Glaucoma drug shows promise against neurodeget

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

Researchers at the UK’s Dementia Research Institute at the University of Cambridge tested more than 1,400 clinically approved drug compounds using zebrafish genetically modified to mimic so-called tauopathies. They found that drugs known as carbonic anhydrase inhibitors, one of which is the glaucoma drug methazolamide, eliminated the buildup of tau and reduced signs of the disease in zebrafish and mice carrying mutant forms of tau that cause dementia in humans.

Tauopathies are neurodegenerative diseases characterized by the accumulation of tau protein “aggregates” within nerve cells in the brain. These include forms of dementia, Pick’s disease and progressive supranuclear palsy, in which the tau cell is thought to be the main driver of the disease, as well as Alzheimer’s disease and chronic traumatic encephalopathy (neurodegeneration caused by repeated head trauma, as reported in football and rugby players), where the accumulation of tau is one of the consequences of the disease, but leads to degeneration of brain tissue.

Progress in finding effective drugs to treat these conditions has been limited. One option is to repurpose existing drugs. However, drug screening, in which compounds are tested in disease models, is usually performed in cell cultures, but does not reflect many of the characteristics of tau accumulation in vivo.

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

In a study published today in Nature Chemical BiologyProfessor David Rubinstein, Dr Angeline Fleming and colleagues modeled tauopathy in zebrafish and screened 1,437 drug compounds. Each of these compounds has been clinically approved for the treatment of other diseases.

Dr Ana López Ramirez, from the Cambridge Institute of Health Research, Department of Physiology, Development and Neuroscience and the UK Dementia Research Institute at the University of Cambridge, co-author, said: “Rinio rerio provides a much more effective and realistic way of drug screening. compounds than using cell cultures, which function completely differently than living organisms. They also allow us to do this on a large scale, which is not possible or ethical for larger animals like mice.”

Using this approach, the team showed that inhibiting an enzyme known as carbonic anhydrase, which is important for regulating acidity levels in cells, helps cells clear the buildup of tau protein. He did this by causing lysosomes—the “cellular incinerators”—to move to the cell surface, where they fused with the cell membrane and “splashed” tau.

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

Analysis of the mice’s brains showed that they actually had fewer tau aggregates and therefore less brain cell shrinkage compared to untreated mice.

Fellow co-author Dr Farah Siddiqui, also from Cambridge Institute of Health Research and Dementia Research UK, said: “We were pleased to see in our mouse studies that methazolamide reduced tau levels in the brain and protected against further tau formation. up. This confirms what we showed in screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”

Professor Rubinstein, from the UK Dementia Research Institute and the Cambridge Institute of Health Research at the University of Cambridge, said: “Metazolamide is showing promise as a much-needed drug to help prevent the build-up of dangerous tau proteins in the brain. Although we have only studied its effects in zebrafish and mice, so it is still early days, we at least know the safety profile of this drug in patients. This will allow us to move to clinical trials much faster than we might expect if we were starting from scratch with an unknown drug compound.

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

The team hopes to test methazolamide in a variety of disease models, including more common diseases characterized by the accumulation of aggregation-prone proteins, such as Huntington’s and Parkinson’s diseases.

The study was supported by the UK Dementia Research Institute (through UK DRI Ltd, primarily funded through the Medical Research Council), the Tau Consortium and Wellcome.

Link
Lopez A. and Siddiqui F.H. etc. Inhibition of carbonic anhydrase reduces tau toxicity by increasing tau secretion. Nat Chem Bio; October 31, 2024; DOI: 10.1038/s41589-024-01762-7

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