Developmental Biology - Alzheimer's|
Salk study demonstrates how a drug called CMS121 reverses memory loss in mice...
A drug candidate developed by Salk research, and known to slow aging in brain cells, has successfully reversed memory loss in mice. This particular mouse is a model for the inherited version of Alzheimer's disease. The research just published this July 2020 in the journal Redox Biology.
The research also revealed that the drug, at this point called CMS121, works by changing how brain cells use fatty molecules known as lipids.
"This was a more rigorous test of how well this compound works in a therapeutic setting than in our previous studies. Based on the success of these results, we're now beginning to pursue clinical trials."
Pamela Maher PhD, Senior Staff Scientist, David Schubert laboratory; professor and senior author of the paper.
Over the last few decades, Pamela Maher, senior staff scientist in the David Schubert laboratory at the Salk Institute for Biological Studies in La Jolla, California, has studied fisetin found in fruits and vegetables - and known to improve memory. Maher found it can also prevent Alzheimer's-like disease.
More recently, the Salk team synthesized different variants of fisetin and found that one, CMS121, is especially effective at improving memory in mice, and slowing the degeneration of brain cells.
In this newest study, Maher and colleagues tested the effect of CMS121 on mice that develop an equivalent of Alzheimer's. Maher's team gave a subset of the mice daily doses of CMS121 beginning at 9 months old — the equivalent of middle age in people — and after the mice have already begun to show learning and memory problems. The timing of the lab's treatment approximates when a human patient might visit a doctor for continuing cognitive problems.
After three months on CMS121, at 12 months old, the mice — both treated and untreated — were given a battery of memory and behavior tests. In both types of tests, mice with Alzheimer's-like disease having received CMS121 performed equally as well as healthy control animals. However, untreated mice with the disease performed poorly.
To better understand the impact of CMS121, the team compared levels of different molecules within the brains of the three groups of mice to find:
• Levels of lipids (fatty molecules) play a key role in cells throughout the body — mice with brain disease had several differences when compared to both healthy mice and those treated with CMS121.
• In particular — degrading of lipids produces free radical molecules that cause cell damage or lipid peroxidation.
• 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 normalizing those changes."
Gamze Ates, postdoctoral fellow, Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA and first author of the new paper.
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 analyzed levels of FASN in brain samples from human patients who had died of Alzheimer's, they found these patients had higher amounts of the FASN protein than similarly aged control patients who were cognitively healthy. This observation suggests FASN could be a drug target for treating Alzheimer's disease.
While the group is pursuing clinical trials, they hope other researchers will explore additional compounds that may treat Alzheimer's by targeting FASN and lipid peroxidation.
"There has been a big struggle in the field right now to find targets to go after. So, identifying a new target in an unbiased way like this is really exciting and opens lots of doors."
Pamela Maher PhD
• CMS121, a fisetin-derivative, alleviates memory decline in a double transgenic AD mouse model.
• CMS121 is able to reduce lipid peroxidation and neuroinflammation, both in vitro and in vivo.
• We identify fatty acid synthase (FASN), which shows increased protein levels in human AD patients, as a target of CMS121.
• Our results confirm the involvement of lipid peroxidation and perturbed lipid metabolism in AD pathophysiology.
• Decreasing lipid levels through FASN inhibition can be effective against excess lipid peroxidation.
The oxidative degradation of lipids has been shown to be implicated in the progression of several neurodegenerative diseases and modulating lipid peroxidation may be efficacious for treating Alzheimer’s disease (AD). This hypothesis is strengthened by recent findings suggesting that oxytosis/ferroptosis, a cell death process characterized by increased lipid peroxidation, plays an important role in AD-related toxicities. CMS121 is a small molecule developed against these aspects of neurodegeneration. Here we show that CMS121 alleviates cognitive loss, modulates lipid metabolism and reduces inflammation and lipid peroxidation in the brains of transgenic AD mice. We identify fatty acid synthase (FASN) as a molecular target of CMS121 and demonstrate that modulating lipid metabolism through the inhibition of FASN protects against several AD-related toxicities. These results support the involvement of lipid peroxidation and perturbed lipid metabolism in AD pathophysiology and propose FASN as a target in AD-associated toxicities.
Gamze Ates, Joshua Goldberg, Antonio Currais and Pamela Maher.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements and funding information
This study was supported by grants from the Shiley Foundation (GA, JG), National Institutes of Health (RO1 AG046153, RF1 AG054714 and R41 AI104034 to PM), and the Edward N. & Della Thome Memorial Foundation (PM) and the Shiley-Marcos Alzheimer’s Disease Research Center at University of California San Diego (UCSD) (AC). We thank Dr. David Schubert (Salk Institute) for his insightful comments and critical revision of the manuscript, Dr. Oswald Quehenberger (UCSD) for his advice and support regarding the eicosanoid analyses and Dr. Robert Riessman and Jeffrey Metcalf from the UCSD Alzheimer’s Disease Research Center and the Shiley-Marcos Alzheimer’s Disease Research Center for providing the human tissue.
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is a small molecule that inhibits the activity of the glutamate/cystine antiporter system (xc-). This depletes cells of glutathione (GSH) and triggers the regulated cell death process.
CREDIT Pamela Maher, Salk Institutes.