Astrocyte Lipometabolic Regulation by Acyl-CoA Binding Protein as a Neurobiological Target Underlying Central Metabolic Dysfunction in Alzheimer's Disease

Abstract Metabolic perturbations as an early mechanism driving the pathophysiology of Alzheimer’s disease (AD) have received increased attention in recent decades as the field demands new strategies to address disease burden. Astrocyte lipid metabolism, which is inextricably linked with neuronal functioning, is profoundly remodeled in AD in ways that promote oxidative stress, inflammation, and apoptosis. In light of the projected increase in AD prevalence and number of individuals with preexisting metabolic disease which further increases AD risk, establishing the role of astrocyte lipid dysregulation in AD pathology and pursuing therapeutic strategies to address the presymptomatic metabolic dysfunction of AD and is timely and essential. Acyl-CoA Binding Protein (ACBP) is a key cytosolic regulator of lipid metabolism expressed dominantly by astroglial cells in the brain. ACBP binds long chain fatty acid acyl-CoA molecules (FACoA) and shuttles them to various metabolic fates, including to the mitochondria for β-oxidation. This proposal will assess how selective genetic disruption of astrocyte ACBP FACoA binding or ODN-GPCR signaling alters cellular metabolic and bioenergetic activity, vulnerability to oxidative damage, and neurocognitive behavior in AD models.