Glaucoma drug could counteract tau protein accumulation in neurodegenerative diseases

Using zebrafish and mice, scientists at the University of Cambridge have shown that a common glaucoma drug may be able to protect the brain from the buildup of tau protein, which is linked to various forms of dementia and Alzheimer's disease. Details of the study were published in Natural chemical biology in an article titled: “Inhibition of carbonic anhydrase improves tau toxicity by increasing tau secretion.”

For the study, conducted under the auspices of the UK Dementia Research Institute in Cambridge, scientists tested more than 1,400 clinically approved drugs using zebrafish genetically engineered to mimic tauopathies. They found that a class of drugs called carbonic anhydrase inhibitors successfully eliminated tau accumulation and reduced signs of the disease in zebrafish. The list of carbonic anhydrase inhibitors includes methazolamide, which is used to treat open-angle glaucoma and acute angle-closure glaucoma. The researchers report similar results in mouse models carrying mutated forms of tau.

“Methazolamide holds promise as a much-needed drug to prevent the formation of dangerous tau proteins in the brain,” said Dr. David Rubinsztein, lead author of the study, group leader at the UK Dementia Research Institute and professor of molecular neurogenetics at Cambridge. He noted that while the team had only studied the effects in zebrafish and mice, these initial results were promising. “We at least know the safety profile of this drug in patients. This will allow us to move to clinical trials much more quickly than we would normally expect if we were starting from scratch with an unknown drug substance,” he said.

Methazolamide and similar drugs from the carbonic anhydrase inhibitor family may provide a new treatment option for various tauopathies, including Alzheimer's disease, Pick's disease and progressive supranuclear palsy, which are associated with the accumulation of tau leading to degeneration of brain tissue. Because these drugs are already approved, it is critical that scientists do not start from scratch in their efforts to find effective drugs to treat these diseases. For this study, researchers examined 1,437 drug compounds, all previously approved for other diseases.

Instead of using cell cultures for screening, which typically do not capture many of the characteristics of tau accumulation in living organisms, the Cambridge researchers chose zebrafish, which reproduce and mature quickly. Their genomes can also be easily manipulated to mimic human diseases, making them ideal for these types of studies.

Their tests on zebrafish showed that methazolamide inhibited the enzyme carbonic anhydrase, which is important for regulating acidity in cells. This helped cells rid themselves of tau buildup by activating lysosomes to fuse with cell membranes and expel tau protein.

When the team tested the same drug on mice engineered to carry the human disease-causing P301S mutation in tau, they found that treated subjects performed better on memory tasks and showed improved cognitive performance compared to untreated mice . Analysis of the brains of the treated mice also showed that they had fewer tau aggregates compared to untreated mice.

“We were excited to see in our mouse studies that methazolamide lowers tau levels in the brain and protects against its further accumulation,” said paper co-author Farah Siddiqi, PhD, from the Cambridge Institute for Medical Research at the UK Dementia Research Institute. “This confirms what we showed when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”

For next steps, the team hopes to test methazolamide in various disease models, including more common diseases characterized by the accumulation of aggregatable proteins, such as Huntington's and Parkinson's diseases.