Another victory has been won in one of the seemingly unending skirmishes that researchers have been fighting with neurodegenerative diseases for many years now. While past victories may have been due to novel drugs, today’s victory is due to researchers beginning to uncover promising new uses for existing medications (Wareham et al., 2022). One such drug being repurposed is methazolamide. Methazolamide is traditionally used to treat glaucoma, but researchers have recently shown its potential in tackling diseases associated with toxic protein build-up in the brain, such as Alzheimer’s disease and other tauopathies (Lopez et al., 2024).
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Alzheimer’s disease
Methazolamide’s Effect on Tau Accumulation
Table of Contents
Drs Ana Lopez Ramirez and Farah Siddiqi had tested over 1400 known drug compounds on zebrafish. These zebrafish had been genetically engineered to achieve the typical phenotype of most tauopathies. Following review, it was then discovered that carbonic anhydrase inhibitors not only reduced the buildup of tau protein aggregates but also ameliorated the clinical features of the disease. Following these findings, methazolamide was tested on mice genetically engineered to carry the P301S mutation, a human gene variant linked to excessive tau accumulation in the brain. In these mice, the drug produced encouraging results once again. Treated mice performed better on memory tests and demonstrated overall improved cognitive abilities compared to their untreated counterparts. Brain analysis confirmed that treated mice had significantly fewer tau aggregates and exhibited a lesser degree of loss of brain cells.
A Deeper Dive into Carbonic Anhydrase Inhibitors
Methazolamide in particular and other carbonic anhydrase inhibitors seem to be able to achieve this tau-tapering effect by modifying the acid-base balance in the cell, a balance in which carbonic anhydrase plays a major role. Following this, the previous acidic lysosomes which contain the tau proteins rise through the cytoplasm, fuse with the cell membrane, and are expelled from the cell. Dr. Siddiqi overjoyed, commented, “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. This confirms what we had shown when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”
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Accelerating Drug Development through Repurposing
One of the primary advantages of methazolamide is that it is already an approved drug, with a known safety profile in humans, which could enable researchers to fast-track the transition to clinical trials for neurodegenerative diseases (Papich, 2016). Professor David Rubinsztein, a senior researcher from the UK Dementia Research Institute and Cambridge Institute for Medical Research, noted methazolamide showed a lot of promise and could accelerate clinical trials to a degree faster than would normally have been expected.
Implications and Future Directions
This study provides early but significant evidence of methazolamide’s potential to treat neurodegenerative diseases. There is a very long list of diseases associated with tau accumulation, including but not limited to Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. For now, researchers will be taking methazolamide through the relevant clinical trials. Deep in their hearts will be the hope that the repurposed drug could be a solution to perhaps one, but maybe all of the cognition-impairing conditions associated with tau protein accumulation.
References
Lopez, A. & Siddiqi, F.H., et al. Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion. Nat Chem Bio; 31 Oct 2024; https://doi.org/10.1038/s41589-024-01762-7
Papich, M. G. (2016). Methazolamide. Elsevier EBooks, 503–505. https://doi.org/10.1016/b978-0-323-24485-5.00375-2
Wareham, L. K., Liddelow, S. A., Temple, S., Benowitz, L. I., Di Polo, A., Wellington, C., Goldberg, J. L., He, Z., Duan, X., Bu, G., Davis, A. A., Shekhar, K., Torre, A. L., Chan, D. C., Canto-Soler, M. V., Flanagan, J. G., Subramanian, P., Rossi, S., Brunner, T., & Bovenkamp, D. E. (2022). Solving neurodegeneration: common mechanisms and strategies for new treatments. Molecular Neurodegeneration, 17(1). https://doi.org/10.1186/s13024-022-00524-0
FAQs
1. Is methazolamide an Alzheimer’s disease drug?
No. Methazolamide is a carbonic anhydrase inhibitor that is used in the management of glaucoma.
2. Why use zebrafish for testing?
Zebrafish are ideal test subjects for three reasons. First, they grow quickly, reaching maturity in under three months. Secondly, they lay a tremendous number of eggs which grow into potential test subjects. Lastly, they can be genetically engineered to mimic many of the genes associated with human diseases.
3. Can Alzheimer’s disease be cured?
At the moment, there is no verified cure for Alzheimer’s disease. Management is mostly symptomatic and supportive.
4. Is Alzheimer’s disease heritable?
While Alzheimer’s disease is not heritable in the classic Mendelian pattern, having a family member with the disease increases the risks of your developing it.
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