Glaucoma drug shows promise in fight against neurodegenerative diseases, say University of Cambridge experts

A drug used to treat glaucoma holds promise in the fight against various forms of dementia, according to University of Cambridge scientists.

They found that methazolamide helped protect the brains of zebrafish and mice from the build-up of tau.

Tau protein aggregates in nerve cells characterise a number of neurodegenerative diseases known as tauopathies, including forms of dementia, Pick's disease and progressive supranuclear palsy, where tau is believed to be the primary driver.

Tau build-up is also a consequence of Alzheimer’s disease and chronic traumatic encephalopathy - the form of neurodegeneration caused by repeated head trauma, as seem in some former football and rugby players. In these, it results in the degeneration of brain tissue.

With little progress made in finding treatments for these conditions, researchers at UK Dementia Research Institute (UK DRI) based at the university screened more than 1,437 drug compounds already clinically approved for other conditions using zebrafish genetically engineered to mimic tauopathies.

Prof David Rubinsztein, Dr Angeleen Fleming and colleagues found a group of drugs called carbonic anhydrase inhibitors – including the approved glaucoma drug methazolamide – were able to clear tau build-up and reduce signs of the disease in zebrafish and mice carrying the mutant forms of tau that cause human dementias.

Prof Rubinsztein from the UK DRI at Cambridge and Cambridge Institute for Medical Research, said: “Methazolamide shows promise as a much-needed drug to help prevent the build-up of dangerous tau proteins in the brain. 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.”

Drug screening usually takes place in cell cultures, but these do not recreate many of the characteristics of tau build-up in a living organism.

Zebrafish can be useful models of human disease as they quickly mature and are able to breed within two to three months, producing large numbers of offspring.

Dr Ana Lopez Ramirez, a joint first author of the study published in Nature Chemical Biology, from the Cambridge Institute for Medical Research, Department of Physiology, Development and Neuroscience and the UK DRI at Cambridge, said: “Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms. They also enable us to do so at scale, something that is not feasible or ethical in larger animals such as mice.”

The team found Inhibiting the enzyme known as carbonic anhydrase, which is key to regulating acidity levels in cells, helps cells to rid themselves of the tau protein build-up.

It causes the lysosomes, which are like the cell’s incinerators, to move to the surfacel, where they fused with the cell membrane and ‘spat out’ the tau.

Following the zebrafish findings, the team tested methazolamide on mice genetically engineered to carry the P301S human disease-causing mutation in tau, which leads to the progressive accumulation of tau aggregates in the brain.

These mice performed better at memory tasks and showed improved cognitive performance compared with untreated mice.

Analysing the mouse brains showed they had fewer tau aggregates and, as a result, less reduction in brain cells.

Dr Farah Siddiqi, another joint author also from the Cambridge Institute for Medical Research and the UK DRI, said: “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.”

The team now intends to test methazolamide on different disease models, including for more common diseases characterised by the build-up of aggregate-prone proteins, such as Huntington’s and Parkinson’s diseases.

The research was supported by the UK DRI, Tau Consortium and Wellcome.