̽��ֱ�� of Cambridge - UK Dementia Research Institute

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

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Scientists identify genes linked to DNA damage and human disease

cjb250 — Fri, 16 Feb 2024 10:17:07 +0000

̽��ֱ��work, published in Nature, provides insights into cancer progression and neurodegenerative diseases as well as a potential therapeutic avenue in the form of a protein inhibitor.

̽��ֱ��genome contains all the genes and genetic material within an organism's cells. When the genome is stable, cells can accurately replicate and divide, passing on correct genetic information to the next generation of cells. Despite its significance, little is understood about the genetic factors governing genome stability, protection, repair, and the prevention of DNA damage.

In this new study, researchers from the UK Dementia Research Institute, at the ̽��ֱ�� of Cambridge, and the Wellcome Sanger Institute set out to better understand the biology of cellular health and identify genes key to maintaining genome stability.

Using a set of genetically modified mouse lines, the team identified 145 genes that play key roles in either increasing or decreasing the formation of abnormal micronuclei structures. These structures indicate genomic instability and DNA damage, and are common hallmarks of ageing and diseases.

̽��ֱ��most dramatic increases in genomic instability were seen when the researchers knocked out the gene DSCC1, increasing abnormal micronuclei formation five-fold. Mice lacking this gene mirrored characteristics akin to human patients with a number of rare genetic disorders, further emphasising the relevance of this research to human health.

Using CRISPR screening, researchers showed this effect triggered by DSCC1 loss could be partially reversed through inhibiting protein SIRT1. This offers a highly promising avenue for the development of new therapies.

̽��ֱ��findings help shed light on genetic factors influencing the health of human genomes over a lifespan and disease development.

Professor Gabriel Balmus, senior author of the study at the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, formerly at the Wellcome Sanger Institute, said: “Continued exploration on genomic instability is vital to develop tailored treatments that tackle the root genetic causes, with the goal of improving outcomes and the overall quality of life for individuals across various conditions.”

Dr David Adams, first author of the study at the Wellcome Sanger Institute, said: “Genomic stability is central to the health of cells, influencing a spectrum of diseases from cancer to neurodegeneration, yet this has been a relatively underexplored area of research. This work, of 15 years in the making, exemplifies what can be learned from large-scale, unbiased genetic screening. ̽��ֱ��145 identified genes, especially those tied to human disease, offer promising targets for developing new therapies for genome instability-driven diseases like cancer and neurodevelopmental disorders.”

This research was supported by Wellcome and the UK Dementia Research Institute.

Reference
Adams, DJ et al. Genetic determinants of micronucleus formation in vivo. Nature; 14 Feb 2024; DOI: 10.1038/s41586-023-07009-0

Adapted from a press release from the Wellcome Sanger Institute.

Cambridge scientists have identified more than one hundred key genes linked to DNA damage through systematic screening of nearly 1,000 genetically modified mouse lines.

Continued exploration on genomic instability is vital to develop tailored treatments that tackle the root genetic causes

Gabriel Balmus

qimono

DNA puzzle

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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.

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Gene therapy approach to boost ‘cold shock protein’ in the brain without cooling protects mice against neurodegenerative disease

cjb250 — Fri, 24 Mar 2023 08:00:07 +0000

̽��ֱ��discovery is a step towards harnessing the protective effects of cooling the brain to treat patients with acute brain injury and even to prevent dementias, such as Alzheimer’s.

When the body cools down significantly, it increases its levels of RBM3, a molecule known as the cold shock protein – a phenomenon first observed in hibernating animals. It is thought that during hibernation, the protein helps protect the brain from damage and allows it to continue to form new connections.

In 2015, Professor Giovanna Mallucci and colleagues showed in mice that RBM3 can protect the brain against damage associated with build-up of misfolded proteins, which can lead to various forms of dementia, such as Alzheimer’s and Parkinson’s disease, and from prion diseases such as Creutzfeldt-Jakob Disease (CJD).

Induced hypothermia is used to treat patients in intensive care units – including newborn babies and traumatic brain injury patients – with the patients placed into a coma and their brains cooled to protect against damage. But this comes with associated risks, such as blood clotting and pneumonia. Could the cold shock protein be harnessed to treat patients without having to cool the body, offering a safer treatment for acute brain injury or a way of protecting the brain against dementia?

In research published in EMBO Molecular Medicine, scientists at the UK Dementia Research Institute, ̽��ֱ�� of Cambridge, and the Institute of Chemistry and Biochemistry, Freie Universität Berlin, studied whether a form of gene therapy known as antisense oligonucleotides (ASOs) could increase levels of the cold shock protein in the brains of mice – and hence protect them.

̽��ֱ��team examined the gene that codes for production of the cold shock protein and found that it contains a key element which under normal conditions prevents its expression. Removing, or ‘dialling down’ this element using an ASO, results in a long-lasting boost to production of RBM3.

To test whether this approach could protect the brain, the researchers used mice infected with prions. Some of these mice were injected with a single dose of the ASO three weeks later, while the others were given a control treatment.

Twelve weeks after being administered the prions, those mice that had received the control treatment succumbed to prion disease and showed extensive loss of neurons in the hippocampus, an area of the brain important for memory.

̽��ֱ��story was very different for the mice that had received the ASO. At the same time as the other mice were succumbing to prion disease, the ASO-treated mice had levels of RBM3 twice as high as in the other mice. Seven of the eight ASO-treated mice showed extensive preservation of neurons in the hippocampus.

Professor Giovanna Mallucci, who led the work while at the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, said: “Essentially, the cold shock protein enables the brain to protect itself – in this case, against the damage to nerve cells in the brain during prion disease. Remarkably, we showed that just a single injection with the ASO was sufficient to provide long-lasting protection for these mice, preventing the inevitable progression of neurodegeneration.”

Professor Florian Heyd from Freie Universität Berlin added: “This approach offers the prospect of being able to protect against diseases such as Alzheimer’s and Parkinson’s disease, for which we have no reliable preventative treatments.

“We are still a long way off this stage as our work was in mice, but if we can safely use ASOs to boost production of the cold shock protein in humans, it might be possible to prevent dementia. We are already seeing ASOs being used to successfully treat spinal muscular atrophy and they have recently been licenced to treat motor neurone disease.”

If the findings can be replicated in humans, this approach could have major implications for the treatment of patients beyond neurodegeneration. These include acute brain injury from newborn babies with hypoxia through protecting the brain in heart surgery, stroke and head injury in adults who would otherwise be treated by therapeutic hypothermia.

Professor Mallucci is now based at the Alto Labs, Cambridge Institute of Science.

̽��ֱ��research was supported by core funding from the Freie Universität Berlin and by the UK Dementia Research Institute, which in turn is funded by the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.

Reference
Preußner, M et al. ASO targeting temperature-controlled RBM3 poison exon splicing prevents neurodegeneration in vivo. EMBO Molecular Medicine; 22 March 2023; DOI: 10.15252/emmm.202217157

Scientists in Cambridge and Berlin have used a form of gene therapy to increase levels of the so-called ‘cold shock protein’ in the brains of mice, protecting them against the potentially devastating impact of prion disease.

Essentially, the cold shock protein enables the brain to protect itself – in this case, against the damage nerve cells in the brain during prion disease

Giovanna Mallucci

Mika Ruusunen (Unsplash)

Cold water swimming

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‘Stressed’ cells offer clues to eliminating build-up of toxic proteins in dementia

cjb250 — Fri, 06 May 2022 09:00:41 +0000

A characteristic of diseases such as Alzheimer’s and Parkinson’s – collectively known as neurodegenerative diseases – is the build-up of misfolded proteins. These proteins, such as amyloid and tau in Alzheimer’s disease, form ‘aggregates’ that can cause irreversible damage to nerve cells in the brain.

Protein folding is a normal process in the body, and in healthy individuals, cells carry out a form of quality control to ensure that proteins are correctly folded and that misfolded proteins are destroyed. But in neurodegenerative diseases, this system becomes impaired, with potentially devastating consequences.

As the global population ages, an increasing number of people are being diagnosed with dementia, making the search for effective drugs ever more urgent. However, progress has been slow, with no medicines yet available that can prevent or remove the build-up of aggregates.

In a study published today in Nature Communications, a team led by scientists at the UK Dementia Research Institute, ̽��ֱ�� of Cambridge, has identified a new mechanism that appears to reverse the build-up of aggregates, not by eliminating them completely, but rather by ‘refolding’ them.

“Just like when we get stressed by a heavy workload, so, too, cells can get ‘stressed’ if they’re called upon to produce a large amount of proteins,” explained Dr Edward Avezov from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge.

“There are many reasons why this might be, for example when they are producing antibodies in response to an infection. We focused on stressing a component of cells known as the endoplasmic reticulum, which is responsible for producing around a third of our proteins – and assumed that this stress might cause misfolding.”

̽��ֱ��endoplasmic reticulum (ER) is a membrane structure found in mammalian cells. It carries out a number of important functions, including the synthesis, folding, modification and transport of proteins needed on the surface or outside the cell. Dr Avezov and colleagues hypothesised that stressing the ER might lead to protein misfolding and aggregation by diminishing its ability to function correctly, leading to increased aggregation.

They were surprised to discover the opposite was true.

“We were astonished to find that stressing the cell actually eliminated the aggregates – not by degrading them or clearing them out, but by unravelling the aggregates, potentially allowing them to refold correctly,” said Dr Avezov.

“If we can find a way of awakening this mechanism without stressing the cells – which could cause more damage than good – then we might be able to find a way of treating some dementias.”

̽��ֱ��main component of this mechanism appears to be one of a class of proteins known as heat shock proteins (HSPs), more of which are made when cells are exposed to temperatures above their normal growth temperature, and in response to stress.

Dr Avezov speculates that this might help explain one of the more unusual observations within the field of dementia research. “There have been some studies recently of people in Scandinavian countries who regularly use saunas, suggesting that they may be at lower risk of developing dementia. One possible explanation for this is that this mild stress triggers a higher activity of HSPs, helping correct tangled proteins.”

One of the factors that has previous hindered this field of research has been the inability to visualise these processes in live cells. Working with teams from Pennsylvania State ̽��ֱ�� and the ̽��ֱ�� of Algarve, the team has developed a technique that allows them to detect protein misfolding in live cells. It relies on measuring light patterns of a glowing chemical over a scale of nanoseconds - one billionth of a second.

“It’s fascinating how measuring our probe’s fluorescence lifetime on the nanoseconds scale under a laser-powered microscope makes the otherwise invisible aggregates inside the cell obvious,” said Professor Eduardo Melo, one of the leading authors, from the ̽��ֱ�� of Algarve, Portugal.

̽��ֱ��research was supported by the UK Dementia Research Institute, which receives its funding from the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK, as well as the Portuguese Foundation for Science and Technology.

Reference
Melo, EP, et al. Stress-induced protein disaggregation in the Endoplasmic Reticulum catalysed by BiP. Nature Comms; 6 May 2022; DOI: 10.1038/s41467-022-30238-2

It’s often said that a little stress can be good for you. Now scientists have shown that the same may be true for cells, uncovering a newly-discovered mechanism that might help prevent the build-up of tangles of proteins commonly seen in dementia.

We were astonished to find that stressing the cell actually eliminated the aggregates – not by degrading them or clearing them out, but by unravelling the aggregates, potentially allowing them to refold correctly

Edward Avezov

Jasmin Merdan

Taking care of elderly sick woman in wheelchair

̽��ֱ��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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Scientists identify the cause of Alzheimer’s progression in the brain

sc604 — Fri, 29 Oct 2021 18:00:23 +0000

̽��ֱ��international team, led by the ̽��ֱ�� of Cambridge, found that instead of starting from a single point in the brain and initiating a chain reaction which leads to the death of brain cells, Alzheimer’s disease reaches different regions of the brain early. How quickly the disease kills cells in these regions, through the production of toxic protein clusters, limits how quickly the disease progresses overall.

̽��ֱ��researchers used post-mortem brain samples from Alzheimer’s patients, as well as PET scans from living patients, who ranged from those with mild cognitive impairment to those with late-stage Alzheimer’s disease, to track the aggregation of tau, one of two key proteins implicated in the condition.

In Alzheimer’s disease, tau and another protein called amyloid-beta build up into tangles and plaques – known collectively as aggregates – causing brain cells to die and the brain to shrink. This results in memory loss, personality changes and difficulty carrying out daily functions.

By combining five different datasets and applying them to the same mathematical model, the researchers observed that the mechanism controlling the rate of progression in Alzheimer’s disease is the replication of aggregates in individual regions of the brain, and not the spread of aggregates from one region to another.

̽��ֱ��results, reported in the journal Science Advances, open up new ways of understanding the progress of Alzheimer’s and other neurodegenerative diseases, and new ways that future treatments might be developed.

For many years, the processes within the brain which result in Alzheimer’s disease have been described using terms like ‘cascade’ and ‘chain reaction’. It is a difficult disease to study, since it develops over decades, and a definitive diagnosis can only be given after examining samples of brain tissue after death.

For years, researchers have relied largely on animal models to study the disease. Results from mice suggested that Alzheimer’s disease spreads quickly, as the toxic protein clusters colonise different parts of the brain.

“ ̽��ֱ��thinking had been that Alzheimer’s develops in a way that’s similar to many cancers: the aggregates form in one region and then spread through the brain,” said Dr Georg Meisl from Cambridge’s Yusuf Hamied Department of Chemistry, the paper’s first author. “But instead, we found that when Alzheimer’s starts there are already aggregates in multiple regions of the brain, and so trying to stop the spread between regions will do little to slow the disease.”

This is the first time that human data has been used to track which processes control the development of Alzheimer’s disease over time. It was made possible in part by the chemical kinetics approach developed at Cambridge over the last decade which allows the processes of aggregation and spread in the brain to be modelled, as well as advances in PET scanning and improvements in the sensitivity of other brain measurements.

“This research shows the value of working with human data instead of imperfect animal models,” said co-senior author Professor Tuomas Knowles, also from the Department of Chemistry. “It’s exciting to see the progress in this field – fifteen years ago, the basic molecular mechanisms were determined for simple systems in a test tube by us and others; but now we’re able to study this process at the molecular level in real patients, which is an important step to one day developing treatments.”

̽��ֱ��researchers found that the replication of tau aggregates is surprisingly slow – taking up to five years. “Neurons are surprisingly good at stopping aggregates from forming, but we need to find ways to make them even better if we’re going to develop an effective treatment,” said co-senior author Professor Sir David Klenerman, from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge. “It’s fascinating how biology has evolved to stop the aggregation of proteins.”

̽��ֱ��researchers say their methodology could be used to help the development of treatments for Alzheimer’s disease, which affects an estimated 44 million people worldwide, by targeting the most important processes that occur when humans develop the disease. In addition, the methodology could be applied to other neurodegenerative diseases, such as Parkinson’s disease.

“ ̽��ֱ��key discovery is that stopping the replication of aggregates rather than their propagation is going to be more effective at the stages of the disease that we studied,” said Knowles.

̽��ֱ��researchers are now planning to look at the earlier processes in the development of the disease, and extend the studies to other diseases such as Frontal temporal dementia, traumatic brain injury and progressive supranuclear palsy where tau aggregates are also formed during disease.

̽��ֱ��study is a collaboration between researchers at the UK Dementia Research Institute, the ̽��ֱ�� of Cambridge and Harvard Medical School. Funding is acknowledged from Sidney Sussex College Cambridge, the European Research Council, the Royal Society, JPB Foundation, the Rainwater Foundation, the NIH, and the NIHR Cambridge Biomedical Research Centre which supports the Cambridge Brain Bank.

Reference:
Georg Meisl et al. ‘In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease.’ Science Advances (2021). DOI: 10.1126/sciadv.abh1448

For the first time, researchers have used human data to quantify the speed of different processes that lead to Alzheimer’s disease and found that it develops in a very different way than previously thought. Their results could have important implications for the development of potential treatments.

This research shows the value of working with human data instead of imperfect animal models

Tuomas Knowles

National Institute of Mental Health, National Institutes of Health, USA

SumaLateral Whole Brain Image

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Lab-grown ‘mini brains’ hint at treatments for neurodegenerative diseases

cjb250 — Thu, 21 Oct 2021 15:00:41 +0000

A common form of motor neurone disease, amyotrophic lateral sclerosis, often overlaps with frontotemporal dementia (ALS/FTD) and can affect younger people, occurring mostly after the age of 40-45. These conditions cause devastating symptoms of muscle weakness with changes in memory, behaviour and personality. Being able to grow small organ-like models (organoids) of the brain allows the researchers to understand what happens at the earliest stages of ALS/FTD, long before symptoms begin to emerge, and to screen for potential drugs.

In general, organoids, often referred to as ‘mini organs’, are being used increasingly to model human biology and disease. At the ̽��ֱ�� of Cambridge alone, researchers use them to repair damaged livers, study SARS-CoV-2 infection of the lungs and model the early stages of pregnancy, among many other areas of research.

Typically, researchers take cells from a patient’s skin and reprogramme the cells back to their stem cell stage – a very early stage of development at which they have the potential to develop into most types of cell. These can then be grown in culture as 3D clusters that mimic particular elements of an organ. As many diseases are caused in part by defects in our DNA, this technique allows researchers to see how cellular changes – often associated with these genetic mutations – lead to disease.

Scientists at the John van Geest Centre for Brain Repair, ̽��ֱ�� of Cambridge, used stem cells derived from patients suffering from ALS/FTD to grow brain organoids that are roughly the size of a pea. These resemble parts of the human cerebral cortex in terms of their embryonic and fetal developmental milestones, 3D architecture, cell-type diversity and cell-cell interactions.

Although this is not the first time scientists have grown mini brains from patients with neurodegenerative diseases, most efforts have only been able to grow them for a relatively short time frame, representing a limited spectrum of dementia-related disorders. In findings published today in Nature Neuroscience, the Cambridge team reports growing these models for 240 days from stem cells harbouring the commonest genetic mutation in ALS/FTD, which was not previously possible – and in unpublished work the team has grown them for 340 days.

Dr András Lakatos, the senior author who led the research in Cambridge’s Department of Clinical Neurosciences, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and how these cells interact at different times as the diseases progress.

“To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers. Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell.”

While organoids are usually grown as balls of cells, first author Dr Kornélia Szebényi generated patient cell-derived organoid slice cultures in Dr Lakatos’ laboratory. This technique ensured that most cells within the model could receive the nutrients required to keep them alive.

Dr Szebényi said: “When the cells are clustered in larger spheres, those cells at the core may not receive sufficient nutrition, which may explain why previous attempts to grow organoids long term from patients’ cells have been difficult.”

Using this approach, Dr Szebényi and colleagues observed changes occurring in the cells of the organoids at a very early stage, including cell stress, damage to DNA and changes in how the DNA is transcribed into proteins. These changes affected those nerve cells and other brain cells known as astroglia, which orchestrate muscle movements and mental abilities.

“Although these initial disturbances were subtle, we were surprised at just how early changes occurred in our human model of ALS/FTD,” added Dr Lakatos. “This and other recent studies suggest that the damage may begin to accrue as soon as we are born. We will need more research to understand if this is in fact the case, or whether this process is brought forward in organoids by the artificial conditions in the dish.”

As well as being useful for understanding disease development, organoids can be a powerful tool for screening potential drugs to see which can prevent or slow disease progression. This is a crucial advantage of organoids, as animal models often do not show the typical disease-relevant changes, and sampling the human brain for this research would be unfeasible.

̽��ֱ��team showed that a drug, GSK2606414, was effective at relieving common cellular problems in ALS/FTD, including the accumulation of toxic proteins, cell stress and the loss of nerve cells, hence blocking one of the pathways that contributes to disease. Similar drugs that are more suitable as medications and approved for human use are now being tested in clinical trials for neurodegenerative diseases.

Dr Gabriel Balmus from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, collaborating senior author, said: “By modelling some of the mechanisms that lead to DNA damage in nerve cells and showing how these can lead to various cell dysfunctions, we may also be able to identify further potential drug targets.”

Dr Lakatos added: “We currently have no very effective options for treating ALS/FTD, and while there is much more work to be done following our discovery, it at least offers hope that it may in time be possible to prevent or to slow down the disease process.

“It may also be possible in future to be able to take skin cells from a patient, reprogramme them to grow their ‘mini brain’ and test which unique combination of drugs best suits their disease.”

̽��ֱ��study was primarily funded by the Medical Research Council UK, Wellcome Trust and the Evelyn Trust.

Reference

Szebényi, K et al. Human ALS/FTD Brain Organoid Slice Cultures Display Distinct Early Astrocyte and Targetable Neuronal Pathology. Nature Neuroscience; 21 Oct 2021; DOI: 10.1038/s41593-021-00923-4

Cambridge researchers have developed ‘mini brains’ that allow them to study a fatal and untreatable neurological disorder causing paralysis and dementia – and for the first time have been able to grow these for almost a year.

Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell

András Lakatos

Andras Lakatos

Mini brain organoids showing cortical-like structures

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New mechanism preventing toxic DNA lesions opens up therapeutic avenues for Huntington's disease

Anonymous — Wed, 01 Sep 2021 11:04:27 +0000

Researchers say the breakthrough study, published in Cell Reports, could lead to much needed therapies for the rare genetic disease, which is currently incurable.

Huntington's disease is a progressive and devastating neurodegenerative disorder that affects about 1 in 10,000 people in the UK.

̽��ֱ��disease is caused by the accumulation of toxic repetitive expansions of three DNA blocks called nucleotides (C, A and G) in the huntingtin (HTT) gene and is often termed a repeat expansion disorder. These CAG tri-nucleotide repeats are expanding by misuse of a cellular machinery that usually promotes DNA repair called ‘mismatch repair’. This overuse in mismatch repair drives Huntington's disease onset and progression.

In this study researchers investigated the role of FAN1 - a DNA repair protein that has been identified as a modifier of Huntington’s disease in several genetic studies; however, the mechanism affecting disease onset has remained elusive.

Using human cells and techniques that can read DNA repeat expansions, the researchers found that FAN1 can block the accumulation of the DNA mismatch repair factors to stop repeat expansion thus alleviating toxicity in cells derived from patients.

Co-lead authors Dr Rob Goold and PhD researcher Joseph Hamilton, both UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, said: “Evidence for DNA repair genes modifying Huntington's disease has been mounting for years. We show that new mechanisms are still waiting to be discovered, which is good news for patients.”

Medicines that could mimic or potentiate (increase the power of) FAN1 inhibition of mismatch repair would alter disease course. ̽��ֱ��team is now working with the biotechnology company Adrestia Therapeutics, based at the Babraham Research Campus near Cambridge, to translate these discoveries into therapies for substantial numbers of patients in the UK and worldwide.

Senior author of the study, Professor Sarah Tabrizi, director of the UCL Huntington’s Disease Centre, UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL, stated: “Our next step is to determine how important this interaction is in more physiological models and examine if it is therapeutically tractable. We are now working with key pharma partners to try and develop therapies that target this mechanism and might one day reach the clinic.”

Joint senior author, Dr Gabriel Balmus from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, said: "There are currently more than fifty CAG repeat expansion disorders that are incurable. If viable, the field suggests that resulting therapies could be applied not only to Huntington's disease but to all the other repeat expansion disorders.”

Professor Steve Jackson, CSO and Interim CEO of Adrestia, said: “My colleagues and I are delighted to be working with Professor Tabrizi, Dr Balmus and the UK Dementia Research Institute to seek ways to translate their exciting science towards new medicines for Huntington's disease and potentially also other DNA-repeat expansion disorders.”

̽��ֱ��study was funded by the CHDI Foundation and UK Dementia Research Institute.

Reference
Goold, R et al. FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington’s disease. Cell Reports; 31 August 2021; DOI: 10.1016/j.celrep.2021.109649

Adapted from a press release by UCL

A new mechanism that stops the progression of Huntington’s disease in cells has been identified by scientists at the ̽��ֱ�� of Cambridge and UCL, as part of their research groups at the UK Dementia Research Institute.

There are currently more than fifty CAG repeat expansion disorders that are incurable. If viable, the field suggests that resulting therapies could be applied not only to Huntington's disease but to all the other repeat expansion disorders

Gabriel Balmus

qimono

DNA jigsaw

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Public Domain