Elevating acetyl-CoA levels reduces aspects of brain aging.
Antonio Currais1, Ling Huang2, Joshua Goldberg1
1Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States.
Elife
|November 20, 2019
Summary
Two novel drug candidates, CMS121 and J147, target a shared pathway in aging brains and Alzheimer's disease (AD). They improved cognitive function and brain aging markers by regulating acetyl-CoA metabolism, offering potential dementia treatments.
Area of Science:
- Neuroscience
- Gerontology
- Pharmacology
Background:
- Aging is the primary risk factor for dementia, necessitating research into age-related brain changes.
- Understanding the molecular links between brain aging and Alzheimer's disease (AD) is crucial for developing effective therapies.
Purpose of the Study:
- To identify a common molecular pathway in the aging brain and AD using two drug candidates, CMS121 and J147.
- To investigate the therapeutic potential of targeting this pathway for dementia treatment.
Main Methods:
- Administration of CMS121 and J147 to rapidly aging SAMP8 mice.
- Analysis of cognitive function, metabolic markers, and transcriptional changes in the brain.
- Investigation of acetyl-CoA (acetyl-coenzyme A) metabolism and its regulation by CMS121 and J147.
- Assessment of histone acetylation (H3K9) as a marker for memory enhancement.
Main Results:
- CMS121 and J147 treatment reduced cognitive decline and markers of brain aging in SAMP8 mice.
- Both compounds preserved mitochondrial homeostasis by regulating acetyl-CoA metabolism.
- Inhibition of acetyl-CoA carboxylase 1 (ACC1) by CMS121 and J147 increased acetyl-CoA levels, leading to neuroprotection.
- Increased histone H3K9 acetylation was observed, a modification linked to memory enhancement.
Conclusions:
- Targeting specific metabolic pathways, like acetyl-CoA metabolism, in the aging brain shows promise for treating dementia.
- CMS121 and J147 represent potential therapeutic agents for age-related cognitive decline and Alzheimer's disease.
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