Anti-aging drug targets Alzheimer’s by altering metabolism in the brain

Scientists investigating Alzheimer’s treatments at the Salk Institute have uncovered some key mechanisms that enable an experimental drug to reverse memory loss in mouse models of the disease. The discovery not only bodes well for the possibility of clinical trials, but provides researchers with a new target to consider in the wider development of compounds to counter the degenerative effects of the condition.

The research centers on a drug called CMS121, which is a synthetic version of a chemical called fisetin that occurs naturally in fruits and vegetables. The Salk team’s previous studies concerning CMS121 have produced some very promising results, with one paper published last year describing how the drug influences age-related metabolic pathways in the brain, protecting against the type of degeneration associated with Alzheimer’s. This followed earlier studies demonstrating how fisetin can prevent memory loss in mice engineered to develop Alzheimer’s.

Work continues at Salk to understand how exactly fisetin and the synthetic variant CMS121 produces these anti-aging effects on the brain. In their latest study, the researchers again turned to mice engineered to develop Alzheimer’s, which were administered daily doses of CMS121 from the age of nine months. This is the equivalent to middle age in humans, with the mice already exhibiting learning and memory problems before the treatment began.

Three months later, the mice were subjected to memory and behavior tests alongside a control group of mice that received no treatment at all and a group of mice that were perfectly healthy. The Alzheimer’s-like mice that underwent the CMS121 treatment performed just as well as the healthy control group on the tests, but the untreated mice performed much more poorly.

In order to dig into the details of why this might be, the team analyzed levels of certain molecules in the brains of the three different groups. In doing so, they found that the mice exhibited a few key differences surrounding the brain’s metabolism of fatty molecules called lipids. More specifically, in the way that lipids are degraded to produce free radical molecules that go on to cause damage to healthy cells.

The team’s analysis revealed that this process, called lipid peroxidation, was heightened in the mice with the disease that went without treatment, when compared to the two other groups. Further probing revealed that CMS121 seems to inhibit lipid peroxidation by lowering levels of a key lipid-producing molecule, called fatty acid synthetase (FASN).

This prompted the team to analyze FASN levels in brain samples of deceased Alzhiemer’s patients. These human subjects were found to have higher amounts of the FASN molecule than healthy controls of a similar age, indicating that FASN could in fact be a target with plenty of potential in the field of Alzheimer’s research.

“There has been a big struggle in the field right now to find targets to go after,” says Maher. “So, identifying a new target in an unbiased way like this is really exciting and opens lots of doors.”

These results bolster the potential of CMS121 to treat Alzheimer’s, and the team continues to work toward clinical trials to study its effectiveness in humans. But the study also opens up interesting new pathways in the field, with the researchers hopeful it can inspire other scientists to investigate compounds that target FASN and the process of lipid peroxidation.

The research was published in the journal Redox Biology.

Source: Salk Institute

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