A commonly used glaucoma medication has demonstrated protective effects against the accumulation of tau protein in the brain, as observed in studies involving zebrafish and mice. This tau protein build-up is linked to various forms of dementia and is a key factor in Alzheimer’s disease.
A glaucoma medication is found to protect against tau protein accumulation in the brain, which is associated with different types of dementia and linked to Alzheimer’s disease, as shown in research with zebrafish and mice.
Scientists at the UK Dementia Research Institute at the University of Cambridge tested over 1,400 FDA-approved drug compounds using specially modified zebrafish designed to mimic tau-related diseases. They found that carbonic anhydrase inhibitors, including the glaucoma drug methazolamide, can help eliminate tau build-up and lessen disease symptoms in both zebrafish and mice with mutant forms of tau that contribute to human dementias.
Tauopathies are degenerative brain disorders characterized by the accumulation of tau protein aggregates within nerve cells. These disorders include various forms of dementia, Pick’s disease, and progressive supranuclear palsy, where tau is thought to primarily drive the disease process. In cases like Alzheimer’s disease and chronic traumatic encephalopathy—which can occur from repeated head injuries seen in sports—tau build-up is a secondary effect that leads to brain tissue deterioration.
Progress has been slow in finding effective treatments for these ailments. One approach is to repurpose existing medications. Typically, drug screening occurs in laboratory cell cultures, but these do not fully reflect the tau build-up seen in a living organism.
To address this limitation, the Cambridge research team utilized zebrafish models they had developed, as zebrafish mature quickly, allowing them to breed in just two to three months and produce large quantities of offspring. Their genetic similarities with humans make zebrafish suitable for modeling human diseases.
In a study released today in Nature Chemical Biology, Professor David Rubinsztein and Dr. Angeleen Fleming, along with their team, modeled tauopathies in zebrafish and examined 1,437 clinically approved drug compounds.
Dr. Ana Lopez Ramirez, a joint first author from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, stated: “Zebrafish provide a more effective and realistic method for testing drug compounds compared to cell cultures, which do not reflect the realities of living organisms. They also allow large-scale studies, which would be impractical or unethical in larger animals like mice.”
The researchers found that inhibiting carbonic anhydrase, an enzyme vital for managing acidity within cells, assists the cells in removing tau protein buildup. This process involves lysosomes—the cell’s waste disposal units—moving to the cell surface, merging with the membrane, and releasing the tau protein.
When they administered methazolamide to mice with a genetically engineered mutation in tau (P301S), linked to the progressive accumulation of tau aggregates in the brain, the treated mice outperformed the non-treated ones in memory tasks and showed enhanced cognitive abilities.
Examination of the treated mice’s brains revealed a reduction in tau aggregates and a lesser loss of brain cells compared to untreated mice.
Dr. Farah Siddiqi, another joint author from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, remarked: “We were thrilled to discover that methazolamide lowers tau levels in the brain and prevents further accumulation, confirming our findings from screening carbonic anhydrase inhibitors using zebrafish models.”
Professor Rubinsztein noted: “Methazolamide appears promising as a much-needed treatment to impede the accumulation of harmful tau proteins in the brain. While we’ve only observed its effects in zebrafish and mice thus far, its established safety in patients will allow us to expedite clinical trials, which would generally take longer if starting with an untested drug.”
“This highlights the potential of using zebrafish to evaluate existing drugs for new treatment applications, which could significantly accelerate the drug discovery process.”
The team plans to test methazolamide on various disease models, including those more prevalent in patients suffering from protein aggregation disorders like Huntington’s and Parkinson’s diseases.
This research received funding from the UK Dementia Research Institute (via UK DRI Ltd, primarily sponsored by the Medical Research Council), the Tau Consortium, and Wellcome Trust.
