Glaucoma drug shows promise against neurodegenerative diseases, animal studies suggest (Neptazane)

Medical Xpress / University of Cambridge / Nature Chemical Biology ^ | Oct. 31, 2024 | David Rubinsztein et al

[ConservativeMind]

A drug commonly used to treat glaucoma has been shown in zebrafish and mice to protect against the build-up in the brain of the protein tau, which causes various forms of dementia and is implicated in Alzheimer's disease.

Researchers screened more than 1,400 clinically-approved drug compounds using zebrafish genetically engineered to make them mimic so-called tauopathies. They discovered that drugs known as carbonic anhydrase inhibitors—of which the glaucoma drug methazolamide is one—clear tau build-up and reduce signs of the disease in zebrafish and mice carrying the mutant forms of tau that cause human dementias.

Professor David Rubinsztein, Dr. Angeleen Fleming and colleagues modeled tauopathy in zebrafish and screened 1,437 drug compounds. Each of these compounds has been clinically approved for other diseases.

Using this approach, the team showed that inhibiting an enzyme known as carbonic anhydrase—which is important for regulating acidity levels in cells—helped the cell rid itself of the tau protein build-up. It did this by causing the lysosomes—the 'cell's incinerators'—to move to the surface of the cell, where they fused with the cell membrane and 'spat out' the tau.

When the team tested methazolamide on mice that had been genetically engineered to carry the P301S human disease-causing mutation in tau, which leads to the progressive accumulation of tau aggregates in the brain, they found that those treated with the drug performed better at memory tasks and showed improved cognitive performance compared with untreated mice.

Analysis of the mouse brains showed that they indeed had fewer tau aggregates, and consequently a lesser reduction in brain cells, compared with the untreated mice.

[ConservativeMind]

Methazolamide (Neptazane) is currently available, but would need to be used off-label.

[ConservativeMind]

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