Researchers at the University of Cambridge have found that a commonly used glaucoma drug may help protect the brain from tau protein buildup—a factor linked to Alzheimer’s disease and other forms of dementia. Using zebrafish and mice models, the team demonstrated this potential in a study published in Nature Chemical Biology.
For the study, which was performed under the auspices of the UK Dementia Research Institute at Cambridge, the scientists screened more than 1,400 clinically-approved drugs using zebrafish that were genetically engineered to mimic tauopathies. They found that a class of drugs called carbonic anhydrase inhibitors successfully cleared tau build-up 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 mutant forms of tau.
“Methazolamide shows promise as a much-needed drug to help prevent the build-up of dangerous tau proteins in the brain,” said David Rubinsztein, PhD, a lead author on the study, group leader at the UK Dementia Research Institute, and professor of molecular neurogenetics at Cambridge. He noted that though the team has only assessed the effects in zebrafish and mice, these early results are promising. “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,” he said.
Methazolamide and similar drugs in the carbonic anhydrase inhibitors family could offer a new treatment option for various tauopathies including Alzheimer’s disease, Pick’s disease, and progressive supranuclear palsy that are associated with tau build-up that results in degeneration of brain tissue. Crucially, because these drugs have already been approved, scientists are not starting from scratch in their efforts to find effective drugs to treat these conditions. For this study, the researchers screened 1,437 drug compounds, all previously approved for other diseases.
Rather than using cell cultures for screening, which typically don’t capture many of the characteristics of tau build-up in living organisms, the Cambridge researchers opted for zebrafish which breed and mature quickly. Their genomes can also be readily manipulated to mimic human diseases making them ideal for these types of studies.
Their tests in zebrafish showed that methazolamide inhibited the carbonic anhydrase enzyme which is important for regulating acidity levels in cells. This helped cells rid themselves of tau buildup by activating lysosomes to fuse to cell membranes and eject tau protein.
When the team tested the same drug on mice engineered to carry the P301S human-disease-causing mutation in tau, they found that treated subjects did better on memory tasks and showed improved cognitive performance compared to untreated mice. Analysis of the treated mice brains also showed that they had fewer tau aggregates compared to untreated mice.
“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,” said Farah Siddiqi, PhD, a co-author on the paper from the Cambridge Institute for Medical Research and the UK Dementia Research Institute. “This confirms what we had shown when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”
For their next steps, 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.
