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.
Wednesday, January 08, 2020
Brain aging reduced by elevating acetyl-CoA levels.
Acetyl coenzyme A (acetyl-CoA) is a central molecule in the energy metabolism of mitochondria in our cells. Currais et al. show that two Alzheimer's disease (AD) drug candidates known to reduce cognitive decline in a mouse model of AD increase acetyl-CoA levels and preserve mitochondrial function. Here is their technical abstract: