Elevating acetyl-CoA levels reduces aspects of brain aging

Abstract

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.

Intracellular amyloid toxicity induces oxytosis/ferroptosis regulated cell death

“…In a number of publications, we have now demonstrated that several AD drug candidates developed on the basis of being anti-oxytotic/ferroptotic also protect in mouse models of AD and aging where little or no neurodegeneration occurs 22,[26][27][28] . This suggests that the oxytosis/ ferroptosis cell death pathway is important to aging and AD and that it is a process that manifests itself over a lengthy amount of time before the cells die, thereby offering a window for therapeutic intervention.…”

“…In our experiments, mitochondrial dysfunction in MC65 nerve cells mediated by Aβ was indicated by: (1) pathway analysis; (2) omics integration into the KEGG biochemical chart; (3) decreases in mitochondrial metabolites; (4) impaired mitochondrial bioenergetics; and (5) generation of mitochondrial ROS. These data are extremely important because mitochondrial dysfunction may be a critical event that bridges aging to AD and has therapeutic value 22,32 .…”

“…5b). On the other hand, two AD drug candidates CMS121 and J147 22 that were developed on the basis of inhibiting oxytosis/ferroptosis, also prevented Aβ-mediated cell death, as assessed at day 3 (Fig. 5c).…”

The Value of Herbarium Collections to the Discovery of Novel Treatments for Alzheimer’s Disease, a Case Made With the Genus Eriodictyon

“…Based on this premise, our laboratories have developed a number of cell culture models to study nerve cell death pathways that mimic different toxicities and stresses associated with the aging brain and AD (Prior et al, 2014). In the past 10 years, we have used these assays to successfully identify new AD drug candidates that are extremely protective in animal models of dementia by preventing specific aspects of the aging process in the brain (Currais et al, 2014b(Currais et al, , 2015(Currais et al, , 2017(Currais et al, , 2019Goldberg et al, 2018).…”

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…30 The late-onset sporadic form (LOAD) of Alzheimer's disease (AD) [31][32][33] accounts for >90% of disease cases. 31,[34][35][36] Along with advanced aging, 23,[37][38][39][40][41][42][43] inheritance of the apolipoprotein E4 allele (also called APOE4 or APOEe4) remains the most significant known genetic risk factor for LOAD. The risk is higher and the age at onset of dementia is younger for individuals carrying multiple copies of APOE4, whereas other APOE alleles are considered protective.…”