Posted on 6 August 2020
We initially hoped that therapies aimed at clearing amyloid beta, a protein that accumulates in the brains of Alzheimer’s patients, might be an effective strategy to reverse the course of the disease. Unfortunately, these therapies have proven unsuccessful, leaving us no closer to actually curing Alzheimer’s disease than we were when it was first described over a century ago.
We desperately need to find new therapeutic targets and drugs that can be brought to clinical trial. Here, researchers at the Salk Institute show that a drug called CMS121, which targets age-related metabolic pathways in the brain, can reverse Alzheimer’s – like disease in mice.
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.
The brains of treated mice also exhibited differences in lipid metabolism. Specifically, lipid degradation in the brains of treated mice produced fewer free radicals, which are reactive molecules that cause damage to 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).
There is no telling whether this will be effective in humans. Animal models of Alzheimer’s are poor analogues of human disease – due to their short lifespans, mice must be genetically altered in order to develop Alzheimer’s. As a result, the Alzheimer’s disease in mice is an extreme, accelerated form of the condition in humans. This is why many treatments that have proven effective in mice, such as amyloid beta clearance, have failed in humans. However, it does appear that the mechanism targeted by CMS121 in mice may also be important in human disease, and is worthy of further investigation in clinical trials.
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.
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.
CMS121, a fatty acid synthase inhibitor, protects against excess lipid peroxidation and inflammation and alleviates cognitive loss in a transgenic mouse model of Alzheimer's disease: https://doi.org/10.1016/j.redox.2020.101648
Anti-aging drug targets Alzheimer's by altering metabolism in the brain: https://newatlas.com/medical/anti-aging-drug-alzheimers-metabolism-brain/
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