Glaucoma Drug Reduces Tau Buildup in Neurodegeneration Model

A common drug used to treat glaucoma has shown promise for neurodegenerative disease. The drug was able to prevent the buildup of an abnormal protein called tau – implicated in dementia and more specifically, Alzheimer’s disease – in the brains of zebrafish and mice.

The study is published in Nature Chemical Biology.

Repurposing drugs for difficult targets

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

Tau is thought to be the main driver of diseases like dementia, progressive supranuclear palsy, while also having a role in diseases like chronic traumatic encephalopathy (a condition caused by repeated head trauma, particularly from sports such as football and rugby).

Though we know tau is a major player in these diseases, efforts to develop new drugs that target tauopathies have been challenging. Other methods, such as drug repurposing, can be used to find drugs for conditions that suffer from a lack of available treatments. Drug repurposing involves screening existing drugs in models of the chosen disease – such as lab-cultured cells – to identify drugs that have promising effects.

One downside to using this method to target tauopathies is that lab-grown cells often fail to capture all the characteristics of tau buildup we see in whole organisms. Researchers from the University of Cambridge used various animal models to recreate tauopathies and build a whole-organism picture of the screened drugs.

“Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms,” said co-first author Dr. Ana Lopez Ramirez, a research associate from the UK Dementia Research Institute from at the University of Cambridge. “They also enable us to do so at scale, something that it not feasible or ethical in larger animals such as mice.”  

Glaucoma drug reduced tau levels in the mouse brain

The researchers screened over 1,400 existing drugs that are already approved to treat other conditions. In genetically-engineered mice carrying a disease-causing tau mutation, administering a drug called methazolamide helped reduce tau aggregation in the brain.

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

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

“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,” said co-first author Dr. Farah Siddiqi, a research associate in the lab of Prof. David Rubinsztein at the Cambridge Institute for Medical Research. “This confirms what we had shown when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.”

“Methazolamide shows promise as a much-needed drug to help prevent the build-up of dangerous tau proteins in the brain,” said Rubinsztein. “Although we’ve only looked at its effects in zebrafish and mice, so it is still early days, we at least know about this drug’s safety profile in patients. This will enable us to move to clinical trials much faster than we might normally expect if we were starting from scratch with an unknown drug compound.”

“This shows how we can use zebrafish to test whether existing drugs might be repurposed to tackle different diseases, potentially speeding up significantly the drug discovery process,” he continued.

The team hope to test methazolamide on different disease models next, such as Huntington’s and Parkinson’s diseases, also characterized by the build-up of aggregate-prone proteins.

Reference: Lopez A, Siddiqi FH, Villeneuve J, et al. Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion. Nat Chem Biol. 2024:1-11. doi: 10.1038/s41589-024-01762-7

This article is a rework of a press release issued by the University of Cambridge. Material has been edited for length and content.