a knotted polymer structure), to travel around the brain and wreak havoc by interacting harmfully with other molecules. The result is the gradual death of neurons that cause loss of memory and the other known symptoms of dementia.

Before this study scientists knew that toxic oligomers were more likely to be the cause of Alzheimer's, but were mystified about where they came from.

Knowles says:

"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."

Recreating the Crime Scene at the Root of Alzheimer's

The researchers brought together tools commonly used in other areas of chemistry and physics, but this study is the first time they have been used to their full potential to look at misfolding proteins.

"Increasingly, using quantitative experimental tools and rigorous theoretical analysis to understand complex biological processes are leading to exciting and game-changing results," says Knowles.

He explains that they are essentially borrowing tools from chemistry and physics to look at a biomolecular problem: to map the networks of processes and "recreate the crime scene" that is at the molecular root of Alzheimer's.

"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," he adds.

In another breakthrough study published recently researchers suggest new Alzheimer's treatment may come from discovering how plaques lead to tangles.

Written by Catharine Paddock PhD
Copyright: Medical News Today

Major Step Toward an Alzheimer's Vaccine

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

Science News

A team of researchers from Université Laval, CHU de Québec, and pharmaceutical firm GlaxoSmithKline (GSK) has discovered a way to stimulate the brain's natural defense mechanisms in people with Alzheimer's disease. This major breakthrough, details of which are presented January 15 in an early online edition of the Proceedings of the National Academy of Sciences (PNAS), opens the door to the development of a treatment for Alzheimer's disease and a vaccine to prevent the illness

One of the main characteristics of Alzheimer's disease is the production in the brain of a toxic molecule known as amyloid beta. Microglial cells, the nervous system's defenders, are unable to eliminate this substance, which forms deposits called senile plaques.

The team led by Dr. Serge Rivest, professor at Université Laval's Faculty of Medicine and researcher at the CHU de Québec research center, identified a molecule that stimulates the activity of the brain's immune cells. The molecule, known as MPL (monophosphoryl lipid A), has been used extensively as a vaccine adjuvant by GSK for many years, and its safety is well established.

In mice with Alzheimer's symptoms, weekly injections of MPL over a twelve-week period eliminated up to 80% of senile plaques. In addition, tests measuring the mice's ability to learn new tasks showed significant improvement in cognitive function over the same period.

The researchers see two potential uses for MPL. It could be administered by intramuscular injection to people with Alzheimer's disease to slow the progression of the illness. It could also be incorporated into a vaccine designed to stimulate the production of antibodies against amyloid beta. "The vaccine could be given to people who already have the disease to stimulate their natural immunity," said Serge Rivest. "It could also be administered as a preventive measure to people with risk factors for Alzheimer's disease."

"When our team started working on Alzheimer's disease a decade ago, our goal was to develop better treatment for Alzheimer's patients," explained Professor Rivest. "With the discovery announced today, I think we're close to  our objective."

Decline in Alzheimer's because of plaque and protein

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UC San Diego Health Sciences News

Without p-tau protein present, impact of amyloid is “not significantly different from zero”


According to a new study, the neuron-killing pathology of Alzheimer’s disease (AD), which begins before clinical symptoms appear, requires the presence of both amyloid-beta (a-beta) plaque deposits and elevated levels of an altered protein called p-tau.


Without both, progressive clinical decline associated with AD in cognitively healthy older individuals is “not significantly different from zero,” reports a team of scientists in an issue of the Archives of Neurology.


“I think this is the biggest contribution of our work,” said Rahul S. Desikan, MD, PhD, research fellow and resident radiologist in the UC San Diego Department of Radiology and first author of the study. “A number of planned clinical trials – and the majority of Alzheimer’s studies – focus predominantly on a-beta. Our results highlight the importance of also looking at p-tau, particularly in trials investigating therapies to remove a-beta. Older, non-demented individuals who have elevated a-beta levels, but normal p-tau levels, maprogress to Alzheimer’s, while older individuals with elevated levels of both will likely develop the disease.”


The findings also underscore the importance of p-tau as a target for new approaches to treating patients with conditions ranging from mild cognitive impairment (MCI) to full-blown AD. An estimated 5.4 million Americans have AD. It’s believed that 10 to 20 percent of Americans age 65 and older have MCI, a risk factor for AD. Some current therapies appear to delay clinical AD onset, but the disease remains irreversible and incurable.


“It may be that a-beta initiates the Alzheimer’s cascade,” said Desikan. “But once started, the neurodegenerative mechanism may become independent of a-beta, with p-tau and other proteins playing a bigger role in the downstream degenerative cascade. If that’s the case, prevention with anti-a-beta compounds may prove efficacious against AD for older, non-demented individuals who have not yet developed tau pathology. But novel, tau-targeting therapies may help the millions of individuals who already suffer from mild cognitive impairment or Alzheimer’s disease.”


The new study involved evaluations of healthy, non-demented elderly individuals participating in the ongoing, multi-site Alzheimer’s Disease Neuroimaging Initiative, or ADNI. Launched in 2003, ADNI is a longitudinal effort to measure the progression of mild cognitive impairment and early-stage AD.

The researchers studied samples of cerebrospinal fluid (CSF) taken from ADNI participants

Elevated SAP in Alzheimer’s disease

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Healthcanal

The deposition of amyloid beta in the brain of individuals with Alzheimer’s disease is the focus of much research into both its cause and treatment.

While there may not be a consensus as to whether the deposition contributes to the disease or is a consequence of the disease, there is agreement that it is not favoured thermodynamically, meaning that something else is promoting the process.

Other proteins are often co-deposited in vivo with amyloid beta and one such protein is serum amyloid P component (or SAP). Recent evidence has suggested that SAP is elevated in Alzheimer’s disease and a team of researchers from Keele University in Staffordshire, led by Professor Chris Exley, has shown that physiologically-significant concentrations of SAP promote the deposition of amyloid beta under conditions approaching those found in vivo.

Professor Exley said: “We have shown that SAP is bound by fibrils of amyloid beta and that this interaction stabilises the fibrils over timescales which are physiologically significant. This is the first example of a physiologically significant biomolecule promoting and stabilising the formation of amyloid fibrils of amyloid beta 42 under near-physiological conditions.”

The group also found that this property of SAP was enhanced in the presence of aluminium, a metal which has also been shown to be co-deposited with amyloid beta in Alzheimer’s disease. There have been recent efforts to reduce the plasma concentration of SAP as a therapy for Alzheimer’s disease and the research provides strong evidence that SAP is involved in the deposition of amyloid beta 42 in Alzheimer’s disease and that by reducing the plasma concentration of SAP it might also reduce the deposition of amyloid beta. Their observations support serum amyloid P component as a therapeutic target in Alzheimer’s disease.

Serum Amyloid P Component Accelerates the Formation and Enhances the Stability of Amyloid Fibrils in a Physiologically Significant Under-Saturated Solution of Amyloid-β42 by Matthew Mold, Annette K Shrive, Christopher Exley will be published in the Journal of Alzheimer's Disease Volume 29, issue 4 (April 2012); DOI: 10.3233/JAD-2012-120076

Study: Apparent cause of accelerated formation of amyloid beta in Alzheimer's disease

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Cell Press

In their study, first author Dr. Markus P. Kummer and colleagues discovered that amyloid beta(AΒ) is a novel nitric oxide(NO) target. They observed nitrated AΒ in Alzheimer's disease(AD) and AD mouse models and found that this modification accelerated the deposition of human AΒ. Importantly, reduction of nitric oxide synthase(NOS2) reduced AΒ deposition and memory deficits in a mouse model of AD. Further, nitrated AΒ induced the formation of amyloid plaques when injected into the brains of mice with genetic mutations associated with AD.

"Taken together, our results identify a novel modification of AΒ, tyrosine nitration, and propose a causative link between the AΒ cascade, activation of NOS2, and the subsequent increase in its reaction product nitric oxide during AD," concludes Dr. Heneka. "We think that nitrated AΒ may serve as marker of early AΒ plaque formation. More importantly, it may be a promising target for an AD therapy, and that application of specific inhibitors of NOS2 may therefore open a new therapeutic avenue in AD."

Antiviral drugs could slow Alzheimer's disease

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University of Manchester

Antiviral drugs used to target the herpes virus could be effective at slowing the progression of Alzheimer’s disease (AD), a new study shows.

The University of Manchester scientists have previously shown that the herpes simplex virus type 1 (HSV1) is a risk factor for Alzheimer’s when it is present in the brains of people who have a specific genetic risk to the disease.

AD is an incurable neurodegenerative condition affecting about 18 million people worldwide. The causes of the disease or of the abnormal protein structures seen in AD brains – amyloid plaques and neurofibrillary tangles – are completely unknown.

The Manchester team has established that the herpes virus causes accumulation of two key AD proteins – β-amyloid (Aβ) and abnormally phosphorylated tau (P-tau) – known to be the main components of plaques and tangles respectively. Both proteins are thought by many scientists to be involved in the development of the disease.

“We have found that the viral DNA in AD brains is very specifically located within amyloid plaques,” said Professor Ruth Itzhaki, who led the team in the University’s Faculty of Life Sciences. “This, together with the production of amyloid that the virus induces, suggests that HSV1 is a cause of toxic amyloid products and of plaques.

“Our results suggest that HSV1, together with the host genetic factor, is a major risk for AD, and that antiviral agents might be used for treating patients to slow disease progression.”

Currently available antiviral agents act by targeting replication of HSV1 DNA, and so the researchers considered that they might be successful in treating AD only if the accumulation of β-amyloid and P-tau accumulation caused by the virus occurs at or after the stage at which viral DNA replication occurs.

“If these proteins are produced independently of HSV1 replication, antivirals might not be effective,” said Professor Itzhaki. “We investigated this and found that treatment of HSV1-infected cells with acyclovir, the most commonly used antiviral agent, and also with two other antivirals, did indeed decrease the accumulation of β-amyloid and P-tau, as well as decreasing HSV1 replication as we would expect.

“This is the first study investigating antiviral effects on AD-like changes and we conclude that since antiviral agents reduce greatly β-amyloid and P-tau levels in HSV1-infected cells, they would be suitable for treating Alzheimer’s disease. The great advantage over current AD therapies is that acyclovir would target only the virus, not the host cell or normal uninfected cells. Further, these agents are very safe and are relatively inexpensive.

“Also, by targeting a cause of Alzheimer’s disease, other viral damage, besides β-amyloid and P-tau, which might be involved in the disease’s pathogenesis, would also be inhibited.

“The next stage of our research – subject to funding – will focus on finding the most suitable antiviral agent – or combination of two agents that operate via different mechanisms – for use as treatment. We then need to investigate the way in which the virus and the genetic risk factor interact to cause the disease, as that might lead to further novel treatments.

“Eventually, we hope to begin clinical trials in humans but this is still some way off yet and again will require new funding.”

The study, carried out with Dr Matthew Wozniak and other colleagues in the Faculty of Life Sciences, is published in the Public Library of Science (PLoS) One journal

Alzheimer's disease research advances

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ScienceDaily Advances in research into Alzheimer's disease: transporter proteins at the blood CSF barrier and vitamin D may help prevent amyloid β build up in the brain.

Advancing age is a major risk factor for Alzheimer's disease and is associated with build- up of the peptide amyloid β in the brain. New research published in BioMed Central's open access journal Fluids and Barriers of the CNS shows that removal of amyloid β from the brain depends on vitamin D and also on an age-related alteration in the production of transporter proteins which move amyloid β in and out of the brain.

Low levels of vitamin D are thought to be involved in age-related decline in memory and cognition and are also associated with Alzheimer's disease. Researchers from Tohoku University, Japan, looked at the mechanism behind this and found that vitamin D injections improved the removal of amyloid β from the brain of mice.

Prof Tetsuya Terasaki said, "Vitamin D appears increase transport of amyloid β across the blood brain barrier (BBB) by regulating protein expression, via the vitamin D receptor, and also by regulating cell signaling via the MEK pathway. These results lead the way towards new therapeutic targets in the search for prevention of Alzheimer's disease."

The transport of amyloid β across the BBB is known to be orchestrated by transporter proteins such as LRP-1 and P-gp, which move amyloid β out of the brain, and RAGE, which controls influx. Looking at the transport of amyloid β from blood to cerebrospinal fluid (CSF), and from CSF to blood, researchers from Rhode Island Hospital and The Warren Alpert Medical School, found that , and P-gp at the blood-cerebrospinal fluid barrier (BCSFB), increased with age so increasing removal of amyloid β from the CSF and brain.

Prof Gerald Silverberg said, "While increased production of transporter proteins at the blood CSF barrier may help amyloid β removal from the older brain, production of these proteins eventually fails. This failure may be an important event in brain function as we age and for people with Alzheimer's disease."

New Insight on Cause of Alzheimer's

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Laboratory Equipment


For years researchers have known that a small peptide named amyloid beta can cause neuronal cell death and Alzheimer’s disease, although the mechanism for how it works has been poorly understood. Recently, genetic evidence has demonstrated that the ability of amyloid beta to kill neurons requires a protein called “tau”; however, what it does to tau has been enigmatic.

Under normal conditions, tau is found in the long axons of neurons that serve to connect neurons with their targets, often far from the cell body itself.

“We know amyloid beta is a bad guy,” says study leader Stuart Feinstein, professor of molecular, cellular and developmental biology at Univ. of California, Santa Barbara. “Amyloid beta causes disease; amyloid beta causes Alzheimer’s. The question is how does it do it?”

Most Alzheimer’s researchers would argue that amyloid beta causes tau to become abnormally and excessively phosphorylated, says Feinstein. This means that the tau proteins get inappropriately chemically modified with phosphate groups. “Many of our proteins get phosphorylated,” adds Feinstein. “It can be done properly or improperly.”

Feinstein’s research team wanted to determine the precise details of the presumed abnormal phosphorylation of tau in order to gain a better understanding of what goes wrong. “That would provide clues for drug companies; they would have a more precise target to work on,” says Feinstein. “The more precisely they understand the biochemistry of the target, the better attack a pharmaceutical company can make on a problem.”

The team’s initial hypothesis suggesting that amyloid beta leads to extensive abnormal tau phosphorylation turned out not to be true. “We all like to get a curve ball tossed our way once in a while, right?” says Feinstein. “You like to see something different and unexpected.”

They found that when they added amyloid beta to neuronal cells, the tau in those cells did not get massively phosphorylated, as predicted. Rather, the surprising observation was the complete fragmentation of tau within one to two hours of exposure of the cells to amyloid beta. Within 24 hours, the cells were dead.

The findings are reported in the Journal of Biological Chemistry.

Could a Diabetes Drug and a Supplement Work Together to Treat Alzheimer's Disease

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AC Content

Metformin is a medication used to treat diabetes. Resveratrol is a supplement that has the benefits of drinking concentrated red wine. Doctors at Dundee University say that taking both of these things together may stop
Alzheimer's disease in its tracks.

The doctors report that metformin interferes with the development of tau which are neurofibratory tangles. Neurofibratory tangles severly limit communication between brain cells in Alzheimer's disease. They also say that Resveratrol limits the formation of these neurofibratory tangles. This research could help millions of people from getting Alzheimer's disease.

Resveratrol is a type of natural phenol, and is produced naturally by several plants when they are under the attack of harmful bacteria or fungi. Resveratrol is found in the skin of red grapes. Red wine seems to contains a high level of it.

Resveratrol was added to the cells that produce abnormal proteins called amyloid-beta. The research scientists who did this found that the levels of this abnormal protein were much lower in the cells treated with resveratrol over the untreated cells. While the scientists do not think that the amounts of resveratrol found in grapes and wine could produce the results they found in their studies using larger amounts of resveratrol. These research scientists think that grapes and wine contain molecules that, like resveratrol, are strong antioxidants. The scientists feel that resveratrol can work with other drugs like metformin to fight Alzheimer's disease.

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Can an Asthma Drug Help Those with Alzheimer's Disease

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AC Content

There are several enzymes that researchers at Temple University's School of Medicine have found that indirectly or directly influence the production of amyloid beta a harmful protein that develops in Alzheimer's
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disease.

A drug which is used to treat asthma can reduce the formation of amyloid beta, because it interferes with the production of these enzymes. The name of the drug is Zileuton,

Alzheimer's disease is a brain disorder that affects many functions of the brain. Most often short term memory is decreased. Other functions that are affected are speech, problem solving, ability to express yourself, ability to learn new things, and proper behavior.

Eventually a person with Alzheimer's disease cannot take care of himself. Even simple things like eating and going to the bathroom are affected. The final outcome of Alzheimer's disease is death.

It is thought that the formation of amyloid beta is one of the reasons that brain function is affected. Amyloid beta if left untreated forms harmful plaques. The plaque formation is bad because it interferes with the communication of one brain cell to another. Eventually brain cells die and affected parts of the brain no longer function.

In previous studies at Temple University, researchers have known about an enzyme called 5-lipoxygenase. This enzyme controls the activation of another enzyme called gamma secretase. Gamma secretase is another enzyme that is responsible for the final production of the protein amyloid beta.

Domenico Pratico, an associate professor of pharmacology in Temple's School of Medicine, is in charge of the current study. He and his team of researchers tested the drug called Zileuton. It is an inhibitor of 5-lipoxygenase. Zileuton is a drug of choice in the treatment of asthma.

The researchers are using ...read all of Can an Asthma Drug Help Those with Alzheimer's Disease

Role of Clotting Mechanism in Alzheimer's Disease

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Science Daily

The aggregated proteins strewn about the brain are the hallmark of one of the most common neurodegenerative disorders: Alzheimer's disease. But while these irregular, gunky proteins, called amyloid-β, are believed to contribute to the deterioration of memory and cognitive ability in Alzheimer's patients, no one knows how they lead to these symptoms, and the severity of the dementia doesn't directly depend on the amount of amyloid-β plaques found in diseased brains.


New experiments from The Rockefeller University, building on a paper published earlier this year, show how amyloid-β interacts with a clotting agent in the blood, increasing blood clots that are harder than usual to break down and starving neurons of their regular supply of oxygen. The research suggests that the effects of amyloid-β on the blood vessels feeding the brain could be an important aspect of the havoc they wreak on the brain.




"There has been a suggestion that vascular dementia and Alzheimer's disease might be related, and our current work provides a possible connection between the two," says Sidney Strickland, head of the Laboratory of Neurobiology and Genetics at Rockefeller.



Led by Hyung Jin Ahn, a postdoctoral associate in Strickland's lab, researchers used biochemical tests to home in on exactly how a particularly nasty form of amyloid-β, called Aβ42, interacts with the blood clotting agent fibrinogen, causing fibrinogen to grow into unusual clot structures that are hard to degrade. Ahn and colleagues show, by incubating Aβ42 and fibrinogen and studying the effects, exactly what pieces of the molecules interact and what happens when they do. The results indicate that the interaction between Aβ42 and fibrinogen may induce abnormal fibrinogen structures prior to fibrin clot formation and that this oligomeric fibrinogen plays an important role in Alzheimer's disease pathogenesis, Ahn says.



The findings could suggest a drug target for disrupting this interaction, thereby preventing the downstream consequences, which could include decreased blood flow, cognitive dysfunction and inflammation of the neurons.



In June, researchers from the same lab published a report in Neuron demonstrating that amyloid-β leads to the formation of tougher blood clots, and that decreasing the level of fibrinogen could reduce the pathology of Alzheimer's disease. The latest work, published November 22 in Proceedings of the National Academy of Sciences, shows how those tougher blood clots are formed.

Ahn and colleagues are now in the process of identifying small molecules that can inhibit the Aβ42-fibrinogen interaction and hope these inhibitors could become an effective drug therapy for patients with Alzheimer's disease.

Culprit in Alzheimer's Disease Identified

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Results of a recent study may indicate that a protein superstructure called amyloid beta what is responsible for the damage in the brain of a person with Alzheimer's disease.

Scientists doing research at the University of California have seen that amyloid beta stops an anti-oxidant protein in the brain.They have found a way to protect that protein, and maybe even others, from harmful effects of amyloid.

"Amyloid seems to cause damage to cells. We have reported in a very detailed way one potential interaction of how amyloid can cause disease, and we found a way to stop it," said Jerry Yang.

The study of the reseachers focused on catalase-an enzyme that absorbs excess oxidants. Catalase normally helps to prevent the kind of damage seen in the brains of those with Alzheimer's disease. Work done before had found catalase proteins deposited within the amyloid plaques.

Lila Habib, the first author of the report, added amyloid to cultured neural cells and looked at its effects.

"We were able to determine that......Read all of: Culprit In Alzheimer's Disease Identified

Diet and Behavior Changes May Slow Alzheimer’s

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US News and World Report

By Gwyneth Dickey, Science News

A combination of diet and lifestyle changes decreases Alzheimer’s-like symptoms in dogs more than either treatment does on its own, a new study shows. The findings show the importance of taking multiple approaches to arrest the disease in humans, the authors say. Their results also provide evidence supporting recent research that suggests plaque deposits in the brain are not the cause of Alzheimer’s.


Alzheimer’s disease usually strikes people over the age of 60 and causes memory loss, shrinking brain tissue and eventually death. People with the disease get plaques in their brains made up of a small protein called amyloid-beta, which clumps together and disrupts brain signals.

Research suggests diet and exercise can improve human brain function and defend against Alzheimer’s, but researchers aren’t sure why. Dogs naturally accumulate the same brain plaque, and though they don’t get Alzheimer’s, they do experience age-related cognitive decline. So scientists can study the animals to learn more about the human form of the disease.

In this study, 24 beagles 8 to 12 years old received one of four treatments over about 2 ½ years. Some dogs were fed a diet enriched with high-antioxidant foods, like spinach, tomatoes, grapes, carrots and citrus fruit. Other dogs were given behavioral enrichment, in which they socialized with other dogs, played with new toys, took long walks and learned new tasks. One group of dogs received both treatments, while the last group received none.

This is the first study to look at antioxidant and behavioral enrichment treatments in dogs that naturally accumulate amyloid-beta plaques, says neuroscientist Viorela Pop, who conducted the research as a graduate student at the University of California, Irvine. The results were published July 21 in the Journal of Neuroscience.

The researchers found that compared with controls, dogs given the combined treatment had the greatest benefit. Those dogs had the biggest improvement in cognition and moderately reduced plaques in their brains. Dogs given just antioxidants fared better than dogs that underwent only enrichment activities. “The combination treatment is a key component of this study,” says Pop, who is now a postdoctoral fellow at Loma Linda University in California. “If we were to try to slow down Alzheimer’s disease in humans, we would want to try a multifactorial treatment.”

Her study also adds to a growing body of research that suggests amyloid-beta plaques, once thought to be the cause of Alzheimer’s, are just a symptom of the disease. Beagles receiving both dietary and behavioral treatments showed major improvements in cognition, but only minor decreases in amyloid-beta plaques in their brains.

The results fit with evidence showing that humans and dogs immunized against amyloid-beta plaques have no clumps but continue to experience cognitive decline, says Alex Roher of the Banner Sun Health Research Institute in Sun City, Ariz. “Patients continue to deteriorate in spite of all treatments, which tells you the plaques are not the ultimate cause of the disease.”

That’s not to say amyloid-beta isn’t important. “It just doesn’t seem to be the main thing responsible for cognitive decline in dogs and Alzheimer’s disease in humans,” Pop says.

Researchers need to conduct more studies before these results can be generalized to humans, says psychologist Catherine Roe of the Washington University School of Medicine in St. Louis. “Going from dogs to people is a big jump,” she says, and researchers need to find links between enriched diet and environment in humans. “So far we haven’t found any association.”

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Rethinking Alzheimer's disease and its treatment targets

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PhysOrg.com) -- Psychiatry professor George Bartzokis introduces a new theory about the fundamental cause of Alzheimer's and other neurodegenerative diseases.

The standard explanation for what causes Alzheimer's is known as the amyloid hypothesis, which posits that the disease results from of an accumulation of the peptide amyloid beta, the toxic protein fragments that deposit in the brain and become the sticky plaques that have defined Alzheimer's for more than 100 years.

Billions of dollars are spent yearly targeting this toxic peptide — but what if this is the wrong target? What if the disease begins much earlier, fueled by a natural process? Reporting in the current edition of the journal Neurobiology of Aging, UCLA professor of psychiatry George Bartzokis argues just that and says that a better working hypothesis is the "myelin model."

"The greatest promise of the myelin model of the human brain is its application to the development of new therapeutic approaches," Bartzokis said.

Like insulation around wires, myelin is a fatty sheath that coats our nerve axons, allowing for efficient conduction of nerve impulses. It is key to the fast processing speeds that underlie our higher cognitive functions and encoding of memories.

But the lifelong, extensive myelination of the human brain also makes it uniquely vulnerable to damage. The myelin model's central premise is that it is the normal, routine maintenance and repair of myelin throughout life that ultimately initiates the mechanisms that produce degenerative diseases like Alzheimer's. That is, the amyloid-beta peptide and the tau peptide, which is also implicated in Alzheimer's, as well as the signature clinical signs of the disease, such as memory loss and, ultimately, dementia, are all byproducts of the myelin breakdown and repair processes.

"The pervasive myelination of our brain is the single most unique aspect in which the human brain differs from other species," said Bartzokis, who is a member of the Laboratory of Neuro Imaging in the UCLA Department of Neurology and a member of UCLA's Brain Research Institute. Myelin is produced by oligodendrocytes, specialized glial cells that themselves become more vulnerable with age.

Bartzokis notes that myelination of the brain follows an inverted U-shaped trajectory, growing strongly until our 50s, when it very slowly begins to unravel as we age. The myelin that is deposited in adulthood ensheaths increasing numbers of axons with smaller axon diameters and so spreads itself thinner and thinner, Bartzokis said. As a result, it becomes more susceptible to the ravages of age in the form of environmental and genetic insults and slowly begins to break down faster than it can be repaired.

The exclusive targeting of the amyloid-beta peptide for many years is understandable because the same genes and enzymes involved in controlling myelination and myelin repair are, ironically, also involved in the production of amyloid-beta proteins. Bartzokis' point is that the amyloid beta may actually develop as a result of the natural process of the repair and maintenance of myelin.

"So the breakdown that leads to Alzheimer's and other age-related brain diseases, such as Parkinson's, may begin much earlier, before the formation of the protein deposits that are used to define these diseases," Bartzokis said.

Most drugs being developed for Alzheimer's are targeting amyloid beta, but little if any clinical improvement is being seen. This is, according to Bartzokis, "similar to cleaning up a house that's been flooded by water but never repairing the actual pipe that created the flood.

"For drug development then, the targets should be much further upstream, earlier in the process before the AB plaques even develop," he said.

Instead of focusing on reducing amyloid beta, Bartzokis argues, the myelin model suggests entirely different approaches to treatment and prevention of Alzheimer's disease that precede plaque formation. With modern brain imaging technology, clinicians could track the dynamic changes taking place in the brain and intercede well before any signs of Alzheimer's are seen.

"With earlier intervention," Bartzokis said, "we could reduce and potentially eliminate the increasingly catastrophic burden of dementia on the individual and their family, the health care system, and our society."

Sleep deprivation can lead to dementia, research shows

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Barchester Heathnews

A lack of sleep can cause brain problems and lead to dementia, according to a new study.

Chronic sleep deprivation increases plaques in the brain thought to be a main cause of dementia, research shops.

A protein called orexin that helps to regulate the sleep cycle is directly involved, say the scientists at Washington University School of Medicine and Barnes-Jewish Hospital.

Amyloid beta, which forms plaques, rises and falls with sleep and wakefulness, with deprivation leading to a 25 per cent rise.

Injecting orexin into the brains of mice made them stay awake longer and increased amyloid beta levels, putting them at greater risk of developing plaques.

Neurologist Professor David Holtzman explained that lack of sleep can have "potential long-term impacts on brain health".

It is thought that plaques and tangles "silt up" the brain and cause Alzheimer's.

Earlier this week, it was suggested that difficulties in money management could indicate Alzheimer's, with the University of Alabama in Birmingham saying financial problems may be seen a year ahead of a dementia diagnosis

Research Demonstrates that Optimized Turmeric Extract Inhibits Amyloid-Beta...

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HerbalScience Research Demonstrates that Optimized Turmeric Extract Inhibits
Amyloid-Beta Accumulation, a Hallmark of Alzheimer's Disease
- Results of Laboratory Study Detecting Previously Unidentified Bioactives in
Standardized Turmeric Extract Will Be Published in Upcoming Issue of Current
Alzheimer's Research -




NAPLES, Fla., Sept. 3 /PRNewswire/ -- Alzheimer's disease is the most common
cause of dementia among the elderly and is projected to increase in prevalence
over the next decades as the population ages -- creating an urgent need for
treatments that will prevent or reverse the now-inexorable course of cognitive
deterioration and memory loss. Because development of synthetic drugs is
expensive and complex, many researchers are focusing on botanical extracts
whose benefits have been documented by traditional medicine systems. In that
vein, scientists with HerbalScience Group LLC, working with researchers from
other organizations and medical institutions, conducted an in-depth study of
optimized turmeric extracts, demonstrating that key bioactives in the
botanical extracts inhibit aggregation and release of amyloid, a protein
fragment considered a prime causal suspect in Alzheimer's disease.

An article detailing the study, titled "Optimized Turmeric Extracts Have
Potent Anti-Amyloidogenic Effects," will be published in the December 2009
issue of Current Alzheimer's Research, a peer-reviewed scientific journal. The
authors are affiliated with several research organizations and medical
institutions, including HerbalScience Group LLC; the University of Miami
Leonard M. Miller School of Medicine, Miami, Florida; the University of South
Florida College of Medicine, Tampa, Florida; Veterans Administration Hospital,
Research Service, Tampa, Florida; and Natura Therapeutics, Tampa, Florida.

"The optimized extracts outperformed curcumin, the best studied anti-Alzheimer
extract from turmeric," said Randall S. Alberte, Ph.D., one of the authors of
the study and Chief Scientific Officer of HerbalScience Group LLC, a Naples,
Florida, and Singapore-based company dedicated to applying advanced science
and technology to the production of botanical drugs and nutraceuticals.

For the research, three standardized turmeric extracts were prepared that were
enriched in curcuminoids and turmerones, two major classes of compounds
present in turmeric. Each of the three proprietary extracts had a different
chemical profile and was standardized using advanced extraction technology
developed by HerbalScience to create herbal extracts that are dose-reliable
and efficacious. The activities of the extracts were compared to standard
curcuminoids.

Inhibition of amyloid aggregation and secretion was studied in vitro among the
different extracts and standards, and it was found that one of the extracts
had the greatest activity in inhibiting the aggregation and secretion of
amyloid. This extract, containing the highest levels of curcuminoids among all
of the extracts, demonstrated activity that was significantly greater than
curcumin alone, the most active of the four curcuminoid standards. This result
indicates that an enriched turmeric extract could be just as or more effective
than curcumin, the most commonly studied turmeric material for Alzheimer's
disease.

The HerbalScience study also used advanced DART (Direct Analysis in Real Time)
Time-of-Flight mass spectrometry technology to generate detailed chemical
profiles of each extract in order to determine the key bioactive compounds.
Only 5% of the compounds were known chemicals, with the remaining 95% being
identified for the first time. With further chemical analysis and
identification of key bioactives, highly standardized extracts such as these
could offer a rich new source for potential drug discovery for Alzheimer's and
other therapeutic targets.

The journal article detailing the study will appear in the December 2009 issue
of Current Alzheimer's Research (Vol. 6, No. 6). Authors are R. Douglas
Shytle, Paula C. Bickford, Kavon Rezai-zadeh, L Hou, Jin Zeng, Jun Tan, and
Paul Sanberg, with University of South Florida College of Medicine
affiliations including the Department of Neurosurgery Center for Excellence in
Aging and Brain Repair, Department of Psychiatry and Behavioral Medicine
Silver Child Development Center, and Neuroscience Program; Cyndy D. Sanberg of
Natura Therapeutics, Inc., Tampa, Florida; Bill Roschek Jr. and Randall S.
Alberte, of HerbalScience Group LLC, Naples, Florida; and Ryan C. Fink,
Department of Biochemistry and Molecular Biology, The University of Miami
Leonard M. Miller School of Medicine, Miami, Florida. Dr. Bickford is also
affiliated with the Veterans Administration Hospital, Research Service, Tampa,
Florida; and Drs. Shytle, Bickford, Tan, and Paul Sanberg are also affiliated
with Natura Therapeutics.

HerbalScience is a privately-held life sciences company headquartered in
Naples, Florida, with facilities in Singapore. HerbalScience is engaged in the
discovery, development, manufacture, and marketing of proprietary botanical
compounds for human health in the U.S. and international markets. The company
has prominent alliances with prestigious university laboratories and prominent
researchers in the U.S., as well as research institutions in China.

Agents that Speed Up Destruction of Amyloid Beta Found

GEN News Highlights
A group of investigators report that it is possible to enhance insulin-degrading enzyme’s (IDE) ability to destroy amyloid beta (A-beta) with synthetic small molecules. In laboratory experiments, they found that one agent, dubbed Ia1, increased the activity of IDE by about 700%, while the second compound, Ia2, increased it by almost 400%.

The research, which is published in the April 22 online issue of PLoS ONE, was a collaboration between Mayo Clinic Florida, The Scripps Research Institute, and Harvard Medical School. The study is called “Small-Molecule Activators of Insulin-Degrading Enzyme Discovered through High-Throughput Compound Screening.”

IDE was the first degrading enzyme implicated in the imbalance seen between the production and elimination of A-beta in the brains of Alzheimer’s patients, according to lead researcher, Malcolm Leissring, Ph.D., from Mayo's department of neuroscience. “We don't know why that balance is skewed in individuals that develop Alzheimer's disease, but one hypothesis is that as we age, activity of the enzymes that destroy A-beta goes down.”

The scientists thus screened tens of thousands of chemicals looking for ones that could bind to IDE and modulate its activity. That led to discovery and testing of Ia1 and Ia2. Dr. Leissring says that the success they achieved in their test tube experiments offers a new path for more advanced research.


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Past Alzheimer’s Research

Researchers Develop Standard of Testing for.........read the whole article

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