̽��ֱ�� of Cambridge - Chris Dobson

Dementia: Catching the memory thief

cjb250 — Wed, 21 Sep 2016 07:07:53 +0000

You may have heard of the ‘dementia tsunami’. It’s heading our way. As our population ages, the number of cases of dementia is set to rocket, overwhelming our health services and placing an enormous burden on our society.

Only, it’s not quite so simple. A study published last year by Professor Carol Brayne from the Cambridge Institute of Public Health suggested that better education and living standards meant people were at a lower risk of developing the disease than previously thought and so, despite our ageing population, numbers were likely to stabilise – and could even perhaps fall slightly.

Of course, even this more optimistic outlook does not hide the fact that millions of people worldwide will be diagnosed with dementia each year and millions are already living with the condition. An effective treatment for the 'memory thief' still seems like a distant prospect.

“Dementia isn’t one disease: it’s a constellation of changes in an individual’s brain, with many underlying causes,” says Brayne. “Most people, by the time they’re in their eighties or nineties, have some of these changes in their brains, regardless of whether or not they ever develop dementia.”

For this reason, Brayne believes we need a radical approach to tackling brain health throughout the course of our lifetime, with a greater emphasis on reduction in the risk of dementia achieved through measures in society that are related to better health in general, such as social and lifestyle changes, in addition to the focus on early therapeutic approaches to preventing or treating the disease through a pharmaceutical approach.

By far the most common and well-known form of dementia is Alzheimer’s disease. Symptoms include memory problems, changes in behaviour and progressive loss of independence.

At a biological level, the disease sees a build-up of two particular types of proteins in the brain: fragments of beta-amyloid clump together in ‘plaques’ between nerve cells, and twisted strands of tau form ‘tangles’ within the nerve cells. These plaques and tangles lead to the death of nerve cells, causing the brain to shrink.

Clinical trials of Alzheimer’s drugs are always going to be difficult, in part because trial participants are patients with advanced stage disease, who have already lost a significant number of nerve cells. But Professor Chris Dobson, who recently helped secure £17 million from the Higher Education Funding Council for England for a new Chemistry of Health Building, including the Centre for Misfolding Diseases, believes that most of the trials to date were destined to fail from the start because of a fundamental lack of understanding of the mechanisms that lead to Alzheimer’s.

Understandably, most of the researchers tackling Alzheimer’s approach the disease as a clinical – or at least a biological – problem. Dobson instead sees it as also being about chemistry and physics. He argues that the protein tangles and plaques – collectively known as aggregates – are demonstrating a physical property similar to the way in which crystals precipitate out of, say, salty water: all they need is a ‘seed’ to kick off the precipitation and the process runs away with itself. “In essence,” he says, “biology is trying to suppress molecules behaving in a physical way.” For his contributions, Dobson has been awarded the 2014 Heineken Prize for Biochemistry and Biophysics.

In 2009, Dobson, together with colleagues Professors Tuomas Knowles and Michele Vendruscolo, published a study that broke down the aggregation process into a combination of smaller steps, each of which could be tested experimentally. It became apparent to the team that drugs were failing in trials because they were targeting the wrong steps. “And this is still happening,” says Vendruscolo. “Companies are still putting small molecules into clinical trials that, when we test them using our methods, we find stand no chance.”

They believe there may be a role to play for ‘neurostatins’, which could do for Alzheimer’s what statins already do to reduce cholesterol levels and prevent heart attacks and strokes. In fact, they may have already identified compounds that might fit the bill.

Professor Michel Goedert from the Medical Research Council Laboratory of Molecular Biology admits that there is a gap between our understanding of Alzheimer’s and our ability to turn this into effective therapies.

“We know much about the causes of inherited forms of Alzheimer’s disease, but this knowledge has so far not led to any therapies,” he says. “It’s clear now that abnormal protein aggregation is central to Alzheimer’s disease, but we don’t know the mechanisms by which this aggregation leads to neurodegeneration.” Goedert himself played an instrumental part in studies that implicated the aggregation of tau protein in Alzheimer’s disease and other neurodegenerative diseases, work that led to him being awarded the 2014 European Grand Prix from the Paris-based Foundation for Research on Alzheimer’s Disease.

“I don’t think we should talk of a cure,” says Goedert. “At best, we will be able to halt the disease. Prevention will be much more important.” Part of the problem, he says, lies in the fact that there is no absolute way of identifying those at risk of developing Alzheimer’s disease.

̽��ֱ��market for an Alzheimer’s drug is massive, which is why pharmaceutical companies are racing to develop new drugs. Goedert doesn’t believe we will ever find a single ‘magic bullet’, but will need to use combination therapies – in the same way that we treat other diseases, such as HIV – with each drug targeting a particular aspect of the disease.

Professor David Rubinsztein from the Cambridge Institute for Medical Research agrees with Goedert that we need to look at preventing Alzheimer’s rather than just focusing on treating the disease. He, too, believes in the concept of neurostatins. “These compounds would be safe, well tolerated by most people and generally good for you; you could take them for many years before the onset of disease,” he says. “Then we wouldn’t need to worry about identifying people at highest risk of the disease – everyone could take them.”

Rubinsztein is the academic lead for Cambridge’s new Alzheimer’s Research UK Drug Discovery Institute, part of a £30 million Drug Discovery Alliance that also includes the ̽��ֱ�� of Oxford and ̽��ֱ�� College London. This state-of-the-art institute will fast-track the development of new treatments for Alzheimer’s disease and other neurodegenerative diseases. In particular, the Alliance will look at promising drug targets, assess their validity and develop small molecules that target them. These could then be taken up by pharmaceutical companies for clinical trials, removing some of the risk that results in most ‘promising’ drug candidates failing early on.

Rubinsztein is optimistic about our chances of fighting Alzheimer’s. “If you could delay the onset of Alzheimer’s, even by three to five years, that discovery would be transformative and massively reduce the number of people getting the disease,” he says. “We’re not asking to stop the disease, just to delay it. It’s really not such a big ask.”

Cambridge Neuroscience plays a key role in coordinating dementia research across the large and diverse community of neuroscientists in Cambridge, helping scientists and clinicians to work together.

It's over a hundred years since the first case of Alzheimer’s disease was diagnosed. Since then we’ve learned a great deal about the protein ‘tangles’ and ‘plaques’ that cause the disease. How close are we to having effective treatments – and could we even prevent dementia from occurring in the first place?

I don't think we should talk of a cure. At best, we will be able to halt the disease. Prevention will be much more important.

Michel Goedert

Dementia: Catching the memory thief

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Gene signature in healthy brains pinpoints the origins of Alzheimer’s disease

sc604 — Wed, 10 Aug 2016 18:00:00 +0000

Researchers have discovered a gene signature in healthy brains that echoes the pattern in which Alzheimer’s disease spreads through the brain much later in life. ̽��ֱ��findings, published in the journal Science Advances, could help uncover the molecular origins of this devastating disease, and may be used to develop preventative treatments for at-risk individuals to be taken well before symptoms appear.

̽��ֱ��results, by researchers from the ̽��ֱ�� of Cambridge, identified a specific signature of a group of genes in the regions of the brain which are most vulnerable to Alzheimer’s disease. They found that these parts of the brain are vulnerable because the body’s defence mechanisms against the proteins partly responsible for Alzheimer’s disease are weaker in these areas.

Healthy individuals with this specific gene signature are highly likely to develop Alzheimer’s disease in later life, and would most benefit from preventative treatments, if and when they are developed for human use.

Alzheimer’s disease, the most common form of dementia, is characterised by the progressive degeneration of the brain. Not only is the disease currently incurable, but its molecular origins are still unknown. Degeneration in Alzheimer’s disease follows a characteristic pattern: starting from the entorhinal region and spreading out to all neocortical areas. What researchers have long wondered is why certain parts of the brain are more vulnerable to Alzheimer’s disease than others.

“To answer this question, what we’ve tried to do is to predict disease progression starting from healthy brains,” said senior author Professor Michele Vendruscolo of the Centre for Misfolding Diseases at Cambridge’s Department of Chemistry. “If we can predict where and when neuronal damage will occur, then we will understand why certain brain tissues are vulnerable, and get a glimpse at the molecular origins of Alzheimer’s disease.”

One of the hallmarks of Alzheimer’s disease is the build-up of protein deposits, known as plaques and tangles, in the brains of affected individuals. These deposits, which accumulate when naturally-occurring proteins in the body fold into the wrong shape and stick together, are formed primarily of two proteins: amyloid-beta and tau.

“We wanted to know whether there is something special about the way these proteins behave in vulnerable brain tissue in young individuals, long before the typical age of onset of the disease,” said Vendruscolo.

Vendruscolo and his colleagues found that part of the answer lay within the mechanism of control of amyloid-beta and tau. Through the analysis of more than 500 samples of healthy brain tissues from the Allen Brain Atlas, they identified a signature of a group of genes in healthy brains. When compared with tissue from Alzheimer’s patients, the researchers found that this same pattern is repeated in the way the disease spreads in the brain.

“Vulnerability to Alzheimer’s disease isn’t dictated by abnormal levels of the aggregation-prone proteins that form the characteristic deposits in disease, but rather by the weaker control of these proteins in the specific brain tissues that first succumb to the disease,” said Vendruscolo.

Our body has a number of effective defence mechanisms which protect it against protein aggregation, but as we age, these defences get weaker, which is why Alzheimer’s generally occurs in later life. As these defence mechanisms, collectively known as protein homeostasis systems, get progressively impaired with age, proteins are able to form more and more aggregates, starting from the tissues where protein homeostasis is not so strong in the first place.

Earlier this year, the same researchers behind the current study identified a possible ‘neurostatin’ that could be taken by healthy individuals in order to slow or stop the progression of Alzheimer’s disease, in a similar way to how statins are taken to prevent heart disease. ̽��ֱ��current results suggest a way to exploit the gene signature to identify those individuals most at risk and who would most benefit from taking a neurostatin in earlier life.

Although a neurostatin for human use is still quite some time away, a shorter-term benefit of these results may be the development of more effective animal models for the study of Alzheimer’s disease. Since the molecular origins of the disease have been unknown to date, it has been difficult to breed genetically modified mice or other animals that repeat the full pathology of Alzheimer’s disease, which is the most common way for scientists to understand this or any disease in order to develop new treatments.

“It is exciting to consider that the molecular origins identified here for Alzheimer’s may predict vulnerability for other diseases associated with aberrant aggregation – such as ALS, Parkinson’s and frontotemporal dementia,” said Rosie Freer, a PhD student in the Department of Chemistry and the study’s lead author. “I hope that these results will help drug discovery efforts – that by illuminating the origin of disease vulnerability, there will be a clearer target for those working to cure Alzheimer’s.”

“ ̽��ֱ��results of this particular study provide a clear link between the key factors that we have identified as underlying the aggregation phenomenon and the order in which the effects of Alzheimer’s disease are known to spread through the different regions of the brain,” said study co-author Professor Christopher Dobson, who is Master of St John’s College, Cambridge. “Linking the properties of specific protein molecules to the onset and spread of neuronal damage is a crucial step in the quest to find effective drugs to combat this dreadful neurodegenerative condition, and potentially other diseases related to protein misfolding and aggregation.”

Addressing these problems represents the core programme of research of the Centre for Misfolding Diseases, which is directed by Chris Dobson, Tuomas Knowles and Michele Vendruscolo. ̽��ֱ��primary mission of the Centre is to develop a fundamental understanding of the molecular origins of the variety of disorders associated with the misfolding and aggregation of proteins, which include Parkinson's disease, ALS and type II diabetes as well as Alzheimer's disease, and then to use such understanding for the rational design of novel therapeutic strategies.

Reference:
R. Freer et. al. ‘A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease.’ Science Advances (2016). DOI: 10.1126/sciadv.1600947

A specific gene expression pattern maps out which parts of the brain are most vulnerable to Alzheimer’s disease, decades before symptoms appear, and helps define the molecular origins of the disease.

We wanted to know whether there is something special about the way these proteins behave in vulnerable brain tissue in young individuals, long before the typical age of onset of the disease.

Michele Vendruscolo

J. Freer

In healthy tissues, a gene expression signature associated with amyloid-beta and tau aggregation echoes the progression of AD well before the onset of the disease.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Researchers identify ‘neurostatin’ that may reduce the risk of Alzheimer’s disease

sc604 — Fri, 12 Feb 2016 19:00:00 +0000

Researchers have identified a drug that targets the first step in the toxic chain reaction leading to the death of brain cells, suggesting that treatments could be developed to protect against Alzheimer’s disease, in a similar way to how statins are able to reduce the risk of developing heart disease.

̽��ֱ��drug, which is an approved anti-cancer treatment, has been shown to delay the onset of Alzheimer’s disease, both in a test tube and in nematode worms. It has previously been suggested that statin-like drugs – which are safe and can be taken widely by those at risk of developing disease – might be a prospect, but this is the first time that a potential ‘neurostatin’ has been reported.

When the drug was given to nematode worms genetically programmed to develop Alzheimer’s disease, it had no effect once symptoms had already appeared. But when the drug was given to the worms before any symptoms became apparent, no evidence of the condition appeared, raising the possibility that this drug, or other molecules like it, could be used to reduce the risk of developing Alzheimer’s disease. ̽��ֱ��results are reported in the journal Science Advances.

By analysing the way the drug, called bexarotene, works at the molecular level, the international team of researchers, from the ̽��ֱ�� of Cambridge, Lund ̽��ֱ�� and the ̽��ֱ�� of Groningen, found that it stops the first step in the molecular cascade that leads to the death of brain cells. This step, called primary nucleation, occurs when naturally occurring proteins in the body fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. This process also creates smaller clusters called oligomers, which are highly toxic to nerve cells and are thought to be responsible for brain damage in Alzheimer’s disease.

“ ̽��ֱ��body has a variety of natural defences to protect itself against neurodegeneration, but as we age, these defences become progressively impaired and can get overwhelmed,” said Professor Michele Vendruscolo of Cambridge’s Department of Chemistry, the paper’s senior author. “By understanding how these natural defences work, we might be able to support them by designing drugs that behave in similar ways.”

For the past two decades, researchers have attempted to develop treatments for Alzheimer’s that could stop the aggregation and proliferation of oligomers. However, these attempts have all failed, in part because there was not a precise knowledge of the mechanics of the disease’s development: Vendruscolo and his colleagues have been working to understand exactly that.

Using a test developed by study co-author Professor Tuomas Knowles, also from the Department of Chemistry, and by Professor Sara Linse, from Lund ̽��ֱ��, the researchers were able to determine what happens during each stage of the disease’s development, and also what might happen if one of those stages was somehow switched off.

“In order to block protein aggregation, we need accurate understanding of exactly what is happening and when,” said Vendruscolo. “ ̽��ֱ��test that we have developed not only measures the rates of the process as a whole, but also the rates of its specific component sub-processes, so that we can reduce the toxicity of the aggregates rather than simply stopping them forming.”

Johnny Habchi, the first author of the paper, and colleagues assembled a library of more than 10,000 small molecules which interact in some way with amyloid-beta, a molecule that plays a vital role in Alzheimer’s disease. Using the test developed by Knowles and Linse, the researchers first analysed molecules that were either drugs already approved for some other purpose, or drugs developed for Alzheimer’s disease or other similar conditions which had failed clinical trials.

̽��ֱ��first successful molecule they identified was bexarotene, which is approved by the US Food and Drug Administration for the treatment of lymphoma. “One of the real steps forward was to take a molecule that we thought could be a potential drug and work out exactly what it does. In this case, what it does is suppress primary nucleation, which is the aim for any neurostatin-type molecule,” said Vendruscolo. “If you stop the process before aggregation has started, you can’t get proliferation.”

One of the key advances of the current work is that by understanding the mechanisms of how Alzheimer’s disease develops in the brain, the researchers were able to target bexarotene to the correct point in the process.

“Even if you have an effective molecule, if you target the wrong step in the process, you can actually make things worse by causing toxic protein assemblies to build up elsewhere,” said study co-author Professor Chris Dobson, Master of St John’s College, ̽��ֱ�� of Cambridge. “It’s like traffic control – if you close a road to try to reduce jams, you can actually make the situation worse if you put the block in the wrong place. It is not necessarily the case that all the molecules in earlier drug trials were ineffective, but it may be that in some cases the timing of the delivery was wrong.”

Earlier studies of bexarotene had suggested that the drug could actually reverse Alzheimer’s symptoms by clearing amyloid-beta aggregates in the brain, which received a great deal of attention. However, the earlier results, which were later called into question, were based on a completely different mode of action – the clearance of aggregates – than the one reported in the current study. By exploiting their novel approach, which enables them to carry out highly quantitative analysis of the aggregation process, the researchers have now shown that compounds such as bexarotene could instead be developed as preventive drugs, because its primary action is to inhibit the crucial first step in the aggregation of amyloid-beta.

“We know that the accumulation of amyloid is a hallmark feature of Alzheimer’s and that drugs to halt this build-up could help protect nerve cells from damage and death,” said Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK. “A recent clinical trial of bexarotene in people with Alzheimer’s was not successful, but this new work in worms suggests the drug may need to be given very early in the disease. We will now need to see whether this new preventative approach could halt the earliest biological events in Alzheimer’s and keep damage at bay in in further animal and human studies.”

Over the next 35 years, the number of people with Alzheimer’s disease is predicted to go from 40 million to 130 million, with 70% of those in middle or low-income countries. “ ̽��ֱ��only way of realistically stopping this dramatic rise is through preventive measures: treating Alzheimer’s disease only after symptoms have already developed could overwhelm healthcare systems around the world.”

̽��ֱ��body has a number of natural defences designed to keep proteins in check. But as we get older, these processes can become impaired and get overwhelmed, and some proteins can slip through the safety net, resulting in Alzheimer’s disease and other protein misfolding conditions. While neurostatins are not a cure for Alzheimer’s disease, the researchers say that they could reduce its risk by acting as a backup for the body’s natural defences against misfolding proteins.

“You wouldn’t give statins to someone who had just had a heart attack, and we doubt that giving a neurostatin to an Alzheimer’s patient who could no longer recognise a family member would be very helpful,” said Dobson. “But if it reduces the risk of the initial step in the process, then it has a serious prospect of being an effective preventive treatment.”

But is there hope for those already affected by the disease? ̽��ֱ��methods that have led to the present advance have enabled the researchers to identify compounds that, rather than preventing the disease, could slow down its progression even when symptoms have become evident. “ ̽��ֱ��next target of our research is also to be able to treat victims of this dreadful disease,” said Vendruscolo.

Reference:
Johnny Habchi et. al. ‘ An anti-cancer drug suppresses the primary nucleation reaction that produces the toxic Aβ42 aggregates linked with Alzheimer’s disease.’ Science Advances (2016). DOI: 10.1126/sciadv.1501244

An approved anti-cancer drug successfully targets the first step in the toxic chain reaction that leads to Alzheimer’s disease, suggesting that treatments may be found to lower the risk of developing the neurodegenerative condition.

̽��ֱ��body has a variety of natural defences to protect itself against neurodegeneration, but as we age, these defences become progressively impaired and can get overwhelmed.

Michele Vendruscolo

Fibrils of amyloid-beta

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Molecular inhibitor breaks cycle that leads to Alzheimer’s

tdk25 — Mon, 16 Feb 2015 16:00:28 +0000

A molecule that can block the progress of Alzheimer’s disease at a crucial stage in its development has been identified by researchers in a new study, raising the prospect that more such molecules may now be found.

̽��ֱ��report shows that a molecular chaperone, a type of molecule that occurs naturally in humans, can play the role of an “inhibitor” part-way through the molecular process that is thought to cause Alzheimer’s, breaking the cycle of events that scientists believe leads to the disease.

Specifically, the molecule, called Brichos, sticks to threads made up of malfunctioning proteins, called amyloid fibrils, which are the hallmark of the disease. By doing so, it stops these threads from coming into contact with other proteins, thereby helping to avoid the formation of highly toxic clusters that enable the condition to proliferate in the brain.

This step – where fibrils made up of malfunctioning proteins assist in the formation of toxic clusters – is considered to be one of the most critical stages in the development of Alzheimer’s in sufferers. By finding a molecule that prevents it from occurring, scientists have moved closer to identifying a substance that could eventually be used to treat the disease. ̽��ֱ��discovery was made possible by an overall strategy that could now be applied to find other molecules with similar capabilities, extending the range of options for future drug development.

̽��ֱ��research was carried out by an international team comprising academics from the Department of Chemistry at the ̽��ֱ�� of Cambridge, the Karolinska Institute in Stockholm, Lund ̽��ֱ��, the Swedish ̽��ֱ�� of Agricultural Sciences, and Tallinn ̽��ֱ��. Their findings are reported in the journal Nature Structural & Molecular Biology.

Dr Samuel Cohen, a Research Fellow at St John’s College, Cambridge, and a lead author of the report, said: “A great deal of work in this field has gone into understanding which microscopic processes are important in the development of Alzheimer’s disease; now we are now starting to reap the rewards of this hard work. Our study shows, for the first time, one of these critical processes being specifically inhibited, and reveals that by doing so we can prevent the toxic effects of protein aggregation that are associated with this terrible condition.”

Alzheimer’s disease is one of a number of conditions caused by naturally occurring protein molecules folding into the wrong shape and then sticking together – or nucleating – with other proteins to create thin filamentous structures called amyloid fibrils. Proteins perform important functions in the body by folding into a particular shape, but sometimes they can misfold, potentially kick-starting this deadly process.

Recent research, much of it by the academics behind the latest study, has however suggested a second critical step in the disease’s development. After amyloid fibrils first form from misfolded proteins, they help other proteins which come into contact with them to misfold and form small clusters, called oligomers. These oligomers are highly toxic to nerve cells and are now thought to be responsible for the devastating effects of Alzheimer's disease.

This second stage, known as secondary nucleation, sets off a chain reaction which creates many more toxic oligomers, and ultimately amyloid fibrils, generating the toxic effects that eventually manifest themselves as Alzheimer’s. Without the secondary nucleation process, single molecules would have to misfold and form toxic clusters unaided, which is a much slower and far less devastating process.

By studying the molecular processes by which each of these steps takes effect, the research team assembled a wealth of data that enabled them to model not only what happens during the progression of Alzheimer’s disease, but also what might happen if one stage in the process was somehow switched off.

“We had reached a stage where we knew what the data should look like if we inhibited any given step in the process, including secondary nucleation,” Cohen said. “Working closely with our collaborators in Sweden - who had developed groundbreaking experimental methods to monitor the process - we were able to identify a molecule that produced exactly the results that we were hoping to see in experiments.”

̽��ֱ��results indicated that the molecule, Brichos, effectively inhibits secondary nucleation. Typically, Brichos functions as a “molecular chaperone” in humans; a term given to "housekeeping" molecules that help proteins to avoid misfolding and aggregation. Lab tests, however, revealed that when this molecular chaperone encounters an amyloid fibril, it binds itself to catalytic sites on its surface. This essentially forms a coating that prevents the fibrils from assisting other proteins in misfolding and nucleating into toxic oligomers.

̽��ֱ��research team then carried out further tests in which living mouse brain tissue was exposed to amyloid-beta, the specific protein that forms the amyloid fibrils in Alzheimer’s disease. Allowing the amyloid-beta to misfold and form amyloids increased toxicity in the tissue significantly. When this happened in the presence of the molecular chaperone, however, amyloid fibrils still formed but the toxicity did not develop in the brain tissue, confirming that the molecule had suppressed the chain reaction from secondary nucleation that feeds the catastrophic production of oligomers leading to Alzheimer’s disease.

By modelling what might happen if secondary nucleation is switched off and then finding a molecule that performs that function, the research team suggest that they have discovered a strategy that may lead to the identification of other molecules that could have a similar effect.

“It may not actually be too difficult to find other molecules that do this, it’s just that it hasn't been clear what to look for until recently,” Cohen said. “It's striking that nature – through molecular chaperones – has evolved a similar approach to our own by focusing on very specifically inhibiting the key steps leading to Alzheimer's. A good tactic now is to search for other molecules that have this same highly targeted effect and to see if these can be used as the starting point for developing a future therapy.”

̽��ֱ��other members of the Cambridge team were Dr Tuomas Knowles, Dr Paolo Arosio, Professor Michele Vendruscolo and Professor Chris Dobson. All are members of the Centre for Misfolding Diseases, which is based in the ̽��ֱ��'s Department of Chemistry.

A molecular chaperone has been found to inhibit a key stage in the development of Alzheimer’s disease and break the toxic chain reaction that leads to the death of brain cells, a new study shows. ̽��ֱ��research provides an effective basis for searching for candidate molecules that could be used to treat the condition.

It may not actually be too difficult to find other molecules that do this, it’s just that it hasn't been clear what to look for until recently. A good tactic now is to search for other molecules that have this same highly targeted effect and to see if these can be used as the starting point for developing a future therapy.

Sam Cohen

S. Cohen

Transmission electron microscopy image showing a molecular chaperone (the black dots) binding to thread-like amyloid-beta (Aβ42)

̽��ֱ��text in this work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page. For image rights, please see the credits associated with each individual image.

Yes

New headway in battle against neurodegenerative diseases

tdk25 — Thu, 15 May 2014 07:19:20 +0000

Two significant breakthroughs which could inform future treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s, have been announced by scientists.

̽��ֱ��research, published in two separate studies this week, advances understanding of the early development of such disorders and how they might be prevented – in particular by identifying the biological areas and processes that could be pinpointed by future drugs.

Both sets of results have emerged from collaborations between the research groups led by Chris Dobson, Tuomas Knowles and Michele Vendruscolo at the ̽��ֱ�� of Cambridge, who focus on understanding protein “misfolding” diseases. These include Alzheimer’s and Parkinson’s diseases, as well as numerous others.

̽��ֱ��first study provides evidence that the early spread of the protein aggregates associated with Parkinson’s appears to happen at an accelerated rate in mildly acidic conditions. This suggests that particular compartments within brain cells, which are slightly more acidic than others, may turn out to be appropriate targets for future treatments fighting the disease.

Meanwhile, researchers behind the second study appear to have identified a way in which the effectiveness of so-called molecular “chaperones”, responsible for limiting the damage caused by misfolded proteins, can be significantly enhanced.

̽��ֱ��papers appear in the latest issue of Proceedings of the National Academy of Sciences of the USA.

As the term suggests, protein misfolding diseases stem from the fact that proteins, which need to fold into a particular shape to carry out their assigned function in the body, can sometimes misfold. In certain cases these misfolded proteins then clump together into fibre-like threads, called amyloid fibrils, potentially becoming toxic to other cells.

How this formation begins at a molecular level is still not completely understood, but comprehending the process will be fundamental to the development of future therapies and is the subject of extensive current research.

̽��ֱ��first of the new studies builds on research published in 2013, which showed that in Alzheimer’s sufferers, the initial “nucleation” between proteins, which leads to amyloid formation, is followed by an amplification process called secondary nucleation. In these secondary events, the existing amyloid structures facilitate the formation of new aggregates, leading to their exponential increase. This process is likely to be at the heart of the development and spread of the disease in affected brains.

Using the same techniques, the researchers behind the latest study identified a similar process that is relevant in the early stage development of Parkinson’s Disease. Their work focused on a protein called α-synuclein, which is associated with the disorder, and simulated different conditions in which this protein might misfold and form clumps.

As with the previous study on Alzheimer’s, the research identified that Parkinson’s could spread through a series of secondary nucleation events. In addition, however, it showed that in the case of α-synuclein, this happens at a highly accelerated rate only in solutions which are mildly acidic, with a pH below 5.8. ̽��ֱ��finding is important because certain sub-compartments within cells are more acidic than others, meaning that these may be particularly productive areas for future treatments to target.

Dr Tuomas Knowles, from the Department of Chemistry and a Fellow of St John’s College, Cambridge, said: “This tells us much more about the molecular mechanisms underlying protein aggregation in Parkinson’s and suggests that mildly acidic microenvironments within cells may enhance that process by several orders of magnitude. Not every sub-cellular compartment offers these conditions, so it takes us much closer to understanding how the disease might spread.”

̽��ֱ��second study meanwhile suggests a potential route to improving the effectiveness of a particular molecular “chaperone” – a loose classification for proteins which assist in the folding of others, thereby preventing them from causing damage when they misfold.

̽��ֱ��researchers focused on a chaperone called α2-macroglobulin (α2M), which is found outside cells themselves. This is important because neurodegenerative diseases often stem from a process which begins with extracellular misfolding. ̽��ֱ��α2M was tested on a substrate of the amyloid-beta peptide associated with Alzheimer’s Disease.

Typically, the potency of α2M is limited. ̽��ֱ��new study, however, found that when it comes into contact with the oxidant hypochlorite – the same chemical found in household bleach, which also naturally occurs in our immune systems – its structure is modified in a manner that makes it into a much more dynamic defence.

In their report, the researchers suggest that this increased effectiveness stems from the fact that α2M, which is usually found in a four-part, “tetrameric” form, breaks down into “dimeric”, two-part forms when it comes into contact with hypochlorite.

̽��ֱ��chaperone usually plays its role by preventing a misfolded protein from interacting with the membranes that surround and protect cells. Once in its dimeric form, however, receptor binding sites within the α2M are exposed, leading to specific interactions with receptors on the cell itself. If the α2M has already interacted with misfolded proteins, this connection triggers the cell to break the potentially harmful protein down.

“It’s almost like a warning flag for the cell, telling it that something is wrong,” Dr Janet Kumita, from the Department of Chemistry, explained. “It triggers the cell to react in a way that subjects the cargo of misfolded protein to a degradation pathway.”

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

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

“We are beginning to understand exactly how a single, aberrant event can lead to the proliferation and spreading of toxic species throughout the brain, and the manner in which our sophisticated defence mechanisms do their best to suppress such phenomena. It will undoubtedly provide vital clues to the development in due course of new and effective drugs to combat these debilitating and increasingly common disorders.”

For more information, please contact: Tom Kirk, St John’s College, ̽��ֱ�� of Cambridge. Tel: +44 (0)1223 768377, Mob: +44 (0)7764 161923; Email: tdk25@cam.ac.uk

Conditions which may accelerate the spread of Parkinson’s disease, and a potential means of enhancing naturally-occurring defences against neurodegenerative disorders, have been identified in two new studies.

We are beginning to understand exactly how a single, aberrant event can lead to the proliferation and spreading of toxic species throughout the brain, and the manner in which our sophisticated defence mechanisms do their best to suppress such phenomena

Chris Dobson

Andrew Mason, via Flickr

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Professor Christopher Dobson awarded 2014 Heineken Prize for Biochemistry and Biophysics

jfp40 — Tue, 15 Apr 2014 09:31:55 +0000

Professor Dobson is working to uncover the molecular processes that underlie a number of extremely devastating illnesses – among them Alzheimer’s, Parkinson’s and type II diabetes. In particular, his research is focused on a phenomenon whereby otherwise normal proteins sometimes “misfold” and trigger chain reactions in the body that ultimately cause the diseases. Such understanding may form the basis of future therapies based on rational design of innovative types of drugs.

Professor Dobson said: “It is clear that illnesses such as Alzheimer’s disease and type 2 diabetes are a consequence of the aberrant behaviour of our own proteins. And this behaviour is undoubtedly linked to the dramatic and rapid changes in lifestyles and lifespans of many people living in the modern world.”

“Understanding the principles behind these diseases is critical to avert the consequences for the future of their continued proliferation. And history tells us that breakthroughs in our knowledge of the origin and the reason for the progression of any disease is an essential precursor to the development of effective strategies for their prevention and treatment.”

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̽��ֱ��Heineken Prize is among the most prestigious in the scientific community, and a recognition of lifetime achievement which is widely regarded as second only to a Nobel Prize. ̽��ֱ��award recognises Professor Dobson's achievements in helping to identify the root causes of so-called “modern” disorders, such as Alzheimer’s and Parkinson’s diseases.

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Cambridge heads for Hay

jfp40 — Thu, 10 Apr 2014 09:20:09 +0000

̽��ֱ��Cambridge Series has been running for six years at the prestigious Festival and is part of the ̽��ֱ��’s commitment to public engagement. ̽��ֱ��Festival runs from 22nd May to 1st June and is now open for bookings.

This year's line-up includes Sir John Gurdon who was jointly awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells. He will talk about his pioneering work on cloning.

Other speakers include Dr Ha-Joon Chang on economics, classicist Professor Paul Cartledge on after Thermopylae, Dame Barbara Stocking, former chief executive of Oxfam GB and president of Murray Edwards College, on the challenges for women in the workplace, Professor Chris Dobson and Dr Mary Dobson on Alzheimer's and other plagues, economist Professor Noreena Hertz on smart thinking and Professor Robert Mair on tunnelling into the future of our cities.

Professor Richard Evans, president of Wolfson College, will talk about the history of conspiracy theories, Dr John Swenson-Wright from the Faculty of Asian and Middle Eastern Studies will ask if North Korea is the perennial crisis state and Dr Robin Hesketh from the Department of Biochemistry will attempt to demystify cancer.

Several of the talks will take the form of a conversation: Professor Simon Blackburn will debate the uses and abuses of self love with journalist Rosie Boycott; novelist and playwright Biyi Bandele, a former Judith E. Wilson Fellow at Churchill College, will be in conversation with Dr Malachi McIntosh from the Department of English about migrant writing; Professor Henrietta Moore, William Wyse Chair of Social Anthropology, will talk about the future of civil activism with Ricken Patel, founding President of Avaaz, the world's largest online activist community; and psychologist Dr Terri Apter will debate how women follow, resist and play with the stereotypes that define them with author and alumna Zoe Strimpel.

Other Cambridge academics speaking at Hay are Professor Stefan Collini discussing higher education’s two cultures - the humanities and science - and historian Professor David Reynolds.

Peter Florence, director of the Hay Festival, said: "Cambridge ̽��ֱ�� nurtures and challenges the world's greatest minds, and offers the deepest understanding of the most intractable problems and the most thrilling opportunities. And for one week a year they bring that thinking to a field in Wales and share it with everyone. That's a wonderful gift."

Nicola Buckley, head of public engagement at the ̽��ֱ�� of Cambridge, said: “ ̽��ֱ��Cambridge series is a wonderful way to share fascinating research from the ̽��ֱ�� with the public. ̽��ֱ��Hay Festival draws an international cross-section of people, from policy makers to prospective university students. We have found that Hay audiences are highly interested in the diversity of Cambridge speakers, and ask some great questions. We look forward to another fantastic series of speakers, with talks and debates covering so many areas of research and key ideas emerging from Cambridge, relevant to key issues faced globally today."

For tickets, go to: www.hayfestival.org

A host of Cambridge academics, including Nobel Laureate Sir John Gurdon, will be speaking on subjects ranging from stem cell technology and Alzheimer’s to the future of North Korea and the history of conspiracy theories at this year’s Hay Festival.

Cambridge ̽��ֱ�� nurtures and challenges the world's greatest minds, and offers the deepest understanding of the most intractable problems and the most thrilling opportunities

Peter Florence, Director of Hay Festival

Hay Festival

Night shot at Hay Festival

This work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page.

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