Healthcare (Commonwealth Union) – A widely-used glaucoma medication has shown promise in preventing the accumulation of tau protein in the brains of zebrafish and mice, which is linked to various forms of dementia, including Alzheimer’s disease. Scientists at the UK Dementia Research Institute, University of Cambridge, evaluated more than 1,400 clinically approved drug compounds utilizing genetically modified zebrafish models designed to imitate tau-related diseases, or “tauopathies.” They identified a group of drugs known as carbonic anhydrase inhibitors, including the glaucoma drug methazolamide, which effectively reduced tau buildup and signs of disease in zebrafish and mice carrying human-like tau mutations.
Tauopathies are neurodegenerative diseases that have the characteristic for the buildup of tau protein clusters in neurons. These include certain forms of dementia, Pick’s disease, and progressive supranuclear palsy, where tau is believed to play a key role, as well as Alzheimer’s and chronic traumatic encephalopathy (CTE), a condition seen in individuals exposed to repetitive head trauma, such as athletes. In such situations the tau accumulation plays a role in brain tissue degeneration.
Despite limited progress in developing effective treatments, repurposing existing drugs remains a viable strategy. Traditional drug screening in cell cultures, however, often fails to capture the full characteristics of tau accumulation in living organisms. To address this, the Cambridge team utilized genetically modified zebrafish, which mature and reproduce quickly, allowing them to model human diseases effectively due to genetic similarities.
In a study that appeared in Nature Chemical Biology, Professor David Rubinsztein, Dr. Angeleen Fleming, and their team modeled tauopathies in zebrafish and screened 1,437 drugs, all previously approved for other conditions.
Dr Ana Lopez Ramirez who is from the Cambridge Institute for Medical Research, Department of Physiology, Development and Neuroscience and the UK Dementia Research Institute at the University of Cambridge, and is the joint first author, says “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 strategy, the researchers found that blocking an enzyme called carbonic anhydrase—key for maintaining cellular pH—enabled cells to clear tau protein accumulation. This process involved the lysosomes, often described as the cell’s “waste disposal units,” moving to the cell surface, where they fused with the cell membrane and expelled the tau proteins.
When methazolamide was tested on mice genetically modified to carry the P301S human tau mutation, which causes tau aggregates to build up in the brain over time, those given the drug performed better on memory tests and demonstrated improved cognitive abilities when contrasted with the untreated mice.
Further analysis of the brains of treated mice revealed significantly fewer tau aggregates and, as a result, less neuron loss than in untreated mice.
Dr. Farah Siddiqi, co-author from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, indicated that they were thrilled to observe that methazolamide reduces tau levels in the brain and guards against further buildup in our mouse studies. Dr. Siddiqi further pointed out that it supports their findings from the initial zebrafish screenings of carbonic anhydrase inhibitors in tauopathy models.
Professor Rubinsztein from the UK Dementia Research Institute and Cambridge Institute for Medical Research at the University of Cambridge indicated that Methazolamide demonstrates potential as a crucial medication to prevent the accumulation of hazardous tau proteins in the brain. While their research has focused on its effects in zebrafish and mice, this is still an early phase. However, Professor Rubinsztein is confident about the drug’s safety profile in patients, which will allow them to expedite the transition to clinical trials more quickly than usual when working with an unfamiliar drug compound.
