̽��ֱ�� of Cambridge - David Rubinsztein

Glaucoma drug shows promise against neurodegenerative diseases, animal studies suggest

cjb250 — Thu, 31 Oct 2024 10:00:09 +0000

Researchers in the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge screened more than 1,400 clinically-approved drug compounds using zebrafish genetically engineered to make them mimic so-called tauopathies. They discovered that drugs known as carbonic anhydrase inhibitors – of which the glaucoma drug methazolamide is one – clear tau build-up and reduce signs of the disease in zebrafish and mice carrying the mutant forms of tau that cause human dementias.

Tauopathies are neurodegenerative diseases characterised by the build-up in the brain of tau protein ‘aggregates’ within nerve cells. These include forms of dementia, Pick's disease and progressive supranuclear palsy, where tau is believed to be the primary disease driver, and Alzheimer’s disease and chronic traumatic encephalopathy (neurodegeneration caused by repeated head trauma, as has been reported in football and rugby players), where tau build-up is one consequence of disease but results in degeneration of brain tissue.

There has been little progress in finding effective drugs to treat these conditions. One option is to repurpose existing drugs. However, drug screening – where compounds are tested against disease models – usually takes place in cell cultures, but these do not capture many of the characteristics of tau build-up in a living organism.

To work around this, the Cambridge team turned to zebrafish models they had previously developed. Zebrafish grow to maturity and are able to breed within two to three months and produce large numbers of offspring. Using genetic manipulation, it is possible to mimic human diseases as many genes responsible for human diseases often have equivalents in the zebrafish.

In a study published today in Nature Chemical Biology, Professor David Rubinsztein, Dr Angeleen Fleming and colleagues modelled tauopathy in zebrafish and screened 1,437 drug compounds. Each of these compounds has been clinically approved for other diseases.

Dr Ana Lopez Ramirez from the Cambridge Institute for Medical Research, Department of Physiology, Development and Neuroscience and the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, joint first author, said: “Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms. They also enable us to do so at scale, something that it not feasible or ethical in larger animals such as mice.”

Using this approach, the team showed that inhibiting an enzyme known as carbonic anhydrase – which is important for regulating acidity levels in cells – helped the cell rid itself of the tau protein build-up. It did this by causing the lysosomes – the ‘cell’s incinerators’ – to move to the surface of the cell, where they fused with the cell membrane and ‘spat out’ the tau.

When the team tested methazolamide on mice that had been genetically engineered to carry the P301S human disease-causing mutation in tau, which leads to the progressive accumulation of tau aggregates in the brain, they found that those treated with the drug performed better at memory tasks and showed improved cognitive performance compared with untreated mice.

Analysis of the mouse brains showed that they indeed had fewer tau aggregates, and consequently a lesser reduction in brain cells, compared with the untreated mice.

Fellow joint author Dr Farah Siddiqi, also from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, said: “We were excited to see in our mouse studies that methazolamide reduces levels of tau in the brain and protects against its further build-up. This confirms what we had shown when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”

Professor Rubinsztein from the UK Dementia Research Institute and Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge, said: “Methazolamide shows promise as a much-needed drug to help prevent the build-up of dangerous tau proteins in the brain. Although we’ve only looked at its effects in zebrafish and mice, so it is still early days, we at least know about this drug’s safety profile in patients. This will enable us to move to clinical trials much faster than we might normally expect if we were starting from scratch with an unknown drug compound.

“This shows how we can use zebrafish to test whether existing drugs might be repurposed to tackle different diseases, potentially speeding up significantly the drug discovery process.”

̽��ֱ��team hopes to test methazolamide on different disease models, including more common diseases characterised by the build-up of aggregate-prone proteins, such as Huntington’s and Parkinson’s diseases.

̽��ֱ��research was supported by the UK Dementia Research Institute (through UK DRI Ltd, principally funded through the Medical Research Council), Tau Consortium and Wellcome.

Reference
Lopez, A & Siddiqi, FH et al. Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion. Nat Chem Bio; 31 Oct 2024; DOI: 10.1038/s41589-024-01762-7

A drug commonly used to treat glaucoma has been shown in zebrafish and mice to protect against the build-up in the brain of the protein tau, which causes various forms of dementia and is implicated in Alzheimer’s disease.

Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms

Ana Lopez Ramirez

Kuznetsov_Peter

Zebrafish

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Public Domain

HIV drug helps protect against build-up of dementia-related proteins in mouse brains

cjb250 — Wed, 26 Apr 2023 15:00:46 +0000

A common characteristic of neurodegenerative diseases such as Huntington’s disease and various forms of dementia is the build-up in the brain of clusters – known as aggregates – of misfolded proteins, such as huntingtin and tau. These aggregates lead to the degradation and eventual death of brain cells and the onset of symptoms.

One method that our bodies use to rid themselves of toxic materials is autophagy, or ‘self-eating’, a process whereby cells ‘eat’ the unwanted material, break it down and discard it. But this mechanism does not work properly in neurodegenerative diseases, meaning that the body is no longer able to get rid of the misfolded proteins.

In a study published today in Neuron, a team from the Cambridge Institute for Medical Research and the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge has identified a process that causes autophagy not to work properly in the brains of mouse models of Huntington’s disease and a form of dementia – and importantly, has identified a drug that helps restore this vital function.

̽��ֱ��team carried out their research using mice that had been genetically-altered to develop forms of Huntington’s disease or a type of dementia characterised by the build-up of the tau protein.

̽��ֱ��brain and central nervous system have their own specialist immune cells, known as microglia, which should protect against unwanted and toxic materials. In neurodegenerative diseases, the microglia kick into action, but in such a way as to impair the process of autophagy.

Using mice, the team showed that in neurodegenerative diseases, microglia release a suite of molecules which in turn activate a switch on the surface of cells. When activated, this switch – called CCR5 – impairs autophagy, and hence the ability of the brain to rid itself of the toxic proteins. These proteins then aggregate and begin to cause irreversible damage to the brain – and in fact, the toxic proteins also create a feedback loop, leading to increased activity of CCR5, enabling even faster build-up of the aggregates.

Professor David Rubinsztein from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, the study’s senior author, said: “ ̽��ֱ��microglia begin releasing these chemicals long before any physical signs of the disease are apparent. This suggests – much as we expected – that if we’re going to find effective treatments for diseases such as Huntington’s and dementia, these treatments will need to begin before an individual begins showing symptoms.”

When the researchers used mice bred to ‘knock out’ the action of CCR5, they found that these mice were protected against the build-up of misfolded huntingtin and tau, leading to fewer of the toxic aggregates in the brain when compared to control mice.

This discovery has led to clues to how this build-up could in future be slowed or prevented in humans. ̽��ֱ��CCR5 switch is not just exploited by neurodegenerative diseases – it is also used by HIV as a ‘doorway’ into our cells. In 2007, the US and European Union approved a drug known as maraviroc, which inhibits CCR5, as a treatment for HIV.

̽��ֱ��team used maraviroc to treat the Huntington’s disease mice, administering the drug for four weeks when the mice were two months old. When the researchers looked at the mice’s brains, they found a significant reduction in the number of huntingtin aggregates when compared to untreated mice. However, as Huntington’s disease only manifests in mice as mild symptoms by 12 weeks even without treatment, it was too early to see whether the drug would make an impact on the mice’s symptoms.

̽��ֱ��same effect was observed in the dementia mice. In these mice, not only did the drug reduce the amount of tau aggregates compared to untreated mice, but it also slowed down the loss of brain cells. ̽��ֱ��treated mice performed better than untreated mice at an object recognition test, suggesting that the drug slowed down memory loss.

Professor Rubinsztein added: “We’re very excited about these findings because we’ve not just found a new mechanism of how our microglia hasten neurodegeneration, we’ve also shown this can be interrupted, potentially even with an existing, safe treatment.

“Maraviroc may not itself turn out to be the magic bullet, but it shows a possible way forward. During the development of this drug as a HIV treatment, there were a number of other candidates that failed along the way because they were not effective against HIV. We may find that one of these works effectively in humans to prevent neurodegenerative diseases.”

̽��ֱ��research was supported by Alzheimer’s Research UK, the UK Dementia Research Institute, Alzheimer’s Society, Tau Consortium, Cambridge Centre for Parkinson-Plus, Wellcome and the European Union's Horizon 2020 research and innovation programme.

Reference
Festa, BP, Siddiqi, FH, & Jimenez-Sanchez, M, et al. Microglial-to-neuronal CCR5 signalling regulates autophagy in neurodegeneration. Neuron; 26 Apr 2023; DOI: 10.1016/j.neuron.2023.04.006

Cambridge scientists have shown how the brain’s ability to clear out toxic proteins is impaired in Huntington’s disease and other forms of dementia – and how, in a study in mice, a repurposed HIV drug was able to restore this function, helping prevent this dangerous build-up and slowing progression of the disease.

We’re very excited about these findings because we’ve not just found a new mechanism of how our microglia hasten neurodegeneration, we’ve also shown this can be interrupted

David Rubinsztein

Understanding Animal Research

Brown mouse

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Attribution

Blood pressure drug shows promise for treating Parkinson’s and dementia in animal studies

cjb250 — Thu, 18 Apr 2019 09:00:42 +0000

A common feature of these diseases – collectively known as neurodegenerative diseases – is the build-up of misfolded proteins. These proteins, such as huntingtin in Huntington’s disease and tau in some dementias, form ‘aggregates’ that can cause irreversible damage to nerve cells in the brain.

In healthy individuals, the body uses a mechanism to prevent the build-up of such toxic materials. This mechanism is known as autophagy, or ‘self-eating’, and involves ‘Pac-Man’-like cells eating and breaking down the materials. However, in neurodegenerative diseases this mechanism is impaired and unable to clear the proteins building up in the brain.

As the global population ages, an increasing number of people are being diagnosed with neurodegenerative diseases, making the search for effective drugs ever more urgent. However, there are currently no drugs that can induce autophagy effectively in patients.

In addition to searching for new drugs, scientists often look to re-purpose existing drugs. These have the advantage that they have already been shown to be safe for use in humans. If they can be shown to be effective against the target diseases, then the journey to clinical use is much faster.

In a study published today in the journal Nature Communications, scientists at the UK Dementia Research Institute and the Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge have shown in mice that felodipine, a hypertension drug, may be a candidate for re-purposing.

Epidemiological studies have already hinted at a possible link between the drug and reduced risk of Parkinson’s disease, but now the researchers have shown that it may be able to induce autophagy in several neurodegenerative conditions.

A team led by Professor David Rubinsztein used mice that had been genetically modified to express mutations that cause Huntington’s disease or a form of Parkinson’s disease, and zebrafish that model a form of dementia.

Mice are a useful model for studying human disease as their short life span and fast reproductive rate make it possible to investigate biological processes in many areas. Their biology and physiology have a number of important characteristics in common with those of humans, including similar nervous systems.

Felodipine was effective at reducing the build-up of aggregates in the mice with the Huntington’s and Parkinson’s disease mutations and in the zebrafish dementia model. ̽��ֱ��treated animals also showed fewer signs of the diseases.

Studies in mice often use doses that are much higher than those known to be safe to use in humans. Professor Rubinsztein and colleagues showed in the Parkinson’s mice that it is possible to show beneficial effects even at concentrations similar to those tolerated by humans. They did so by controlling the concentrations using a small pump under the mouse’s skin.

“This is the first time that we’re aware of that a study has shown that an approved drug can slow the build-up of harmful proteins in the brains of mice using doses aiming to mimic the concentrations of the drug seen in humans,” says Professor Rubinsztein. “As a result, the drug was able to slow down progression of these potentially devastating conditions and so we believe it should be trialled in patients.”

“This is only the first stage, though. ̽��ֱ��drug will need to be tested in patients to see if it has the same effects in humans as it does in mice. We need to be cautious, but I would like to say we can be cautiously optimistic.”

̽��ֱ��study was funded by Wellcome, the Medical Research Council, Alzheimer’s Research UK, the Alzheimer’s Society, Rosetrees Trust, ̽��ֱ��Tau Consortium, an anonymous donation to the Cambridge Centre for Parkinson-Plus, Open Targets, the Guangdong Province Science and Technology Program, with additional support from the National Institute for Health Research Cambridge Biomedical Research Centre.

Reference
Siddiqi, FH et al. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nature Communications; 18 April 2019; DOI: 10.1038/s41467-019-09494-2

A prescription drug to treat high blood pressure has shown promise against conditions such as Parkinson’s, Huntington’s and forms of dementia in studies carried out in mice and zebrafish at the ̽��ֱ�� of Cambridge.

̽��ֱ��drug will need to be tested in patients to see if it has the same effects in humans as it does in mice. We need to be cautious, but I would like to say we can be cautiously optimistic

David Rubinsztein

Understanding Animal Research

White mouse in purple gloved hands

Researcher profile: Dr Farah Siddiqi

Fifteen years ago, when Farah Siddiqi was studying for a PhD in genetics, she had an encounter that was to change the direction of her career.

“During my PhD, I had the opportunity to help as a part-time research assistant for a few hours during the weekend with a professor of economics who suffered from Parkinson’s disease,” she says.

“I saw first-hand the pain and helplessness of someone suffering from a devastating neurodegenerative disease and I began to ponder how I could help reduce the suffering of others affected by these conditions.”

Farah is now part of Professor David Rubinsztein’s research group at the Cambridge Institute for Medical Research where her work focuses on neurodegenerative disorders, such as Huntington’s disease and Parkinson’s disease. She uses mice to model what is going wrong in these conditions, particularly in relation to autophagy, the body’s self-defence mechanism for disposing of unwanted matter at a cellular level.

Their research group is very diverse, with expertise from various fields, such as cell biologists and researchers who carry out in vivo work in zebrafish and mouse research.

“Cambridge is a great place to do research and our institute in particular is a great source of inspiration and knowledge. David is a great supervisor and a big support. ̽��ֱ��intellectual and practical contribution of his team of scientists made this study possible.”

Most of all for Farah, it is the sense that her research could make a difference to the lives of people living with neurodegenerative diseases that inspires her.

“My research gives me a feeling of contentment, especially when I began to observe the beneficial effects of the drug, felodipine, on mice,” she says. “It might be a little optimistic, but we really hope the effect we’ve seen in our mice can be observed in human patients. Only time will tell. We always do our best.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Attribution

̽��ֱ��Royal Society announces election of new Fellows 2017

cjb250 — Fri, 05 May 2017 10:51:45 +0000

In addition, a further three researchers from the MRC Laboratory of Molecular Biology, based at the Cambridge Biomedical Campus, have also been elected Fellows.

̽��ֱ��Royal Society is a self-governing Fellowship of many of the world’s most distinguished scientists drawn from all areas of science, engineering and medicine. ̽��ֱ��Society’s fundamental purpose is to recognise, promote and support excellence in science and to encourage the development and use of science for the benefit of humanity.

Sir Venki Ramakrishnan, President of the Royal Society, said: “Science is a great triumph of human achievement and has contributed hugely to the prosperity and health of our world. In the coming decades it will play an increasingly crucial role in tackling the great challenges of our time including food, energy, health and the environment. ̽��ֱ��new Fellows of the Royal Society have already contributed much to science and it gives me great pleasure to welcome them into our ranks.”

̽��ֱ��Cambridge academics announced today as Royal Society Fellows are:

Professor Krishna Chatterjee, Metabolic Research Laboratories, Department of Medicine
Professor Anne Ferguson-Smith, Department of Genetics
Professor Mark Gross, Department of Pure Mathematics and Mathematical Statistics
Professor David Owen, Cambridge Institute for Medical Research
Professor Lawrence Paulson, Computer Laboratory
Professor David Rubinsztein, Cambridge Institute for Medical Research
Professor Andrew Woods, BP Institute

̽��ֱ��MRC Laboratory of Molecular Biology Fellows are:

Dr Andrew McKenzie, MRC Laboratory of Molecular Biology
Professor John David Sutherland, MRC Laboratory of Molecular Biology
Dr Roger Williams, MRC Laboratory of Molecular Biology

Seven Cambridge academics are among the new Fellows announced today by the Royal Society. Fellows are chosen for their outstanding contributions to science. ̽��ֱ��50 newly-elected Fellows announced today join a list of scientists, engineers and technologists from the UK and Commonwealth. Past Fellows and Foreign Members have included Newton, Darwin and Einstein.

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

Yes

Yoshinori Ohsumi – a deserving winner of the Nobel Prize for physiology or medicine

cjb250 — Mon, 03 Oct 2016 16:24:09 +0000

I am delighted that Yoshinori Ohsumi won this year’s Nobel Prize in physiology or medicine. His pioneering work in yeast led to the discovery of genes and biological processes that are needed for autophagy.

Autophagy (from the Greek for “self-eating”) is the mechanism by which cells break down and recycle cellular content. Without this vital housekeeping role we’d be more prone to cancer, Parkinson’s and other age-related disorders.

Although scientists have been aware of autophagy since the 1960s, it wasn’t until Ohsumi’s experiments with yeast in the 1990s that we began to understand the important role of this biological process.

̽��ֱ��autophagy process is remarkably similar across lifeforms. One function that is the same, from yeast to humans, is to protect cells against starvation and related stresses. In these conditions, autophagy allows cells to degrade large molecules into basic building blocks, which are used as energy sources. ̽��ֱ��discovery of key yeast autophagy genes that was led by Ohsumi was particularly powerful because it helped scientists to quickly identify the genes in mammals that have similar functions. This, in turn, has provided vital tools for laboratories around the world to study the roles of autophagy in human health and disease.

With the knowledge that various mammalian genes are needed for autophagy, researchers could then remove these genes from cells or animals, including mice, and examine their functions. These types of studies have highlighted the importance of autophagy in processes including infection and immunity, neurodegenerative diseases and cancer.

̽��ֱ��importance of Ohsumi’s findings

My laboratory, for example, found that autophagy can break down the proteins responsible for various neurological diseases, including forms of dementia (caused by tau), Parkinson’s disease (alpha-synuclein) and Huntington’s disease (mutant huntingtin). We are pursuing the idea that by increasing the autophagy process we could potentially treat some of these conditions.

A tau protein fragment. molekuul_be/Shutterstock.com

Another important consequence of Ohsumi’s discoveries is that they allowed subsequent studies that aimed to understand the mechanisms by which autophagy proteins actually control this process. Indeed, Ohsumi’s group have also made seminal contributions in this domain.

This Nobel prize highlights some other key characteristics of Ohsumi and his work. One is that his laboratory works on yeast. At the time he made his discoveries in the 1990s, no one would have guessed that they would have such far-reaching implications for human health. Essentially, he was studying autophagy in yeast because he was curious. This basic research yielded the foundation for an entire field, which has grown rapidly in recent years, especially as its relevance for health has become more apparent. This should serve as a reminder to those influencing science strategy that groundbreaking discoveries are often unexpected and that one should not only support science where the endpoint appears to be obviously relevant to health.

Ohsumi has also nurtured outstanding scientists like Noboru Mizushima and Tamotsu Yoshimori, who have been major contributors to the understanding of autophagy in mammals. Perhaps most importantly, he continues to do interesting and fundamental work. This Nobel prize is very well deserved for the man who opened the door to an important field.

David Rubinsztein, Professor of molecular neurogenetics, ̽��ֱ�� of Cambridge

This article was originally published on ̽��ֱ��Conversation. Read the original article.

Yoshinori Ohsumi is a deserving winner of this year's Nobel Prize in physiology or medicine, whose work shows the value of basic research, writes Professor David Rubinsztein, Deputy Director of the Cambridge Institute for Medical Research on ̽��ֱ��Conversation website.

KIMIMASA MAYAMA/EPA

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

Yes

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

Cambridge Drug Discovery Institute to fast-track development of new treatments for dementia

cjb250 — Mon, 16 Feb 2015 08:43:36 +0000

Dementia affects over 830,000 people in the UK and costs the UK economy £23 billion a year. Increasing political focus on improving the outlook for people with dementia in recent years has led to small increases in research funding, but there remains a desperate lack of effective treatments for those with the condition. It has been 12 years since the last treatment for dementia was licensed in the UK and while current treatments help with symptoms, they are only modestly effective and not suitable for all dementias. At the G8 Dementia Summit one year ago, health leaders from across the world pledged a research ambition for a disease-modifying therapy for dementia by 2025.

Alzheimer’s Research UK’s Drug Discovery Alliance will make a major contribution to delivering this ambition – a network of Drug Discovery Institutes dedicated to early stage drug discovery. Each Institute will be led by a Chief Scientific Officer working in tandem with some of the UK’s leading academic researchers based at each of the three universities and Alzheimer’s Research UK’s own in-house research leaders. New ideas and breakthroughs from academic research teams in each university, and beyond, will be driven straight into the hands of dedicated biology and chemistry teams in each Institute, expert in designing and developing potential new medicines.

̽��ֱ��Cambridge Drug Discovery Institute will be located on the Cambridge Biomedical Campus, the centrepiece of the largest biotech cluster outside the United States, and involves many members of Cambridge Neuroscience, a multidisciplinary network of researchers across the city. Its academic lead will be Professor David Rubinsztein, Wellcome Trust Principal Research Fellow and Deputy Director of the Cambridge Institute for Medical Research.

Professor Rubinsztein says: “ ̽��ֱ��new institute will be a world class environment in which to conduct research aimed at transforming the lives of patients living with dementia. It will build on our strengths in basic research and its translation into new treatments for patients. Its location on the Cambridge Biomedical Campus will give it unparalleled access to scientists, clinical researchers and patient cohorts, as well as strong links with pharma and biotech companies in the region.”

With one dementia researcher for every six working on cancer, attracting new expertise to tackle the growing global health problem is crucial. Over the next five years, the Drug Discovery Institutes aim to attract around 90 world-class researchers into dementia drug discovery, who will be equipped with the latest technology and infrastructure through the hosting universities.

Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said: “Academic research is a goldmine of knowledge about diseases such as Alzheimer’s, and by tapping into the innovation, creativity, ideas and flexibility of scientists in these universities, we can re-energise the search for new dementia treatments. Working in universities and hospitals alongside people affected by dementia and their families, academic researchers are best placed to take research breakthroughs and progress them into real world benefits for the people that so desperately need them.

“ ̽��ֱ��Drug Discovery Alliance is one of the first of its kind for dementia research in the world. We’re providing the investment and infrastructure that is needed to maintain and grow a healthy pipeline of potential new treatments to take forward into clinical testing. It’s only by boosting the number of promising leads to follow-up, that we’ll have the best chance of developing pioneering medicines that can change the outlook of this devastating condition.”

̽��ֱ��Drug Discovery Alliance builds on the experiences of similar initiatives driven by cancer charities over the last two decades, which are now starting to deliver effective new treatments to patients.

Cambridge Science Festival
On Tuesday 17 March, Alzheimer’s research UK will be sponsoring an event, Dementia research in Cambridge: from bench to bedside at the 21st Cambridge Science Festival. Visitors will be able to hear short talks from researchers using different techniques from stem cells to brain scans to understand what happens in the brain in dementia and find out what progress is being made to help.

Alzheimer’s Research UK, the world’s largest dedicated dementia research charity, has announced a £30 million Drug Discovery Alliance, launching three flagship Drug Discovery Institutes at the Universities of Cambridge, Oxford and UCL ( ̽��ֱ�� College London). ̽��ֱ��Drug Discovery Institutes will see 90 new research scientists employed in state-of-the-art facilities to fast-track the development of new treatments for Alzheimer’s disease and other dementias.

̽��ֱ��new institute will be a world class environment in which to conduct research aimed at transforming the lives of patients living with dementia

David Rubinsztein

Ann Gordon

My Mom's Hands

̽��ֱ��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

Licence type:

Attribution-ShareAlike

Research sheds light on cell mechanism which plays a role in such diseases as Huntington’s and Parkinson’s

ns480 — Tue, 26 Jul 2011 11:58:27 +0000

(Macro) autophagy is a bulk degradation process that mediates the clearance of long-lived or damaged proteins and organelles in cells. Autophagosomes are formed by double-membraned structures which engulf portions of cytoplasm and ultimately fuse with lysosomes, where the cellular waste is broken down.

̽��ֱ��Rubinsztein lab at the Cambridge Institute for Medical Research have become increasingly involved in studying autophagy, since the time of their discovery that it regulates the levels of aggregate-prone proteins that cause many neurodegenerative diseases, including Huntington's disease, mutant forms of alpha-synuclein (causing forms of Parkinson's disease), and wild-type and mutant forms of tau (causing various dementias). ̽��ֱ��clearance of such proteins is retarded in cell models when autophagy is compromised. Rubinsztein's group showed that drugs that enhance autophagy can alleviate the toxicity of such proteins in cell and animal models of such disease.

In addition to its roles in neurodegeneration, autophagy may have functions in a wide range of normal and disease states, including cancer, protection against certain infectious diseases, and ageing.

One of the key mysteries in the autophagy field has been the origin(s) of autophagosome membranes. Rubinsztein's lab has made key contributions to autophagy cell biology by recently identifying the plasma membrane (the cell membrane) as a critical source of the membranes that form autophagosome precursors (published in Nature Cell Biology in 2010). These studies thus identified an initiating step and site in autophagosome formation that was previously unknown.

Their new research, funded by the Wellcome Trust, shows how these plasma membrane-derived autophagosome precursors mature into autophagosomes by undergoing fusion to increase their size, which they found was a prerequisite for the acquisition of the key autophagosome protein, LC3. This study thus identifies a new regulatable step in the formation of autophagosomes.

Professor David Rubinsztein said: "Autophagy is emerging as a key process regulating many diseases, however, there are still important mysteries to resolve regarding the origins of autophagosomes. We are excited that we have been able to contribute to characterising some of the earliest stages of this process."

̽��ֱ��paper, 'Autophagosome Precursor Maturation Requires Homotypic Fusion’, was published last week in the journal Cell.

New research from scientists at the ̽��ֱ�� of Cambridge provides critical insight into the formation of autophagosomes, which are responsible for cleaning up cellular waste.

Autophagy is emerging as a key process regulating many diseases, however, there are still important mysteries to resolve regarding the origins of autophagosomes.

Professor David Rubinsztein

Geraint Warlow from Creative Commons on Flickr

cell

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

Yes