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Drug Treats Protein That May Cause Alzheimer’s Disease

photo credit: The tau protein, modelled here, is suspected of causing Alzheimer’s disease. Now, we may finally have a drug that can stop its build up. Credit: molekuul.be/Shutterstock

The drug salsalate has been found to prevent and even reverse the development of tau protein tangles in mice with a condition similar to Alzheimer’s disease. While so far the success is only in animals, salsalate has a head start on other potential treatments as it has already passed the safety trials required to be used to treat arthritis.

As society ages, Alzheimer’s disease – the most common cause for dementia – looms ever larger as a prime source of suffering. Drugs with promise have been identified, but progress has been slowed in part by debates over the disease’s main culprit.

Debate rages between those who blame the formation of tau protein tangles within neurons, and those who believe a buildup of beta amyloid plaques are the main cause. Even prions are suspected by some scientists, and other researchers argue Alzheimer’s is actually a complex of diseases with different causes but similar symptoms.

Currently, available drugs treat the symptoms but not the causes, and have limited benefits. Potential medications at different stages of development exist. Most of thesetarget the amyloid plaques, raising little hope among those who favor the tau theory. This makes the announcement in Nature Medicine that salsalate inhibits and reverses theacetylation of tau particularly significant. Dr. Li Gan of Gladstone Institutes found evidence that acetylated tau is particularly damaging, impeding the capacity of neurons to avoid the buildup of tau. Gan sought a drug that would prevent acetylization from occurring.

“We identified for the first time a pharmacological approach that reverses all aspects of tau toxicity,” said Gan in a statement. “Remarkably, the profound protective effects of salsalate were achieved even though it was administered after disease onset, indicating that it may be an effective treatment option.”

When salsalate was given to mice, it blocked the enzyme that acetalyzes the protein, protecting brain cells and improving the rodents’ memory. While there is as yet no evidence that salsalate has similar effects in humans, co-author Dr. Eric Verdin pointed out that salsalate has “a long-history of a reasonable safety profile,” expediting the process of moving to clinical application.

Salsalate, a nonsteroidal anti-inflammatory, does carry risks, particularly an increased danger of heart attacks and strokes. However, these have been assessed as low enough to justify the drug’s use against pain from both osteoarthritis and rheumatoid arthritis, and to be explored to counteract insulin resistance in Type II diabetes.

Tau buildup is also observed in rarer conditions, including progressive supranuclear palsy and frontotemporal dementia (FTD). The same mouse model is used to study Alzheimer’s and FTD, with researchers believing that a single gene in mice triggers the two conditions that have differing, but related, causes in humans.

Consequently, hopes are high that salsalate could be effective for FTD as well. However, the first trial to be initiated is against progressive supranuclear palsy, a much rarer condition where tau proteins affect the motor centers of the brain.

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