Glaucoma drug reduces tau accumulation in neurodegeneration model

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A common drug used to treat glaucoma has shown promise in neurodegenerative diseases. The drug was able to prevent the formation of an abnormal protein called tau in the brains of zebrafish and mice, which is involved in dementia and particularly Alzheimer's disease.

The study is published in Natural chemical biology.

Repurposing drugs for difficult targets

The accumulation of abnormal tau proteins in the brain can cause so-called “tauopathies” – neurodegenerative diseases caused by protein aggregates in nerve cells.

Tau is believed to be the main trigger of diseases such as dementia and progressive supranuclear palsy, while it also plays a role in diseases such as chronic traumatic encephalopathy (a condition caused by repeated head injuries, particularly in sports such as football and rugby ).

Although we know that tau plays an important role in these diseases, efforts to develop new drugs against tauopathies have been challenging. Other methods, such as Other technologies, such as drug reuse, can be used to find medicines for diseases for which there is a lack of available treatment options. When repurposing drugs, existing drugs are examined in models of the selected disease – for example in laboratory cell cultures – in order to identify drugs with promising effects.

A drawback to using this method to combat tauopathies is that cells grown in the laboratory often do not capture all of the features of tau accumulation that we see in whole organisms. Researchers at the University of Cambridge used various animal models to recreate tauopathies and create a whole-organism picture of the drugs they were studying.

“Zebrafish offer a much more effective and realistic way to screen drug compounds than using cell cultures, which function very differently than living organisms,” said co-first author Dr. Ana Lopez Ramirez, a research fellow at the UK Dementia Research Institute at the University of Cambridge. “They also allow us to do this on a large scale, which is neither feasible nor ethical for larger animals like mice.”

Glaucoma drug reduced tau levels in brains of mice

The researchers examined over 1,400 existing drugs that are already approved to treat other diseases. Genetically modified mice are carriers of a disease-causing substance dew mutation, administration of a drug called methazolamide helped reduce tau aggregation in the brain.

Methazolamide is a medication used to treat glaucoma (increased eye pressure that can lead to vision loss) and works by inhibiting the enzyme carbonic anhydrase, which regulates the acidity of cells. This also helped reduce tau accumulation in cells by moving the cells' waste disposal organelles – called lysosomes – to the surface of the cell, where they could “spit out” the tau protein from the cell membrane.

The brains of mice treated with methazolamide showed fewer tau aggregates and a smaller reduction in brain cells compared to the untreated mice.

“We were excited to see in our mouse studies that methazolamide lowers tau levels in the brain and protects against its further accumulation,” said co-first author Dr. Farah Siddiqi, research associate in Prof. David Rubinsztein's laboratory at the Cambridge Institute for Medical Research. “This confirms what we showed when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”

“Methazolamide is a promising drug that is urgently needed to prevent the formation of dangerous tau proteins in the brain,” said Rubinsztein. “Although we have only studied its effects in zebrafish and mice so far, so it is still early days, we at least know the safety profile of this drug in patients. This will allow us to move to clinical trials much more quickly than we would normally expect if we were starting from scratch with an unknown drug substance.”

“This shows how we can use zebrafish to test whether existing drugs could be used to combat various diseases, potentially significantly speeding up the drug development process,” he continued.

The team hopes to next test methazolamide in different disease models, such as Huntington's disease and Parkinson's disease, which are also characterized by the formation of aggregate-prone proteins.

Reference: Lopez A, Siddiqi FH, Villeneuve J, et al. Inhibition of carbonic anhydrase improves tau toxicity by increasing tau secretion. Nat Chem Biol. 2024:1-11. doi: 10.1038/s41589-024-01762-7

This article is adapted from a press release from the University of Cambridge. The material has been edited for length and content.