̽��ֱ�� of Cambridge - Michele Vendruscolo

AI speeds up drug design for Parkinson’s ten-fold

sc604 — Wed, 17 Apr 2024 09:00:00 +0000

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge, designed and used an AI-based strategy to identify compounds that block the clumping, or aggregation, of alpha-synuclein, the protein that characterises Parkinson’s.

̽��ֱ��team used machine learning techniques to quickly screen a chemical library containing millions of entries, and identified five highly potent compounds for further investigation.

Parkinson’s affects more than six million people worldwide, with that number projected to triple by 2040. No disease-modifying treatments for the condition are currently available. ̽��ֱ��process of screening large chemical libraries for drug candidates – which needs to happen well before potential treatments can be tested on patients – is enormously time-consuming and expensive, and often unsuccessful.

Using machine learning, the researchers were able to speed up the initial screening process ten-fold, and reduce the cost by a thousand-fold, which could mean that potential treatments for Parkinson’s reach patients much faster. ̽��ֱ��results are reported in the journal Nature Chemical Biology.

Parkinson’s is the fastest-growing neurological condition worldwide. In the UK, one in 37 people alive today will be diagnosed with Parkinson’s in their lifetime. In addition to motor symptoms, Parkinson’s can also affect the gastrointestinal system, nervous system, sleeping patterns, mood and cognition, and can contribute to a reduced quality of life and significant disability.

Proteins are responsible for important cell processes, but when people have Parkinson’s, these proteins go rogue and cause the death of nerve cells. When proteins misfold, they can form abnormal clusters called Lewy bodies, which build up within brain cells stopping them from functioning properly.

“One route to search for potential treatments for Parkinson’s requires the identification of small molecules that can inhibit the aggregation of alpha-synuclein, which is a protein closely associated with the disease,” said Professor Michele Vendruscolo from the Yusuf Hamied Department of Chemistry, who led the research. “But this is an extremely time-consuming process – just identifying a lead candidate for further testing can take months or even years.”

While there are currently clinical trials for Parkinson’s currently underway, no disease-modifying drug has been approved, reflecting the inability to directly target the molecular species that cause the disease.

This has been a major obstacle in Parkinson’s research, because of the lack of methods to identify the correct molecular targets and engage with them. This technological gap has severely hampered the development of effective treatments.

̽��ֱ��Cambridge team developed a machine learning method in which chemical libraries containing millions of compounds are screened to identify small molecules that bind to the amyloid aggregates and block their proliferation.

A small number of top-ranking compounds were then tested experimentally to select the most potent inhibitors of aggregation. ̽��ֱ��information gained from these experimental assays was fed back into the machine learning model in an iterative manner, so that after a few iterations, highly potent compounds were identified.

“Instead of screening experimentally, we screen computationally,” said Vendruscolo, who is co-Director of the Centre for Misfolding Diseases. “By using the knowledge we gained from the initial screening with our machine learning model, we were able to train the model to identify the specific regions on these small molecules responsible for binding, then we can re-screen and find more potent molecules.”

Using this method, the Cambridge team developed compounds to target pockets on the surfaces of the aggregates, which are responsible for the exponential proliferation of the aggregates themselves. These compounds are hundreds of times more potent, and far cheaper to develop, than previously reported ones.

“Machine learning is having a real impact on drug discovery – it’s speeding up the whole process of identifying the most promising candidates,” said Vendruscolo. “For us, this means we can start work on multiple drug discovery programmes – instead of just one. So much is possible due to the massive reduction in both time and cost – it’s an exciting time.”

̽��ֱ��research was conducted in the Chemistry of Health Laboratory in Cambridge, which was established with the support of the UK Research Partnership Investment Fund (UKRPIF) to promote the translation of academic research into clinical programmes.

Reference:
Robert I Horne et al. ‘Discovery of Potent Inhibitors of α-Synuclein Aggregation Using Structure-Based Iterative Learning.’ Nature Chemical Biology (2024). DOI: 10.1038/s41589-024-01580-x

Researchers have used artificial intelligence techniques to massively accelerate the search for Parkinson’s disease treatments.

Machine learning is having a real impact on drug discovery – it’s speeding up the whole process of identifying the most promising candidates

Michele Vendruscolo

Nathan Pitt

Michele Vendruscolo

̽��ֱ��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.

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AI-driven techniques reveal new targets for drug discovery

Anonymous — Wed, 27 Sep 2023 14:17:57 +0000

̽��ֱ��research team, led by the ̽��ֱ�� of Cambridge, presented an approach to identify therapeutic targets for human diseases associated with a phenomenon known as protein phase separation, a recently discovered phenomenon widely present in cells that drives a variety of important biological functions.

Protein phase separation at the wrong place or time could disrupt key cellular functions or create aggregates of molecules linked to neurodegenerative diseases. It is believed that poorly formed cellular condensates could contribute to cancers and might help explain the aging process.

̽��ֱ��Cambridge researchers, working in collaboration with generative artificial intelligence (AI)-driven drug discovery company Insilico Medicine, developed a method for finding new targets for drug discovery in diseases caused by dysregulation of the protein phase separation process. ̽��ֱ��team found that they could replicate disease characteristics in cells by controlling the behaviour of these targets. Their results are reported in the Proceedings of the National Academy of Sciences (PNAS).

“ ̽��ֱ��discovery of protein phase separation opens up new opportunities for drug discovery,” said Professor Michele Vendruscolo from Cambridge’s Yusuf Hamied Department of Chemistry, who led the research. “However, it has been unclear which proteins undergo this process and represent the best targets for effective pharmacological interventions.”

In the study, researchers combined Insilico’s proprietary target identification engine PandaOmics with the FuzDrop method to identify disease-associated proteins prone to phase separation. PandaOmics is an AI-driven therapeutic target discovery tool that integrates multiple omics and text AI bioinformatics models to assess the potential of proteins as therapeutic targets.

FuzDrop is a tool introduced by the Cambridge team, which calculates the propensity of a protein to undergo spontaneous phase separation, aiding in the identification of proteins prone to form liquid-liquid phase-separated condensates.

Using this approach, the researchers conducted a large-scale study of human sample data, quantified the relative impact of protein phase separation in regulating various pathological processes associated with human disease, prioritised candidates with high PandaOmics and FuzDrop scores and generated a list of possible therapeutic targets for human diseases linked with protein phase separation.

̽��ֱ��researchers validated the differential phase separation behaviours of three predicted Alzheimer’s disease targets (MARCKS, CAMKK2 and p62) in two cell models of Alzheimer’s disease, which provides experimental validation for the involvement of these predicted targets in Alzheimer's disease and support their potential as therapeutic targets. By modulating the formation and behaviour of these condensates, it may be possible to develop new interventions to mitigate the pathological processes associated with Alzheimer's disease.

“It has been challenging so far to understand the role of protein phase separation in cellular functions,” said Vendruscolo. “Even more difficult has been to clarify the exact nature of its association with human disease. By working with Insilico Medicine, we have developed an approach to systematically address this problem and identify a variety of possible therapeutic targets. We have thus provided a roadmap for researchers to navigate this complex terrain.”

“We are pleased to reach the milestones of our collaboration with the ̽��ֱ�� of Cambridge,” said Frank Pun, PhD, head of Insilico Medicine Hongkong, and co-author of the paper. “ ̽��ֱ��study is intended to provide initial directions for targeting disease-associated proteins prone to phase separation. With ongoing technical advancements in studying the protein phase separation process, coupled with the growing data about its roles in both cellular function and dysfunction, it is now possible to comprehend the causal relationship between these targets and diseases. We anticipate facilitating the translation of this preclinical research into novel therapeutic interventions soon.”

Reference:
Christine M. Lim et al. ‘Multiomic prediction of therapeutic targets for human diseases associated with protein phase separation.’ Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2300215120

Adapted from an Insilico Medicine press release.

Researchers have developed a method to identify new targets for human disease, including neurodegenerative conditions such as Alzheimer’s disease.

̽��ֱ��discovery of protein phase separation opens up new opportunities for drug discovery

Michele Vendruscolo

Juan Gaertner/Science Photo Library via Getty Images

Alzheimers disease. Computer illustration of amyloid plaques amongst neurons.

̽��ֱ��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

Following the hops of disordered proteins could lead to future treatments of Alzheimer’s disease

sc604 — Thu, 14 Jan 2021 16:09:45 +0000

Researchers from the ̽��ֱ�� of Cambridge, Google Research and the ̽��ֱ�� of Milan have used machine learning techniques to predict how proteins, particularly those implicated in neurological diseases, completely change their shapes in a matter of microseconds.

They found that when amyloid-beta, a key protein implicated in Alzheimer’s disease, adopts a collection of disordered shapes, it actually becomes less likely to stick together and form the toxic clusters which lead to the death of brain cells.

̽��ֱ��results, reported in the journal Nature Computational Science, could aid in the future development of treatments for diseases involving disordered proteins, such as Alzheimer’s disease and Parkinson’s disease.

“We are used to thinking of proteins as molecules that fold into well-defined structures: finding out how this process happens has been a major research focus over the last 50 years,” said Professor Michele Vendruscolo from Cambridge’s Centre for Misfolding Diseases, who led the research. “However, about a third of the proteins in our body do not fold, and instead remain in disordered shapes, sort of like noodles in a soup.”

We do not know much about the behaviour of these disordered proteins, since traditional methods tend to address the problem of determining static structures, not structures in motion. ̽��ֱ��approach developed by the researchers harnesses the power of Google's cloud computing infrastructure to generate large numbers of short trajectories. “Extensive computer simulations allow us to capture the molecular-level motions of thousands of copies of a protein in parallel, and play them back like a movie,” said co-author Dr Kai Kohlhoff from Google Research.

̽��ֱ��most common types of motions show up multiple times in these movies, making it possible to define the frequencies by which disordered proteins jump between different states.

“By counting these motions, we can predict which states the protein occupies and how quickly it transitions between them,” said first author Thomas Löhr from Cambridge’s Yusuf Hamied Department of Chemistry.

̽��ֱ��researchers focused their attention on the amyloid-beta peptide, a protein fragment associated with Alzheimer’s disease, which aggregates to form amyloid plaques in the brains of affected individuals. They found that amyloid-beta hops between widely different states millions of times per second without ever stopping in any particular state. This is the hallmark of disorder, and the main reason for which amyloid-beta has been deemed ‘undruggable’ so far.

“ ̽��ֱ��constant motion of amyloid-beta is one of the reasons it’s been so difficult to target – it’s almost like trying to catch smoke in your hands,” said Vendruscolo.

However, by studying a variant of amyloid-beta, in which one of the amino acids is modified by oxidation, the researchers obtained a glimpse on how to make it resistant to aggregation. They found that oxidated amyloid-beta changes shape even faster than its unmodified counterpart, providing a rationale to explain the decreased tendency for aggregation of the oxidated version.

“From a chemical perspective, this modification is a minor change. But the effect on the states and transitions between them is drastic,” said Löhr.

“By making disordered proteins even more disordered, we can prevent them from self-associating in aberrant manners,” said Vendruscolo.

̽��ֱ��approach provides a powerful tool to investigate a class of proteins with fast and disordered motions, which have remained elusive so far despite their importance in biology and medicine.

Reference:
Thomas Löhr et al. ‘A kinetic ensemble of the Alzheimer's Aβ peptide’ Nature Computational Science (2021). DOI: 10.1038/s43588-020-00003-w

Study shows how to determine the elusive motions of proteins that remain disordered.

̽��ֱ��constant motion of amyloid-beta is one of the reasons it’s been so difficult to target – it’s almost like trying to catch smoke in your hands

Michele Vendruscolo

NIH Image Gallery

Beta-Amyloid Plaques and Tau in the Brain

̽��ֱ��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.

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Researchers show how to target a 'shape-shifting' protein in Alzheimer’s disease

sc604 — Wed, 04 Nov 2020 18:54:26 +0000

A team of researchers, led by the ̽��ֱ�� of Cambridge, have identified a new mechanism of targeting amyloid-beta, a protein fragment that clumps together and kills healthy brain cells in people with Alzheimer’s disease.

Working with colleagues from Imperial College London, Institut Pasteur, and the ̽��ֱ�� of Florence, the researchers found that it is possible for a drug-like molecule to target amyloid-beta in its disordered state, reducing its ability to form the toxic clusters which are the hallmark of Alzheimer’s disease. ̽��ֱ��results, reported in the journal Science Advances, could form the basis of a new avenue for the development of potential treatments for the disease.

“Amyloid-beta is a disordered protein, a type of target that is elusive for standard therapeutic approaches,” said Professor Michele Vendruscolo from Cambridge’s Centre for Misfolding Diseases, who led the research. “It is constantly changing shape, so traditional drug discovery techniques don’t work on it. By revealing a new drug-binding mechanism, we have extended traditional drug discovery approaches based on the optimisation of the binding affinity to include disordered proteins.”

Most drugs work by binding proteins through what is often described as a lock-and-key mechanism, where a drug fits into a protein’s grooves like a key in a lock. However, since they are often changing shape, disordered proteins such as amyloid-beta don’t have stable ‘locks’ for drugs to bind to, which is why they are considered ‘undruggable.’

̽��ֱ��approach developed by the researchers is based on the so-called disordered binding mechanism that they discovered, where small molecules form a disordered complex with the protein target, so that it is like the protein and the drug are ‘dancing’ with one another.

̽��ֱ��researchers characterised this new mechanism using a combination of biophysical experiments, mathematical modelling, in vivo experiments and computation.

First, they tested the aggregation of amyloid-beta in the presence of the compound in in vitro assays. Data from these experiments allowed the researchers to build a mathematical model of how the drug was able to inhibit the aggregation of amyloid-beta at the microscopic level.

̽��ֱ��team also used high-performance computing methods to study the binding interaction at the atomic level. These intensive calculations allowed the researchers to ‘see’ how the binding was occurring at the atomic level, which is otherwise almost impossible to observe experimentally. Further tests were then carried out in nematode worms, which are often used as a model organism to study Alzheimer’s disease.

“In contrast to the traditional lock-and-key binding mechanism, in which a drug tightly interacts with its target in a specific conformation, we found that both the small molecule and the disordered protein remained extremely dynamic, and that the small molecule interacted with many parts of the protein,” said Gabriella Heller, Schmidt Science Fellow and the study’s first author.

“This way of stabilising native states of proteins is a powerful drug discovery strategy, which has so far been extremely challenging for disordered proteins,” said Vendruscolo.

Amyloid beta, the protein which the team targeted, is closely associated with Alzheimer’s disease as it is the primary component of senile plaques, which are characteristically found in the brains of the people affected by the disease.

While this research is still preliminary in terms of clinical translation, it demonstrates that targeting the formation of these plaques by preventing the aggregation of amyloid-beta is a major therapeutic strategy. To date the mainstream approach has been to develop antibodies to bind to the aggregates, promoting their removal and interfering with their self-assembly.

“Disordered proteins are also involved in a wide range of diseases including cancer and cardiovascular disease. We hope that we can extend this understanding to also target disordered proteins involved in other diseases,” said Heller.

Reference:
Gabriella T. Heller et al. ‘Small-molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer’s disease.’ Science Advances (2020). DOI: 10.1126/sciadv.abb5924

A new study suggests that it is possible to design drugs that can target a type of shape-shifting protein involved in Alzheimer’s disease, which was previously thought to be undruggable.

We hope that we can extend this understanding to also target disordered proteins involved in other diseases

Gabriella Heller

National Institute on Aging, NIH

Beta-Amyloid Plaques and Tau in the Brain

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Licence type:

Public Domain

Antibody designed to recognise pathogens of Alzheimer’s disease

sc604 — Mon, 25 May 2020 19:00:00 +0000

Their method is able to recognise these toxic particles, known as amyloid-beta oligomers, which are the hallmark of the disease, leading to hope that new diagnostic methods can be developed for Alzheimer’s disease and other forms of dementia.

̽��ֱ��team, from the ̽��ֱ�� of Cambridge, ̽��ֱ�� College London and Lund ̽��ֱ��, designed an antibody which is highly accurate at detecting toxic oligomers and quantifying their numbers. Their results are reported in the Proceedings of the National Academy of Sciences (PNAS).

“There is an urgent unmet need for quantitative methods to recognise oligomers – which play a major role in Alzheimer’s disease, but are too elusive for standard antibody discovery strategies,” said Professor Michele Vendruscolo from Cambridge’s Centre for Misfolding Diseases, who led the research. “Through our innovative design strategy, we have now discovered antibodies to recognise these toxic particles.”

Dementia is one of the leading causes of death in the UK and costs more than £26 billion each year, a figure which is expected to more than double in the next 25 years. Estimates put the current cost to the global economy at nearly £1 trillion per year.

Alzheimer’s disease, the most prevalent form of dementia, leads to the death of nerve cells and tissue loss throughout the brain, resulting in memory failure, personality changes and problems carrying out daily activities.

Abnormal clumps of proteins called oligomers have been identified by scientists as the most likely cause of dementia. Although proteins are normally responsible for important cell processes, according to the amyloid hypothesis, when people have Alzheimer’s disease these proteins –including specifically amyloid-beta proteins – become rogue and kill healthy nerve cells.

Proteins need to be closely regulated to function properly. When this quality control process fails, the proteins misfold, starting a chain reaction that leads to the death of brain cells. Misfolded proteins form abnormal clusters called plaques which build up between brain cells, stopping them from signalling properly. Dying brain cells also contain tangles, twisted strands of proteins that destroy a vital cell transport system, meaning nutrients and other essential supplies can no longer move through the cells.

There have been over 400 clinical trials for Alzheimer’s disease, but no drug that can modify the course of the disease has been approved. In the UK, dementia is the only condition in the top 10 causes of death without a treatment to prevent, stop, or slow its progression.

“While the amyloid hypothesis is a prevalent view, it has not been fully validated in part because amyloid-beta oligomers are so difficult to detect, so there are differing opinions on what causes Alzheimer’s disease,” said Vendruscolo. “ ̽��ֱ��discovery of an antibody to accurately target oligomers is, therefore, an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control.”

̽��ֱ��lack of methods to detect oligomers has been a major obstacle in the progress of Alzheimer’s research. This has hampered the development of effective diagnostic and therapeutic interventions and led to uncertainty about the amyloid hypothesis.

“Oligomers are difficult to detect, isolate, and study,” said Dr Francesco Aprile, the study’s first author. “Our method allows the generation of antibody molecules able to target oligomers despite their heterogeneity, and we hope it could be a significant step towards new diagnostic approaches.”

̽��ֱ��method is based on an approach for antibody discovery developed over the last ten years at the Centre for Misfolding Diseases. Based on the computational assembly of antibody-antigen assemblies, the method enables the design of antibodies for antigens that are highly challenging, such as those that live only for a very short time.

By using a rational design strategy that enables to target specific regions, or epitopes, of the oligomers, and a wide range of in vitro and in vivo experiments, the researchers have designed an antibody with at least three orders of magnitude greater affinity for the oligomers over other forms of amyloid-beta. This difference is the key feature that enables the antibody to specifically quantify oligomers in both in vitro and in vivo samples.

̽��ֱ��team hopes that this tool will enable the discovery of better drug candidates and the design of better clinical trials for people affected by the debilitating disease. They also co-founded Wren Therapeutics, a spin-out biotechnology company based at the Chemistry of Health Incubator, in the recently opened Chemistry of Health building, whose mission it is to take the ideas developed at the ̽��ֱ�� of Cambridge and translate them into finding new drugs to treat Alzheimer’s disease and other protein misfolding disorders.

̽��ֱ��antibody has been patented by Cambridge Enterprise, the ̽��ֱ��’s commercialisation arm.

Reference:
Francesco A. Aprile et al. ‘Rational design of a conformation-specific antibody for the quantification of Aβ oligomers.’ Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.1919464117

Researchers have found a way to design an antibody that can identify the toxic particles that destroy healthy brain cells – a potential advance in the fight against Alzheimer’s disease.

̽��ֱ��discovery of an antibody to accurately target oligomers is an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control

Michele Vendruscolo

Strittmatter Laboratory, Yale ̽��ֱ��

Mouse model of Alzheimer's disease

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Licence type:

Attribution-Noncommerical

Scientists reveal plan to target the cause of Alzheimer’s disease

Anonymous — Mon, 24 Sep 2018 19:00:00 +0000

Academics at the ̽��ֱ�� of Cambridge and at Lund ̽��ֱ�� in Sweden have devised the first strategy to ‘go after’ the cause of the devastating disease, which could eventually lead to the development of new drugs to treat dementia. Their findings are reported in the journal PNAS.

“This is the first time that a systematic method to go after the pathogens – the cause of Alzheimer’s disease - has been proposed,” said Professor Michele Vendruscolo from Cambridge’s Department of Chemistry, the paper’s senior author. “Until very recently scientists couldn’t agree on what the cause was so we didn’t have a target. As the pathogens have now been identified as small clumps of proteins known as oligomers, we have been able to develop a strategy to aim drugs at these toxic particles.”

Alzheimer’s disease leads to the death of nerve cells and tissue loss throughout the brain. Over time, the brain shrinks dramatically and the cell destruction causes memory failure, personality changes, and problems carrying out daily activities.

Scientists identified abnormal deposits called protein oligomers as the most likely suspects of the cause of dementia. Although proteins are normally responsible for important cell processes, when people have Alzheimer’s disease these proteins become rogue, form clumps and kill healthy nerve cells.

“A healthy brain has a quality control system that effectively disposes of potentially dangerous masses of proteins, known as aggregates,” said Vendruscolo. “As we age, the brain becomes less able to get rid of the dangerous deposits, leading to disease. It is like a household recycling system, if you have an efficient system in place then the clutter gets disposed of in a timely manner. If not, over time, you slowly but steadily accumulate junk that you don’t need. It is the same in the brain.”

̽��ֱ��research was carried out by an international team of scientists that also included Professor Sir Christopher Dobson, Master of St John's College, ̽��ֱ�� of Cambridge, at the Centre for Misfolding Diseases (CMD), which he co-founded. “This interdisciplinary study shows that it is possible not just to find compounds that target the toxic oligomers that give rise to neurodegenerative disorders but also to increase their potency in a rational manner,” he said. “It now makes it possible to design molecules that have specific effects on the various stages of disorders such as Alzheimer’s disease, and hopefully to convert them into drugs that can be used in a clinical environment.”

There have been approximately 400 clinical trials for Alzheimer’s disease but none of them has specifically targeted the pathogens that cause it. In the UK, dementia is the only condition in the top 10 causes of death without a treatment to prevent, cure or slow its progression.

“Our research is based on the major conceptual step of identifying protein oligomers as the pathogens and reports a method to systematically develop compounds to target them. This approach enables a new drug discovery strategy,” said Vendruscolo.

̽��ֱ��team believes their first drug candidates could reach clinical trials in around two years. They have co-founded Wren Therapeutics, a biotechnology company based in the newly opened Chemistry of Health building, whose mission is to take the ideas developed at Cambridge and translate them into finding new ways to diagnose and treat Alzheimer’s disease and other misfolding disorders.

̽��ֱ��group’s new strategy is based on a chemical kinetics approach developed in the last ten years by scientists led jointly by Professor Tuomas Knowles, also a Fellow at St John's College, Professor Dobson and Professor Vendruscolo, working at the new centre in Cambridge, in collaboration with scientists at Lund ̽��ֱ�� led by Professor Sara Linse.

“Since the process of aggregation is highly dynamic, the framework of kinetics allows us to approach this problem in a new way and find approaches to stop the generation of toxic proteins species at their very source,” said Knowles.

“This is a detailed academic study looking at how quickly compounds are able to stop amyloid building up into toxic clumps, which are characteristic of Alzheimer’s disease,” said Dr David Reynolds, Chief Scientific Officer from Alzheimer’s Research UK. “With no treatments to slow or stop the diseases that cause dementia, it’s vital we improve approaches like this that could help refine the drug discovery progress and accelerate new treatments for people living with Alzheimer’s.”

Reference:
Sean Chia et al. ‘SAR by kinetics for drug discovery in protein misfolding diseases.’ PNAS (2018). DOI: 10.1073/pnas.1807884115

Adapted from a St John’s College press release.

Researchers have developed a new way to target the toxic particles that destroy healthy brain cells in Alzheimer’s disease.

This is the first time that a systematic method to go after the pathogens – the cause of Alzheimer’s disease - has been proposed.

Michele Vendruscolo

Kateryna Kon

Conceptual image showing blurred brain with loss of neuronal networks

Yes

New research facility for neurodegenerative disorders opened in Cambridge

sc604 — Fri, 21 Sep 2018 10:52:08 +0000

̽��ֱ��building houses the Centre for Misfolding Diseases, a world-leading research facility focused on the misfolding of proteins in human cells - a phenomenon that causes a number of disorders including Alzheimer’s, Parkinson’s, Huntington’s and Motor Neurone Diseases.

̽��ֱ��building has been funded by £17.6 million from Research England’s UK Research Partnership Investment Fund (UKRPIF), as well as with contributions from Elan Pharmaceuticals and AstraZeneca.

Among the philanthropic contributions to the project is a donation of £5 million from Cambridge alumnus Derek Finlay in memory of his wife, Una, who died in May 2016 after a long struggle with Alzheimer’s disease. ̽��ֱ��first-floor laboratory is named the Una Finlay Laboratory in her memory and as the name-plaque was unveiled, Mr Finlay said: “This is a special and very poignant day for myself and my family. This building will enable world-class research that will speed up the search for ways to delay, ameliorate and – I believe – ultimately abolish these dreadful neurodegenerative diseases.”

“ ̽��ֱ��research carried out in this new facility has the potential to affect millions of lives around the world for the better,” said Cambridge Vice-Chancellor Professor Stephen Toope, who opened the building today. “Through collaboration and the sharing of ideas, our research teams will work to find the keys that unlock the mysteries of neurodegenerative disorders, one of the greatest health problems of our age.”

A 2015 report suggested that by 2030, there will be 75 million people worldwide living with Alzheimer’s disease. While the number of cases of Alzheimer’s diseases and other neurodegenerative disorders continues to rise, so too do the costs to society, both economic and emotional.

̽��ֱ��Centre for Misfolding Diseases is co-directed by Professor Sir Christopher Dobson, Professor Tuomas Knowles and Professor Michele Vendruscolo, three world leaders in their fields who have been studying the molecular origins of neurodegenerative diseases.

“This building will for the first time bring together a large number of scientists from different disciplines who are dedicated to establishing the molecular basis of neurodegenerative disorders and to identifying new ways for treating or preventing these debilitating conditions,” said Dobson.

“ ̽��ֱ��treatment of neurodegenerative disorders represents a major challenge, requiring both the development of innovative biophysical approaches and their translation into diagnostic and therapeutic tools,” said Vendruscolo. “With this new building, we have created favourable conditions to combine these two steps.”

“This facility will be a crucial element in helping us to tackle the challenge of understanding the molecular mechanisms of dementia and develop effective ways to counteract them,” said Knowles.

̽��ֱ��new building is also home to a Chemistry of Health Incubator, which will enable closer collaborations between researchers and industry and host spin-out companies in order to increase the rate at which scientific discoveries are translated into new therapies. ̽��ֱ��new incubator is the first in Cambridge to be directly integrated into a ̽��ֱ�� department, and will provide the resources and complementary know-how required to ensure that fundamental research is ultimately used to develop new treatments for patients. ̽��ֱ��first spin-out company to move into the Incubator will be Wren Therapeutics, which is based on a ground-breaking drug discovery method for neurodegenerative disorders developed at the Centre for Misfolding Diseases.

̽��ֱ��Chemistry of Health building, a new facility dedicated to the use of chemical techniques to combat disease, in particular neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, was officially opened today in Cambridge.

L-R: Vice Chancellor; Derek Finlay; Fiona Finlay; Dame Fiona Reynolds, Master of Emmanuel College; Lord Wilson, former Master of Emmanuel College; and Professor Sir Christopher Dobson

Yes

Brain cholesterol associated with increased risk of Alzheimer’s disease

sc604 — Mon, 07 May 2018 15:00:00 +0000

̽��ֱ��international team, led by the ̽��ֱ�� of Cambridge, have found that in the brain, cholesterol acts as a catalyst which triggers the formation of the toxic clusters of the amyloid-beta protein, which is a central player in the development of Alzheimer’s disease.

̽��ֱ��results, published in the journal Nature Chemistry, represent another step towards a possible treatment for Alzheimer’s disease, which affects millions worldwide. ̽��ֱ��study’s identification of a new pathway in the brain where amyloid-beta sticks together, or aggregates, could represent a new target for potential therapeutics.

It is unclear if the results have any implications for dietary cholesterol, as cholesterol does not cross the blood-brain barrier. Other studies have also found an association between cholesterol and the condition, since some genes which process cholesterol in the brain have been associated with Alzheimer’s disease, but the mechanism behind this link is not known.

̽��ֱ��Cambridge researchers found that cholesterol, which is one of the main components of cell walls in neurons, can trigger amyloid-beta molecules to aggregate. ̽��ֱ��aggregation of amyloid-beta eventually leads to the formation of amyloid plaques, in a toxic chain reaction that leads to the death of brain cells.

While the link between amyloid-beta and Alzheimer’s disease is well-established, what has baffled researchers to date is how amyloid-beta starts to aggregate in the brain, as it is typically present at very low levels.

“ ̽��ֱ��levels of amyloid-beta normally found in the brain are about a thousand times lower than we require to observe it aggregating in the laboratory – so what happens in the brain to make it aggregate?” said Professor Michele Vendruscolo of Cambridge’s Centre for Misfolding Diseases, who led the research.

Using a kinetic approach developed over the last decade by the Cambridge team and their collaborators at Lund ̽��ֱ�� in Sweden, the researchers found in in vitro studies that the presence of cholesterol in cell membranes can act as a trigger for the aggregation of amyloid-beta.

“It's exciting to see that the kinetic analysis approach that we have developed over the past few years is now allowing us to explore increasingly complex systems, including protein-lipid interactions which are likely to be central for the initiation of aberrant protein aggregation,” said co-author Professor Tuomas Knowles.

Since amyloid-beta is normally present in such small quantities in the brain, the molecules don’t normally find each other and stick together. Amyloid-beta does attach itself to lipid molecules, however, which are sticky and insoluble. In the case of Alzheimer’s disease, the amyloid-beta molecules stick to the lipid cell membranes that contain cholesterol. Once stuck close together on these cell membranes, the amyloid-beta molecules have a greater chance to come into contact with each other and start to aggregate – in fact, the researchers found that cholesterol speeds up the aggregation of amyloid-beta by a factor of 20.

So what, if anything, can be done to control cholesterol in the brain? According to Vendruscolo, it’s not cholesterol itself that is the problem. “ ̽��ֱ��question for us now is not how to eliminate cholesterol from the brain, but about how to control cholesterol’s role in Alzheimer’s disease through the regulation of its interaction with amyloid-beta,” he said. “We’re not saying that cholesterol is the only trigger for the aggregation process, but it’s certainly one of them.”

Since it is insoluble, while travelling towards its destination in lipid membranes, cholesterol is never left around by itself, either in the blood or the brain: it has to be carried around by certain dedicated proteins, such as ApoE, a mutation of which has already been identified as a major risk factor for Alzheimer’s disease. As we age, these protein carriers, as well as other proteins that control the balance, or homeostasis, of cholesterol in the brain become less effective. In turn, the homeostasis of amyloid-beta and hundreds of other proteins in the brain is broken. By targeting the newly-identified link between amyloid-beta and cholesterol, it could be possible to design therapeutics which maintain cholesterol homeostasis, and consequently amyloid-beta homeostasis, in the brain.

“This work has helped us narrow down a specific question in the field of Alzheimer’s research,” said Vendruscolo. “We now need to understand in more detail how the balance of cholesterol is maintained in the brain in order to find ways to inactivate a trigger of amyloid-beta aggregation.”

Co-author Professor Chris Dobson, also a member of the Centre for Misfolding Diseases and Master of St John's College, added “This study has added significantly to our understanding of the molecular basis of aggregation of amyloid-beta, which is associated with Alzheimer’s disease. It shows how interdisciplinary studies fostered by the Centre for Misfolding Diseases, and our international collaborators can play a major part in working out how to develop potential therapeutic strategies to reduce the risk of the onset and progression of this highly debilitating and increasingly common disease.”

Dr Tim Shakespeare of the Alzheimer’s Society said: “Previous research has shown people with high cholesterol levels in mid-life are slightly more likely to develop dementia, but until now we didn’t know why. This study has demystified the link. ̽��ֱ��findings suggest managing cholesterol levels in the brain could be a target for future treatments, but it’s still unclear whether there’s any effect from our diet.”

Dr David Reynolds of Alzheimer’s Research UK, said: “Around 20 per cent of the body’s total cholesterol is found in the brain. Cholesterol in our diet can have a big impact on heart health and maintaining a healthy blood supply to the brain can help to keep dementia risk as low as possible.”

Reference:
Johnny Habchi et al. ‘Cholesterol catalyses amyloid-β42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes.’ Nature Chemistry (2018). DOI: 10.1038/s41557-018-0031-x

Researchers have shown how cholesterol – a molecule normally linked with cardiovascular diseases – may also play an important role in the onset and progression of Alzheimer’s disease.

̽��ֱ��question for us now is not how to eliminate cholesterol from the brain, but about how to control cholesterol’s role in Alzheimer’s disease through the regulation of its interaction with amyloid-beta.

Michele Vendruscolo

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Mouse model of Alzheimer's disease

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