Alzheimer's is a devastating disease, and with the world's average population getting older, its effects will be felt further and wider in the future. A drug dubbed J147, developed by the Salk Institute, is one of the most promising candidates to treat Alzheimer's, but just how it worked at the molecular level remained a mystery. Now Salk scientists have figured out the mechanism behind it, which could see J147 used to fight other age-related conditions as well.
J147 was developed in 2011, and in early tests was found to enhance memory in both healthy mice and those with Alzheimer's, and also managed to protect the brain from further damage. A few years later, the drug was found to have wider anti-aging benefits too. But while tests showed that it was working, researchers weren't exactly sure how, and with the drug almost ready for human trials it was important to properly pin down that mechanism.
In a new study, a Salk team found that J147 binds to a protein called ATP synthase, which is responsible for producing a common cellular "energy currency" known as ATP. This protein is known to control aging in worms and flies, and the researchers found that by binding to it the drug was able to prevent age-related damage to the brain.
"We know that age is the single greatest contributing factor to Alzheimer's, so it is not surprising that we found a drug target that's also been implicated in aging," says Josh Goldberg, first author of the study.
Looking deeper, the team found that J147's interactions with ATP synthase affects the levels of ATP and other molecules, which works to make the mitochondria – the energy generators in cells – healthier and more stable. That in turn slows down and even reverses the effects of aging and the progression of disease.
"I was very surprised when we started doing experiments with how big of an effect we saw," says Dave Schubert, senior author of the study. "We can give this to old mice and it really elicits profound changes to make these mice look younger at a cellular and molecular level."
Those results mean that J147 is not only promising as an Alzheimer's drug, but could be useful for other diseases related to aging.
"People have always thought that you need separate drugs for Alzheimer's, Parkinson's and stroke," says Schubert. "But it may be that by targeting aging we can treat or slow down many pathological conditions that are old-age-associated."
The next step for the team is to study the other molecules besides ATP that are affected by J147, in the hopes of finding new drug targets. Meanwhile, the drug has passed the toxicology test in animals, and should move into phase 1 human clinical trials soon, pending further funding.
The research was published in the journal Aging Cell.
Source: The Salk Institute
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