A drug commonly used to treat glaucoma has shown promising effects in reducing tau protein build-up in the brains of zebrafish and mice—an accumulation linked to various forms of dementia, including Alzheimer’s disease.
Researchers from the UK Dementia Research Institute at the University of Cambridge screened over 1,400 clinically approved drugs in zebrafish genetically modified to simulate tauopathies. They found that drugs called carbonic anhydrase inhibitors, including the glaucoma drug methazolamide, could effectively clear tau build-up and reduce disease symptoms in zebrafish and mice engineered to carry tau mutations associated with human dementias.
Understanding Tauopathies and Their Impact
Tauopathies are neurodegenerative disorders marked by tau protein “aggregates” within brain nerve cells. These diseases include several forms of dementia, such as Pick’s disease and progressive supranuclear palsy, where tau appears to be the main driver, as well as Alzheimer’s and chronic traumatic encephalopathy (caused by repeated head trauma, often seen in contact sports). In both cases, tau build-up contributes to brain tissue degeneration.
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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.
Zebrafish: A Model for Rapid Drug Screening
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 modeled 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 University 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.”
Promising Results With Methazolamide
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.
The Potential for Methazolamide in Dementia Prevention
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 University 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.”
The team hopes to test methazolamide on different disease models, including more common diseases characterized by the build-up of aggregate-prone proteins, such as Huntington’s and Parkinson’s diseases.
Reference: “Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion” by Lopez, A & Siddiqi, FH et al., 31 October 2024, Nature Chemical Biology.
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