̽��ֱ�� of Cambridge - Farah Siddiqi

Glaucoma drug shows promise against neurodegenerative diseases, animal studies suggest

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Ana Lopez Ramirez

Kuznetsov_Peter

Zebrafish

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

David Rubinsztein

Understanding Animal Research

White mouse in purple gloved hands

Researcher profile: Dr Farah Siddiqi

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

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

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

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

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

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

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

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

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

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