A drug that is commonly used to treat eye diseases may soon be used to protect against dementia, new research suggests. The drug may also show promise in the treatment of other neurodegenerative diseases, including Huntington's and Parkinson's.
Dementia affects more than 5 million Americans over the age of 65, according to the U.S. Centers for Disease Control and Prevention. Dementia comes in different forms—the most common form is Alzheimer's disease—and is characterized by an impaired ability to remember, think and make decisions.
Today, there is no known cure for Alzheimer's, although scientists believe it is caused by the abnormal buildup of proteins in and around brain cells. One key protein known to build up in the brain cells of Alzheimer's patients is called tau.
Now, new research by the UK Dementia research Institute at the University of Cambridge has shown that a drug commonly used to treat glaucoma—an eye condition whereby the optic nerve becomes damaged—may also clear these tau protein clumps.
The drug, called methazolamide, was one of 1,437 clinically approved compounds that the researchers tested on zebrafish that had been genetically engineered to mimic these protein buildups.
"Zebrafish provide a much more effective and realistic way of screening drug compounds than using cell cultures, which function quite differently to living organisms," the study's joint first author, 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, said in a statement. "They also enable us to do so at scale, something that it not feasible or ethical in larger animals such as mice."
Following promising results in zebrafish models, the team tested methazolamide in mice, which again had been genetically engineered to mimic these tau protein buildups. "We were excited to see in our mouse studies that methazolamide reduces levels of tau in the brain and protects against its further buildup," co-author Dr Farah Siddiqi, also from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, said in a statement.
So, how might this drug clear these protein clumps?
Methazolamide is a type of drug known as a carbonic anhydrase inhibitor, which stops the activity of an important enzyme involved in regulating acidity levels in our cells. This in turn forces the cells to "spit out" the tau proteins, almost like they are having their stomachs pumped.
"Methazolamide shows promise as a much-needed drug to help prevent the buildup of dangerous tau proteins in the brain," Professor David Rubinsztein, another of the study's coauthors, said in a statement. "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."
The study also demonstrates the use of zebrafish for testing existing drugs for their ability to clear Alzheimer's-related protein clumps. "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," Rubinsztein said.
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Lopez, A & Siddiqi, FH et al. Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion. Nat Chem Bio; 31 Oct 2024; DOI: 10.1038/s41589-024-01762-7
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