̽��ֱ�� of Cambridge - European Union Horizon 2020

Shimmering seaweeds and algae antennae: sustainable energy solutions under the sea

sc604 — Thu, 22 Feb 2024 16:40:43 +0000

Funded by the European Union’s Horizon 2020 research and innovation programme, the Bio-inspired and Bionic materials for Enhanced Photosynthesis (BEEP) project, led by Professor Silvia Vignolini in the Yusuf Hamied Department of Chemistry, studied how marine organisms interact with light.

̽��ֱ��four-year sustainable energy project brought together nine research groups from across Europe and drew its inspiration from nature, in particular from the marine world, where organisms including algae, corals and sea slugs have evolved efficient ways to convert sunlight into energy. Harnessing these properties could aid in the development of new artificial and bionic photosynthetic systems.

Some of the brightest and most colourful materials in nature – such as peacock feathers, butterfly wings and opals – get their colour not from pigments or dyes, but from their internal structure alone. ̽��ֱ��colours our eyes perceive originate from the interaction between light and nanostructures at the surface of the material, which reflect certain wavelengths of light.

As part of the BEEP project, the team studied structural colour in marine species. Some marine algae species have nanostructures in their cell walls that can transmit certain wavelengths of visible light or change their structures to guide the light inside the cell. Little is known about the function of these structures, however: scientists believe they might protect the organisms from UV light or optimise light harvesting capabilities.

̽��ֱ��team studied the optical properties and light harvesting efficiency of a range of corals, sea-slugs, microalgae and seaweeds. By understanding the photonic and structural properties of these species, the scientists hope to design new materials for bio-photoreactors and bionic systems.

“We’re fascinated by the optical effects performed by these organisms,” said Maria Murace, a BEEP PhD candidate at Cambridge, who studies structural colour in seaweeds and marine bacteria. “We want to understand what the materials and the structures at the base of these colours are, which could lead to the development of green and sustainable alternatives to the conventional paints and toxic dyes we use today.”

BEEP also studied diatoms: tiny photosynthetic algae that live in almost every aquatic system on Earth and produce as much as half of the oxygen we breathe. ̽��ֱ��silica shells of these tiny algae form into stunning structures, but they also possess remarkable light-harvesting properties.

̽��ֱ��BEEP team engineered tiny light-harvesting antennae and attached them to diatom shells. “These antennae allowed us to gather the light that would otherwise not be harvested by the organism, which is converted and used for photosynthesis,” said Cesar Vicente Garcia, one of the BEEP PhD students, from the ̽��ֱ�� of Bari in Italy. “ ̽��ֱ��result is promising: diatoms grow more! This research could inspire the design of powerful bio-photoreactors, or even better

̽��ֱ��scientists engineered a prototype bio-photoreactor, consisting of a fully bio-compatible hydrogel which sustains the growth of microalgae and structural coloured bacteria. ̽��ֱ��interaction of these organisms is mutually beneficial, enhancing microalgal growth and increasing the volume of biomass produced, which could have applications in the biofuel production industry.

Alongside research, the network has organised several training and outreach activities, including talks and exhibitions for the public at science festivals in Italy, France and the UK.

“Society relies on science to drive growth and progress,” said Floriana Misceo, the BEEP network manager who coordinated outreach efforts. “It’s so important for scientists to share their research and help support informed discussion and debate because without it, misinformation can thrive, which is why training and outreach was an important part of this project.”

“Coordinating this project has been a great experience. I learned immensely from the other groups in BEEP and the young researchers,” said Vignolini. “ ̽��ֱ��opportunity to host researchers from different disciplines in the lab was instrumental in developing new skills and approaching problems from a different perspective.”

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under a Marie Skłodowska-Curie grant.

How could tiny antennae attached to tiny algae speed up the transition away from fossil fuels? This is one of the questions being studied by Cambridge researchers as they search for new ways to decarbonise our energy supply, and improve the sustainability of harmful materials such as paints and dyes.

BEEP

Seaweeds showing structural colour

̽��ֱ��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

Strongest evidence to date of brain’s ability to compensate for age-related cognitive decline

cjb250 — Tue, 06 Feb 2024 14:00:20 +0000

As we age, our brain gradually atrophies, losing nerve cells and connections and this can lead to a decline in brain function. It’s not fully understood why some people appear to maintain better brain function than others, and how we can protect ourselves from cognitive decline.

A widely accepted notion is that some people’s brains are able to compensate for the deterioration in brain tissue by recruiting other areas of the brain to help perform tasks. While brain imaging studies have shown that the brain does recruit other areas, until now it has not been clear whether this makes any difference to performance on a task, or whether it provides any additional information about how to perform that task.

In a study published in the journal eLife, a team led by scientists at the ̽��ֱ�� of Cambridge in collaboration with the ̽��ֱ�� of Sussex have shown that when the brain recruits other areas, it improves performance specifically in the brains of older people.

Study lead Dr Kamen Tsvetanov, an Alzheimer's Society Dementia Research Leader Fellow in the Department of Clinical Neurosciences, ̽��ֱ�� of Cambridge, said: “Our ability to solve abstract problems is a sign of so-called ‘fluid intelligence’, but as we get older, this ability begins to show significant decline. Some people manage to maintain this ability better than others. We wanted to ask why that was the case – are they able to recruit other areas of the brain to overcome changes in the brain that would otherwise be detrimental?”

Brain imaging studies have shown that fluid intelligence tasks engage the ‘multiple demand network’ (MDN), a brain network involving regions both at the front and rear of the brain, but its activity decreases with age. To see whether the brain compensated for this decrease in activity, the Cambridge team looked at imaging data from 223 adults between 19 and 87 years of age who had been recruited by the Cambridge Centre for Ageing & Neuroscience (Cam-CAN).

̽��ֱ��volunteers were asked to identify the odd one out in a series of puzzles of varying difficulty, while lying in a functional magnetic resonance imaging (fMRI) scanner, so that the researchers could look at patterns of brain activity by measuring changes in blood flow.

As anticipated, in general the ability to solve the problems decreased with age. ̽��ֱ��MDN was particularly active, as were regions of the brain involved in processing visual information.

When the team analysed the images further using machine-learning, they found two areas of the brain that showed greater activity in the brains of older people, and also correlated with better performance on the task. These areas were the cuneus, at the rear of the brain, and a region in the frontal cortex. But of the two, only activity in the cuneus region was related to performance of the task more strongly in the older than younger volunteers, and contained extra information about the task beyond the MDN.

Although it is not clear exactly why the cuneus should be recruited for this task, the researchers point out that this brain region is usually good at helping us stay focused on what we see. Older adults often have a harder time briefly remembering information that they have just seen, like the complex puzzle pieces used in the task. ̽��ֱ��increased activity in the cuneus might reflect a change in how often older adults look at these pieces, as a strategy to make up for their poorer visual memory.

Dr Ethan Knights from the Medical Research Council Cognition and Brain Sciences Unit at Cambridge said: “Now that we’ve seen this compensation happening, we can start to ask questions about why it happens for some older people, but not others, and in some tasks, but not others. Is there something special about these people – their education or lifestyle, for example – and if so, is there a way we can intervene to help others see similar benefits?”

Dr Alexa Morcom from the ̽��ֱ�� of Sussex’s School of Psychology and Sussex Neuroscience research centre said: “This new finding also hints that compensation in later life does not rely on the multiple demand network as previously assumed, but recruits areas whose function is preserved in ageing.”

̽��ֱ��research was supported by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, the European Union’s Horizon 2020 research and innovation programme, the Guarantors of Brain, and the Alzheimer’s Society.

Reference

Knights, E et al. Neural Evidence of Functional Compensation for Fluid Intelligence Decline in Healthy Ageing. eLife; 6 Feb 2024; DOI: 10.7554/eLife.93327

Scientists have found the strongest evidence yet that our brains can compensate for age-related deterioration by recruiting other areas to help with brain function and maintain cognitive performance.

Now that we’ve seen this compensation happening, we can start to ask questions about why it happens for some older people, but not others - is there something special about these people?

Ethan Knights

CDC

Woman in purple and white floral shirt washing a carrot

Yes

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Public Domain

Cancer isn’t fair – but care should be

lw355 — Sun, 04 Feb 2024 07:50:57 +0000

Listening to people's lived experiences is helping to improve the awareness and uptake of cancer care. On World Cancer Day, we take a look at some of the ways researchers are working with communities to ‘close the cancer care gap’.

Lab-grown ‘small blood vessels’ point to potential treatment for major cause of stroke and vascular dementia

cjb250 — Thu, 16 Nov 2023 16:00:19 +0000

̽��ֱ��study, published today in Stem Cell Reports, also identifies a drug target to ‘plug’ these leaks and prevent so-called small vessel disease in the brain.

Cerebral small vessel disease (SVD) is a leading cause of age-related cognitive decline and contributes to almost half (45%) of dementia cases worldwide. It is also responsible for one in five (20%) ischemic strokes, the most common type of stroke, where a blood clot prevents the flow of blood and oxygen to the brain.

̽��ֱ��majority of cases of SVD are associated with conditions such as hypertension and type 2 diabetes, and tend to affect people in their middle age. However, there are some rare, inherited forms of the disease that can strike people at a younger age, often in their mid-thirties. Both the inherited and ‘spontaneous’ forms of the disease share similar characteristics.

Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute, ̽��ֱ�� of Cambridge, used cells taken from skin biopsies of patients with one of these rare forms of SVD, which is caused by a mutation in a gene called COL4.

By reprogramming the skin cells, they were able to create induced pluripotent stem cells – cells that have the capacity to develop into almost any type of cell within the body. ̽��ֱ��team then used these stem cells to generate cells of the brain blood vessels and create a model of the disease that mimics the defects seen in patients’ brain vessels.

Dr Alessandra Granata from the Department of Clinical Neurosciences at Cambridge, who led the study, said: “Despite the number of people affected worldwide by small vessel disease, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease. Most of what we know about the underlying causes tends to come from animal studies, but they are limited in what they can tell us.

“That’s why we turned to stem cells to generate cells of the brain blood vessels and create a disease model ‘in a dish’ that mimics what we see in patients.”

Our blood vessels are built around a type of scaffolding known as an extracellular matrix, a net-like structure that lines and supports the small blood vessels in the brain. ̽��ֱ��COL4 gene is important for the health of this matrix.

In their disease model, the team found that the extracellular matrix is disrupted, particularly at its so-called ‘tight junctions’, which ‘zip’ cells together. This leads to the small blood vessels becoming leaky – a key characteristic seen in SVD, where blood leaks out of the vessels and into the brain.

̽��ֱ��researchers identified a class of molecules called metalloproteinases (MMPs) that play a key role in this damage. Ordinarily, MMPs are important for maintaining the extracellular matrix, but if too many of them are produced, they can damage the structure – similar to how in ̽��ֱ��Sorcerer’s Apprentice, a single broom can help mop the floor, but too many wreak havoc.

When the team treated the blood vessels with drugs that inhibit MMPs – an antibiotic and anti-cancer drug – they found that these reversed the damage and stopped the leakage.

Dr Granata added: “These particular drugs come with potentially significant side effects so wouldn’t in themselves be viable to treat small vessel disease. But they show that in theory, targeting MMPs could stop the disease. Our model could be scaled up relatively easily to test the viability of future potential drugs.”

̽��ֱ��study was funded by the Stroke Association, British Heart Foundation and Alzheimer’s Society, with support from the NIHR Cambridge Biomedical Research Centre and the European Union’s Horizon 2020 Programme.

Reference
Al-Thani, M, Goodwin-Trotman, M. A novel human 1 iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases. Stem Cell Reports; 16 Nov 2023; DOI: https://doi.org/10.1016/j.stemcr.2023.10.014

Cambridge scientists have grown small blood vessel-like models in the lab and used them to show how damage to the scaffolding that supports these vessels can cause them to leak, leading to conditions such as vascular dementia and stroke.

Despite the number of people affected worldwide by small vessel disease, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease

Alessandra Granata

Alessandra Granata/ ̽��ֱ�� of Cambridge

Disease mural cells stained for calponin (mural cells marker, green), collagen IV (magenta) and DAPI (nuclei, blue)

̽��ֱ��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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Attribution

Solar-powered device produces clean water and clean fuel at the same time

sc604 — Mon, 13 Nov 2023 16:21:43 +0000

̽��ֱ��device, developed by researchers at the ̽��ֱ�� of Cambridge, could be useful in resource-limited or off-grid environments, since it works with any open water source and does not require any outside power.

It takes its inspiration from photosynthesis, the process by which plants convert sunlight into food. However, unlike earlier versions of the ‘artificial leaf’, which could produce green hydrogen fuel from clean water sources, this new device operates from polluted or seawater sources and can produce clean drinking water at the same time.

Tests of the device showed it was able to produce clean water from highly polluted water, seawater, and even from the River Cam in central Cambridge. ̽��ֱ��results are reported in the journal Nature Water.

“Bringing together solar fuels production and water purification in a single device is tricky,” said Dr Chanon Pornrungroj from Cambridge’s Yusuf Hamied Department of Chemistry, the paper’s co-lead author. “Solar-driven water splitting, where water molecules are broken down into hydrogen and oxygen, need to start with totally pure water because any contaminants can poison the catalyst or cause unwanted chemical side-reactions.”

“In remote or developing regions, where clean water is relatively scarce and the infrastructure necessary for water purification is not readily available, water splitting is extremely difficult,” said co-lead author Ariffin Mohamad Annuar. “A device that could work using contaminated water could solve two problems at once: it could split water to make clean fuel, and it could make clean drinking water.”

Pornrungroj and Mohamad Annuar, who are both members of Professor Erwin Reisner’s research group, came up with a design that did just that. They deposited a photocatalyst on a nanostructured carbon mesh that is a good absorber of both light and heat, generating the water vapour used by the photocatalyst to create hydrogen. ̽��ֱ��porous carbon mesh, treated to repel water, served both to help the photocatalyst float and to keep it away from the water below, so that contaminants do not interfere with its functionality.

In addition, the new device uses more of the Sun’s energy. “ ̽��ֱ��light-driven process for making solar fuels only uses a small portion of the solar spectrum – there’s a whole lot of the spectrum that goes unused,” said Mohamad Annuar.

̽��ֱ��team used a white, UV-absorbing layer on top of the floating device for hydrogen production via water splitting. ̽��ֱ��rest of the light in the solar spectrum is transmitted to the bottom of the device, which vaporises the water.

“This way, we’re making better use of the light – we get the vapour for hydrogen production, and the rest is water vapour,” said Pornrungroj. “This way, we’re truly mimicking a real leaf, since we’ve now been able to incorporate the process of transpiration.”

A device that can make clean fuel and clean water at once using solar power alone could help address the energy and the water crises facing so many parts of the world. For example, the indoor air pollution caused by cooking with ‘dirty’ fuels, such as kerosene, is responsible for more than three million deaths annually, according to the World Health Organization. Cooking with green hydrogen instead could help reduce that number significantly. And 1.8 billion people worldwide still lack safe drinking water at home.

“It’s such a simple design as well: in just a few steps, we can build a device that works well on water from a wide variety of sources,” said Mohamad Annuar.

“It’s so tolerant of pollutants, and the floating design allows the substrate to work in very cloudy or muddy water,” said Pornrungroj. “It’s a highly versatile system.”

“Our device is still a proof of principle, but these are the sorts of solutions we will need if we’re going to develop a truly circular economy and sustainable future,” said Reisner, who led the research. “ ̽��ֱ��climate crisis and issues around pollution and health are closely related, and developing an approach that could help address both would be a game-changer for so many people.”

̽��ֱ��research was supported in part by the European Commission’s Horizon 2020 programme, ̽��ֱ��European Research Council, the Cambridge Trust, the Petronas Education Sponsorship Programme, and the Winton Programme for the Physics of Sustainability. Erwin Reisner is a Fellow of St John’s College. Chanon Pornrungroj is a member of Darwin College, and Ariffin Mohamad Annuar is a member of Clare College.

Reference:
Chanon Pornrungroj, Ariffin Bin Mohamad Annuar et al. ‘Hybrid photothermal-photocatalyst sheets for solar-driven overall water splitting coupled to water purification.’ Nature Water (2023). DOI: 10.1038/s44221-023-00139-9

For more information on energy-related research in Cambridge, please visit the Energy IRC, which brings together Cambridge’s research knowledge and expertise, in collaboration with global partners, to create solutions for a sustainable and resilient energy landscape for generations to come.

A floating, solar-powered device that can turn contaminated water or seawater into clean hydrogen fuel and purified water, anywhere in the world, has been developed by researchers.

These are the sorts of solutions we will need to develop a truly circular economy and sustainable future

Erwin Reisner

Chanon Pornrungroj

Device for making solar fuels on the River Cam near the Bridge of Sighs

̽��ֱ��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

International collaboration identifies new breast cancer susceptibility genes

Anonymous — Thu, 17 Aug 2023 15:00:18 +0000

̽��ֱ��study, published in Nature Genetics, was led by teams at the ̽��ֱ�� of Cambridge and Université Laval, Quebec.

Current genetic tests for breast cancer only consider a few genes, such as BRCA1, BRCA2, and PALB2. However, these only explain a minority of the genetic risk, suggesting that more genes remain to be identified.

Researchers looked at genetic changes in all genes in 26,000 women with breast cancer and 217,000 women without breast cancer. These included women from eight countries in Europe and Asia.

Professor Douglas Easton, Director of the Centre for Cancer Genetic Epidemiology at the ̽��ֱ�� of Cambridge, who co-led the study, said: "To our knowledge, this is the largest study of its kind. It was made possible through the use of data from multiple collaborators in many countries, as well as publicly available data from the UK Biobank.”

̽��ֱ��team found evidence for at least four new breast cancer risk genes, with suggestive evidence for many others. ̽��ֱ��team say identification of these new genes will contribute to our understanding of the genetic risk of breast cancer and help improve risk prediction by better identifying those women at higher risk of the disease.

̽��ֱ��findings will better inform approaches to breast screening, risk reduction and clinical management. ̽��ֱ��aim is to integrate this information into a comprehensive risk prediction tool currently used worldwide by health professionals.

"Improving genetic counselling for high-risk women will promote shared decision-making regarding risk reduction strategies, screening and determination of treatment options," said Professor Jacques Simard of Université Laval, co-lead of the study.

“Although most of the variants identified in these new genes are rare, the risks can be significant for women who carry them. For example, alterations in one of the new genes, MAP3K1, appear to give rise to a particularly high risk of breast cancer.”

Before this information can be used in a clinical setting, scientists need to validate the results in further datasets.

"We need additional data to determine more precisely the risks of cancer associated with variants in these genes, to study the characteristics of the tumours, and to understand how these genetic effects combine with other lifestyle factors affecting breast cancer risks," added Professor Easton.

̽��ֱ��discovery of these novel genes also provides crucial information on the biological mechanisms underlying cancer development, potentially opening the way to identifying new treatments.

̽��ֱ��study was funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie et de l'Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation, the European Union Horizon programme, the Wellcome Trust and the International Alliance for Cancer Early Detection.

Reference
Wilcox, N et al. Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk. Nat Gen; 17 Aug 2023; DOI :10.1038/s41588-023-01466-z

Adapted from a press release by Université Laval

A large-scale international collaboration has identified new genes associated with breast cancer that could eventually be included in tests to identify women at increased risk of the disease.

To our knowledge, this is the largest study of its kind

Douglas Easton

Anna Tarazevich

Two women holding pink ribbons

̽��ֱ��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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Scientists identify first genetic marker for MS severity

cjb250 — Wed, 28 Jun 2023 15:00:58 +0000

Multiple sclerosis (MS) is the result of the immune system mistakenly attacking the brain and the spinal cord, resulting in symptom flares known as relapses as well as longer-term degeneration, known as progression. Despite the development of effective treatments for relapses, some of which were pioneered at the ̽��ֱ�� of Cambridge, none can reliably prevent the accumulation of disability.

In findings published today in Nature, an international collaboration of researchers report a genetic variant that increases disease severity, providing the first real progress in understanding and eventually fighting this aspect of MS.

̽��ֱ��work was the result of a large international collaboration of more than 70 institutions from around the world, led by researchers from UCSF (USA) and the ̽��ֱ�� of Cambridge (UK).

“Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years,” said Professor Sergio Baranzini at UCSF, co-senior author of the study.

“Understanding how the variant exerts its effects on MS severity will hopefully pave the way to a new generation of treatments that are able to prevent disease progression,” said Professor Stephen Sawcer from the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, the other co-senior author of the study.

To address the mystery of MS severity, two large MS research consortia joined forces: ̽��ֱ��International Multiple Sclerosis Genetics Consortium (IMSGC) and ̽��ֱ��MultipleMS Consortium. This enabled MS researchers from around the world to pool the resources needed to begin to identify the genetic factors influencing MS outcomes.

Previous studies have shown that MS susceptibility, or risk, stems in large part from dysfunction in the immune system, and some of this dysfunction can be treated, slowing down the disease. But, explained Baranzini, “these risk factors don’t explain why, ten years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons.”

̽��ֱ��two consortia combined data from over 12,000 people with MS to complete a genome-wide association study (GWAS), which uses statistics to carefully link genetic variants to particular traits. In this case, the traits of interest were related to MS severity, including the years it took for each individual to advance from diagnosis to a certain level of disability.

After sifting through more than seven million genetic variants, the scientists found one that was associated with faster disease progression. ̽��ֱ��variant sits between two genes with no prior connection to MS, called DYSF and ZNF638. ̽��ֱ��first is involved in repairing damaged cells, and the second helps to control viral infections. ̽��ֱ��variant’s proximity to these genes suggests that they may be involved in disease progression.

“These genes are normally active within the brain and spinal cord, rather than the immune system,” said Dr Adil Harroud, lead author of the study and former postdoctoral researcher in the Baranzini Lab. “Our findings suggest that resilience and repair in the nervous system determine the course of MS progression and that we should focus on these parts of human biology for better therapies.”

̽��ֱ��findings give the field its first leads to address the nervous system component of MS.

̽��ֱ��team also used statistical methods known as 'Mendelian randomisation' to explore the importance of environmental effects and found that years of education and parental age reduced the severity of MS, while smoking worsened it. Finding correlation with these indirect measures of brain health further underlines the importance of resilience in determining the outcome of MS.

“Although it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie this resilience,” Sawcer said.

To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients. Those with two copies of the variant became disabled faster.

Further work will be necessary to determine exactly how this genetic variant affects DYSF, ZNF638, and the nervous system more generally. ̽��ֱ��researchers are also collecting an even larger set of DNA samples from people with MS, expecting to find other variants that contribute to long-term disability in MS.

“This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS,” said Harroud.

Studying the genetics of multiple sclerosis has been a major theme of neurological research in Cambridge since the late 1980s. With others, members of the Department of Clinical Neurosciences have been closely involved in discovery of the vast majority of gene variants that increase susceptibility.

Professor Alastair Compston from the ̽��ֱ�� of Cambridge and a founding member of the IMSGC added: “Having been personally involved with the identification of susceptibility genes for multiple sclerosis since the 1970s, it is a tribute to those within IMSGC who led this project that fully independent risk variants for progression have now been discovered.

“Once more, the work illustrates the benefits of international collaboration for advancing the understanding of disease mechanisms in multiple sclerosis and other medical conditions”.

This work was supported in part by funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the European Union’s Horizon 2020 Research and Innovation Funding Programme, and the Multiple Sclerosis Society of Canada.

Reference
International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium. Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature; 28 June 2023 DOI: 10.1038/s41586-023-06250-x

A study of more than 22,000 people with multiple sclerosis has discovered the first genetic variant associated with faster disease progression, which can rob patients of their mobility and independence over time.

Although it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie this resilience

Stephen Sawcer

eyecrave productions (Getty Images)

Woman with multiple sclerosis

̽��ֱ��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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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

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