Glaucoma medication may help prevent Alzheimer’s-related tau build-up

In zebrafish and mice, a drug commonly used to treat glaucoma has been shown to protect against the build-up in the brain of the protein tau, which causes several forms of dementia and is involved in Alzheimer’s disease.

Researchers from the UK’s Dementia Research Institute at the University of Cambridge have screened more than 1,400 clinically approved drugs using zebrafish that have been genetically engineered to mimic so-called tauopathies. They found that drugs known as carbonic anhydrase inhibitors – of which the glaucoma drug methazolamide is one – clear up tau buildup and reduce signs of the disease in zebrafish and mice that carry the mutated forms of tau that cause human dementia.

Tauopathies are neurodegenerative diseases characterized by the accumulation in the brain of ‘aggregates’ of tau proteins in nerve cells. These include forms of dementia, Pick’s disease and progressive supranuclear palsy, where tau is thought to be the main cause of the disease, and Alzheimer’s disease and chronic traumatic encephalopathy (neurodegeneration caused by repetitive head trauma, as has been reported in football and rugby players), where the build-up of tau is a consequence of disease but results in degeneration of brain tissue.

Little progress has been made in finding effective medications to treat these conditions. One option is to reuse existing medicines. However, drug screening – where compounds are tested against disease models – usually takes place in cell cultures, but these do not capture many of the hallmarks of tau buildup in a living organism.

To get around this, the Cambridge team turned to zebrafish models they had previously developed. Zebrafish mature and can reproduce within two to three months, producing large numbers of offspring. Using genetic engineering it is possible to mimic human diseases, as many genes responsible for human diseases often have equivalents in zebrafish.

This is evident from a study published today in Nature Chemical BiologyProfessor David Rubinsztein, Dr Angeleen Fleming and colleagues modeled tauopathy in zebrafish and screened 1,437 drug compounds. Each of these compounds is clinically approved for other diseases.

Dr. Ana Lopez Ramirez from the Cambridge Institute for Medical Research, Department of Physiology, Development and Neuroscience and the UK Dementia Research Institute at the University of Cambridge, joint first author, said: “Zebrafish provide a much more effective and realistic means of screening drug compounds than use of cell cultures, which function very differently from living organisms. They also allow us to do this on a large scale, something that is not feasible or ethical in larger animals such as mice.

Using this approach, the team showed that inhibiting an enzyme known as carbonic anhydrase – which is important for regulating acidity in cells – helped the cell rid itself of tau protein buildup. This was done by causing the lysosomes – the ‘incinerators of the cell’ – to move to the surface of the cell, where they fuse with the cell membrane and ‘spit out’ the tau.

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

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

Fellow author Dr Farah Siddiqi, also from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, said: “We were pleased to see in our mouse studies that methazolamide reduces tau levels in the brain and protects against further construction of it. 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 buildup of dangerous tau proteins in the brain. Although we’ve only looked at its effects in zebrafish and mice, so it’s still early, we at least know what the safety profile of this drug is in patients. This will allow us to move to clinical trials much faster than we would 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 can be repurposed to target different diseases, potentially significantly accelerating the drug discovery process.”

Professor Rubinsztein from the UK Dementia Research Institute and the Cambridge Institute for Medical Research at the University of Cambridge

The team hopes to test methazolamide on various disease models, including more common diseases characterized by the accumulation of aggregate-prone proteins, such as Huntington’s and Parkinson’s diseases.

The research was supported by the UK Dementia Research Institute (through UK DRI Ltd, funded mainly by the Medical Research Council), Tau Consortium and Wellcome.