A glaucoma medication has shown promise in preventing the build-up of tau protein in the brain, a key factor in several forms of dementia, including Alzheimer’s disease. Researchers at the UK Dementia Research Institute at the University of Cambridge conducted tests using zebrafish and mice, revealing that carbonic anhydrase inhibitors, including the drug methazolamide, can clear tau build-up and lessen disease symptoms.
Tauopathies are a group of neurodegenerative diseases marked by the accumulation of tau protein within nerve cells. Conditions such as dementia, Pick’s disease, and progressive supranuclear palsy are driven primarily by tau. Meanwhile, Alzheimer’s disease and chronic traumatic encephalopathy—often seen in athletes with repeated head trauma—also involve tau build-up, contributing to brain tissue degeneration.
Despite the significance of these conditions, effective treatments have been scarce. One potential solution lies in repurposing existing medications. Traditional drug screening typically occurs in cell cultures, which do not fully replicate the complexities of tau build-up in living organisms.
To address this gap, the Cambridge team utilized genetically engineered zebrafish models. These fish can mature and reproduce in just two to three months, allowing for large-scale testing. Their genetic similarities to humans make them suitable for mimicking various diseases.
In a study published in Nature Chemical Biology, Professor David Rubinsztein and Dr. Angeleen Fleming led the effort to model tauopathy in zebrafish, screening 1,437 clinically approved drug compounds.
Dr. Ana Lopez Ramirez, a co-author from the Cambridge Institute for Medical Research, emphasized the advantages of using zebrafish for drug screening. “Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently from living organisms,” she said. “They also allow us to do this at scale, which isn’t feasible or ethical with larger animals like mice.”
The research demonstrated that inhibiting carbonic anhydrase, an enzyme crucial for regulating cell acidity, helps eliminate tau protein. This occurs as lysosomes—the cell’s waste disposal units—move to the cell surface and expel tau.
Further tests involved administering methazolamide to mice engineered with the P301S mutation in tau, which leads to progressive tau accumulation. Results indicated that treated mice performed better in memory tasks and exhibited improved cognitive function compared to untreated counterparts. Analysis revealed fewer tau aggregates in the brains of treated mice, resulting in less brain cell loss.
Dr. Farah Siddiqi, another co-author from the Cambridge Institute, expressed excitement about the findings. “We were thrilled to see that methazolamide reduces tau levels in the brain and prevents further accumulation. This confirms our previous findings using zebrafish models.”
The research team plans to investigate methazolamide in other disease models, including those associated with the build-up of proteins linked to Huntington’s and Parkinson’s diseases.
This study was supported by the UK Dementia Research Institute, the Tau Consortium, and Wellcome.
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