Experiments on zebrafish and mice have shown that a drug used to treat glaucoma may protect against tau protein buildup in the brain, a key marker of dementias such as Alzheimer's disease. The corresponding study was published in Nature Chemical Biology.
Tauopathies are neurodegenerative conditions that occur with the buildup of tau protein. They include conditions like Pick's disease and progressive supranuclear palsy, where tau is thought to be the primary driver of disease, as well as secondary tauopathies like Alzheimer's disease. Owing to the high incidence of these conditions, a need exists to develop effective treatments.
To accelerate drug discovery, several compound libraries of clinically approved drugs have been put together due to their potential for being repurposed for novel indications. As they have already been studied in preclinical and human contexts, such drugs can move through the discovery pipeline faster than new drugs.
Until now, most large compound screens aiming to identify tauopathy modulators have taken place in cell cultures. These, however, fail to capture in vivo environments. In the current study, researchers thus decided to use a zebrafish model of tauopathy to assess compounds. As many genes that underlie human conditions have equivalents in zebrafish, it is possible to mimic human diseases in these models via genetic manipulation. Altogether, the researchers screened 1 437 drug compounds using their zebrafish models.
In doing so, they found that inhibiting enzyme carbonic anhydrase- key for regulating cellular activity levels - helped cells rid themselves of tau protein buildup. The team then tested methazolamide- a carbonic anhydrase inhibitor used in the clinic- on mice genetically engineered to develop a buildup of tau protein. Those treated with the drug performed better on memory tasks and showed improved cognitive performance compared to untreated mice. Analysis of their brains showed that they had fewer tau aggregates and a smaller reduction in brain cells than untreated mice.
"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 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," study author Professor David C. Rubinsztein from the UK Dementia Research Institute and Cambridge Institute for Medical Research at the University of Cambridge, said in a press release.
"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 added.
In the future, the researchers hope to test methazolamide on different disease models, including other diseases characterized by the buildup of aggregate-prone proteins like Huntington's and Parkinson's disease.
Sources: Science Daily, Nature Chemical Biology
