Salk researchers have developed a drug candidate, previously shown to slow aging in brain cells, successfully reversed memory loss in a mouse model of inherited Alzheimer’s disease. Published recently in the journal Redox Biology, the research reveals that the drug, CMS121, works by changing how brain cells metabolize fatty molecules known as lipids. The team is so confident that based on their findings, they seek to pursue clinical trials.
On a Mission to Pursue Clinical Trials
Researcher Pamela Maher, senior staff scientists in the lab of Salk Professor David Schubert, and the senior author of the paper, recently commented in a Salk press release, “This was a more rigorous test of how well this compound would work in a therapeutic setting than our previous studies on it.” Dr. Maher is now on a mission to pursue clinical trials.
Maher has been studying for decades now how a chemical called fisetin, found in fruits and vegetables, can improve memory and even prevent Alzheimer’s-like diseases in mice. The Salk team recently synthesized different variants of fisetin and uncovered CMS121, one that was particularly effective at improving the animals’ memory as well as actually slowing down the degeneration of brain cells.
Maher and team tested CMS121 on mice that have the equivalent of Alzheimer’s disease. The team gave a subset of the mice daily doses of CMS121 beginning at 9 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 say the researchers.
With three months of CMS121 treatments, at 12 months old, the mice, both treated and untreated, were give a battery of memory and behavior 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.
CMS121 had real impact. The team discovered that when it came to levels of lipids—that is 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. For example the team pinpointed the 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.
Commenting on this point, Salk postdoctoral fellow Gamze Ate, first author commented, “That not only confirmed that lipid peroxidation is altered in Alzheimer’s, but that this drug is actually normalizing those changes.
The Salk researchers demonstrated that CMS121 lowered levels of a lipid-producing molecule called fatty acid synthetase (FASN), which in turn, lowered levels of lipid peroxidation. In a fascinating example, the researchers analyzed FASN levels in brain samples from human patients who had died of Alzheimer’s and found that the patients actually had higher amounts of the FASN protein than similarly aged controls who were cognitively healthy: this suggests FASN could be a drug target for treating Alzheimer’s disease.
Could this Open up New Alzheimer’s Targets?
Salk’s Maher suggested in the institute’s press release that “There has been a big struggle in the field right now to find targets to go after.” She continued, “So, identifying a new target in an unbiased way like this is really exciting and opens lots of doors.”
This study was funded by grants from the Shiley Foundation, the National Institutes of Health, the Edward N. & Della Thome Memorial Foundation and the Shiley-Marcos Alzheimer’s Disease Research Center at the University of California, San Diego.
Based in La Jolla, San Diego, CA, the Salk Institute for Biological Studies is an independent, non-profit scientific research institute founded in 1960 by Jonas Salk, the developer of the polio vaccine, among the founding consultants were Jacob Bronowski and Francis Crick.
· Pamela Maher, senior staff scientists
· Gamze Ate, Postdoctoral Fellow
· Joshua Goldberg
· Antonio Currais
Call to Action: Interested in partnering with Salk on the development of CMS121? Check out their licensing team.