Drug candidate reverses memory loss in mice

A newly developed drug candidate, previously shown to slow ageing in brain cells, has successfully reversed memory loss in a mouse model of inherited Alzheimer’s disease. Described in the journal Redox Biology, the drug works by changing how brain cells metabolise fatty molecules known as lipids.

Over the last few decades, Pamela Maher from the Salk Institute for Biological Studies has studied how a chemical called fisetin, found in fruits and vegetables, can improve memory and even prevent Alzheimer’s-like disease in mice. She and her team synthesised different variants of fisetin and found that one, called CMS121, was especially effective at improving the animals’ memory, and slowing the degeneration of brain cells.

In the new study, Maher and colleagues tested the effect of CMS121 on mice that develop the equivalent of Alzheimer’s disease. The team gave a subset of the mice daily doses of CMS121 beginning at nine months old — the equivalent of middle age in humans, and after the mice have already begun to show learning and memory problems. The timing of the lab’s treatment is akin to how a patient who visits the doctor for cognitive problems might be treated, the researchers say.

After three months on CMS121, at 12 months old, the mice — both treated and untreated — were given a battery of memory and behaviour tests. In both types of tests, mice with Alzheimer’s-like disease that had received the drug performed equally well as healthy control animals, while untreated mice with the disease performed more poorly.

To better understand the impact of CMS121, the team compared the levels of different molecules within the brains of the three groups of mice. They discovered that when it came to levels of lipids — fatty molecules that play key roles in cells throughout the body — mice with the disease had several differences compared to both healthy mice and those treated with CMS121. In particular, the researchers pinpointed differences in something known as lipid peroxidation — the degradation of lipids that produces free radical molecules that can go on to cause cell damage. Mice with Alzheimer’s-like disease had higher levels of lipid peroxidation than either healthy mice or those treated with CMS121.

“That not only confirmed that lipid peroxidation is altered in Alzheimer’s, but that this drug is actually normalising those changes,” said postdoctoral fellow Gamze Ates, first author of the study.

The researchers went on to show that CMS121 lowered levels of a lipid-producing molecule called fatty acid synthetase (FASN), which in turn lowered levels of lipid peroxidation. When the group analysed levels of FASN in brain samples from human patients who had died of Alzheimer’s, they found that the patients had higher amounts of the FASN protein than similarly aged controls who were cognitively healthy, which suggests FASN could be a drug target for treating Alzheimer’s disease.

Based on the success of their study, the team is now pursuing clinical trials. They also hope other researchers will explore additional compounds that may treat Alzheimer’s by targeting FASN and lipid peroxidation.

Image credit: ©stock.adobe.com/au/fergregory

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