Researchers at the Salk Institute have discovered that a drug candidate that scientists have previously shown to slow aging in brain cells has successfully reversed memory loss in a mouse model of inherited Alzheimer’s disease.
The new findings appear in the journal Redox Biology.
Alzheimer’s is a progressive brain disease that destroys brain cells, leading to memory loss and impairments in thinking and behavior. These symptoms are severe enough to restrict an individual’s daily life and activities.
According to the National Institute on Aging, Alzheimer’s disease, the most common form of dementia, is the sixth leading cause of death in the United States. Additionally, they note that studies suggest that more than 5.5 million people in the U.S. may have dementia due to Alzheimer’s.
Old age is the biggest risk factor, with symptoms usually first appearing in adults in their mid-60s. However, it remains unclear what occurs in the brain at the molecular level with aging that contributes to Alzheimer’s disease.
Evaluating the drug candidate in mice
Over the last few decades, Dr. Pamela Maher and colleagues at the Salk Institute have studied a chemical called fisetin, found in fruits and vegetables, which can improve memory. The team developed a version of fisetin called CMS121, which they found to be effective in slowing the loss of brain cells.
In the current study, Maher and the team evaluated the effect of CMS121 on a type of mouse that ages very quickly and develops a disease similar to Alzheimer’s in humans.
The scientists gave one group of mice daily doses of CMS121. They started this when the mice were 9 months old — the equivalent of late middle age in humans — and had already begun showing symptoms of declining memory and learning.
They chose this timing of treatment to mirror the time when an individual would typically visit a doctor to receive treatment for cognitive issues.
The other two groups consisted of healthy untreated mice or untreated mice with the disease. After 3 months, when the mice were 12 months old, the team tested their memory and behavior and analyzed genetic and molecular indicators in their brains. They compared the results of the CMS121 group with those of the untreated mice.
CMC121 improves memory and behavior
The results revealed that in both memory and behavior tests, mice with Alzheimer’s-like disease that received CMS121 treatment performed equally well as healthy control mice, while untreated mice with the disease performed poorly.
Not only that, but the brains of the treated mice showed differences at the cellular and molecular levels.
The researchers observed differences in the levels of lipids (fatty molecules that play key roles in cells throughout the body) in mice with the disease compared with both healthy mice and those treated with CMS121. Specifically, they discovered differences in lipid peroxidation, which leads to cell damage.
Mice that received CMC121 and healthy mice had lower levels of lipid peroxidation than mice with Alzheimer’s-like disease.
“That not only confirmed that lipid peroxidation is altered in Alzheimer’s, but that this drug is actually normalizing those changes,” explains the first author of the study, Dr. Gamze Ates.
CMS121 targets a specific molecule
Next, Maher and colleagues demonstrated that CMS121 reduced the levels of a lipid-producing molecule called fatty acid synthetase (FASN), which, subsequently, reduces lipid peroxidation levels.
When the researchers analyzed brain samples from people who had died of Alzheimer’s, they discovered that these individuals had higher amounts of the FASN protein compared with healthy individuals. These results indicate that FASN may be a potential drug target for treating Alzheimer’s disease.
However, a limitation of the current study is that the researchers did not measure the baseline cognitive function for the mice at the beginning of the study.
The scientists hope that their findings will lead other researchers to evaluate additional compounds that may treat Alzheimer’s disease by targeting FASN and lipid peroxidation, as well as identifying new targets.
“This was a more rigorous test of how well this compound would work in a therapeutic setting than our previous studies on it. Based on the success of this study, we’re now beginning to pursue clinical trials,” concludes Dr. Maher.
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