Summary: CMS121 and J147, two drug candidates that improve memory and slow neurodegeneration associated with Alzheimer’s disease, also slow aging in healthy, older mice. The compounds block damage to neurons caused by general aging and restore levels of specific molecules to those seen in younger animals.
Source: Salk Institute
In mouse models of Alzheimer’s disease, the investigational drug candidates known as CMS121 and J147 improve memory and slow the degeneration of brain cells. Now, Salk researchers have shown how these compounds can also slow aging in healthy older mice, blocking the damage to brain cells that normally occurs during aging and restoring the levels of specific molecules to those seen in younger brains.
The research, published last month in the journal eLife, suggests that the drug candidates may be useful for treating a broader array of conditions and points out a new pathway that links normal aging to Alzheimer’s disease.
“This study further validated these two compounds not only as Alzheimer’s drug candidates but also as potentially more widely useful for their anti-aging effects,” says Pamela Maher, a senior staff scientist at Salk and a co-corresponding author of the new paper.
Old age is the biggest risk factor for Alzheimer’s disease–above the age of 65, a person’s risk of developing the disease doubles about every five years. However, at a molecular level, scientists aren’t sure what occurs in the brain with aging that contributes to Alzheimer’s.
“The contribution of old age-associated detrimental processes to the disease has been largely neglected in Alzheimer’s disease drug discovery,” says Antonio Currais, a Salk staff scientist and first author of the new paper.
Maher and David Schubert, the head of Salk’s Cellular Neurobiology Lab, previously developed CMS121 and J147, variants of plant compounds with medicinal properties. Both compounds tested positive for their ability to keep neurons alive when exposed to cellular forms of stress related to aging and Alzheimer’s disease. Since then, the researchers have used the drug candidates to treat Alzheimer’s in animal models of the disease. But experiments revealing exactly how the compounds work suggested that they were targeting molecular pathways also known to be important in longevity and aging.
In the new research, Maher, Currais and their colleagues turned to a strain of mice that ages unusually fast. A subset of these mice was given CMS121 or J147 beginning at nine months old–the equivalent of late middle age in humans. After four months, the team tested the memory and behavior of the animals and analyzed genetic and molecular markers in their brains.
Not only did the animals given either of the drug candidates perform better on memory tests than mice that hadn’t received any treatment, but their brains showed differences at the cellular and molecular levels. In particular, expression of genes associated with the cell’s energy-generating structures called mitochondria was preserved by CMS121 and J147 with aging.
“The bottom line was that these two compounds prevent molecular changes that are associated with aging,” says Maher.
More detailed experiments showed that both drugs affected mitochondria by increasing levels of the chemical acetyl-coenzyme A (acetyl-coA). In isolated brain cells, when the researchers blocked an enzyme that normally breaks down acetyl-CoA, or when they added extra amounts of an acetyl-coA precursor, they saw the same beneficial effect on mitochondria and energy generation. The brain cells became protected against the normal molecular changes associated with aging.
“There was already some data from human studies that the function of mitochondria is negatively impacted in aging and that it’s worse in the context of Alzheimer’s,” says Maher. “This helps solidify that link.”
Maher and Currais are planning future experiments to test the effects of CMS121 and J147 on how other organs age. They also hope to use the new results to inform the development of new Alzheimer’s drugs; targeting other molecules in the acetyl-coA pathway may help treat the disease, they hypothesize.
“We are now using a variety of animal models to investigate how this neuroprotective pathway regulates specific molecular aspects of mitochondrial biology, and their effects on aging and Alzheimer’s,” says Currais.
Other researchers on the study were Ling Huang, Joshua Goldberg, Gamze Ates, António Pinto-Duarte, Maxim Shokhirev and David Schubert of the Salk Institute, and Michael Petrascheck of The Scripps Research Institute.
Funding: The work was supported by grants from the National Institutes of Health, the Glenn Foundation for Medical Research, the Shiley Foundation and the Edward N. and Della L. Thome Memorial Foundation.
David Schubert is an unpaid advisor for Abrexa Pharmaceuticals, a company working on the development of J147 for Alzheimer’s therapy. The Salk Institute holds the patents for CMS121 and J147.
About this neuroscience research article
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Elevating acetyl-CoA levels reduces aspects of brain aging
Because old age is the greatest risk factor for dementia, a successful therapy will require an understanding of the physiological changes that occur in the brain with aging. Here, two structurally distinct Alzheimer’s disease (AD) drug candidates, CMS121 and J147, were used to identify a unique molecular pathway that is shared between the aging brain and AD. CMS121 and J147 reduced cognitive decline as well as metabolic and transcriptional markers of aging in the brain when administered to rapidly aging SAMP8 mice. Both compounds preserved mitochondrial homeostasis by regulating acetyl-coenzyme A (acetyl-CoA) metabolism. CMS121 and J147 increased the levels of acetyl-CoA in cell culture and mice via the inhibition of acetyl-CoA carboxylase 1 (ACC1), resulting in neuroprotection and increased acetylation of histone H3K9 in SAMP8 mice, a site linked to memory enhancement. These data show that targeting specific metabolic aspects of the aging brain could result in treatments for dementia.