Researchers at the University of Cambridge have discovered that methazolamide, a drug commonly used to treat glaucoma, may help protect the brain against the buildup of tau protein, a key factor in Alzheimer's disease and other dementias. The findings, published in Nature Chemical Biology, demonstrate the drug's potential in zebrafish and mouse models.
The study, conducted under the UK Dementia Research Institute at Cambridge, involved screening over 1,400 clinically-approved drugs using zebrafish genetically engineered to mimic tauopathies. The researchers found that carbonic anhydrase inhibitors, including methazolamide, successfully cleared tau buildup and reduced disease signs in zebrafish. Similar results were observed in mouse models carrying mutant forms of tau.
Mechanism of Action
The researchers' tests in zebrafish revealed that methazolamide inhibits the carbonic anhydrase enzyme, which plays a crucial role in regulating acidity levels within cells. This inhibition helps cells eliminate tau buildup by activating lysosomes, which then fuse with cell membranes to eject the tau protein.
Promising Results in Mouse Models
When methazolamide was tested on mice engineered to carry the P301S human-disease-causing mutation in tau, the treated subjects showed improved performance on memory tasks and enhanced cognitive function compared to untreated mice. Brain analysis of the treated mice also revealed a reduction in tau aggregates compared to the control group.
"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 Dr. Farah Siddiqi, a co-author of 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."
Clinical Implications and Future Directions
According to Dr. David Rubinsztein, a lead author of the study, group leader at the UK Dementia Research Institute, and professor of molecular neurogenetics at Cambridge, methazolamide holds promise as a much-needed drug to help prevent the buildup of dangerous tau proteins in the brain. He noted that while the team has only assessed the effects in zebrafish and mice, the 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, all of which are associated with tau buildup that results in the degeneration of brain tissue. Because these drugs have already been approved for other uses, scientists are not starting from scratch in their efforts to find effective treatments for these conditions.
The team plans to test methazolamide on different disease models, including more common diseases characterized by the buildup of aggregate-prone proteins, such as Huntington’s and Parkinson’s diseases.
