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

Dysfunctions in astrocyte-neuronal metabolic cooperation develop years before the presentation of neurocognitive dysfunction in Alzheimer’s disease (AD). A hallmark of AD is the excess accumulation of lipid globules in astrocytes which promote oxidative stress, mitochondrial impairments, and accelerate neurodegeneration. Acyl-CoA Binding Protein (ACBP) is a key regulator of astrocyte lipid metabolism which facilitates the mobilization and oxidation of cytosolic lipids to prevent lipid accumulation. Evidence supports that ACBP function is critical in neuronal health as an anti-malaria drug known to induce neuropsychiatric symptoms and cognitive dsyfunction, binds to ACBP and outcompetes its binding for fatty acids, resulting in lipid globule formation, redox stress, and apoptosis. Expression of ACBP is downregulated in human AD patients and mouse preclinical AD models, yet the impact of blunted lipometabolic regulation by ACBP in the underlying metabolic perturbations and pathogenesis of AD has never been tested. ACBP is a multifunctional protein and in addition to its cytosolic lipid binding activity, its extracellular cleavage product octadecaneuropeptide (ODN) exerts antioxidant and cytoprotective effects through its metabotropic receptor. While ODN action has received much attention, no work thus far has examined the impact of ACBP’s lipid regulation on brain health. This research will test the hypothesis that lipid mobilization by ACBP represents a previously unrecognized cytoprotective mechanism which facilitates astrocyte lipid metabolism to relieve the lipotoxic burden and mitigate development of AD. The goal of this research is to isolate the contribution of ACBP's lipid binding from ODN receptor signaling on central metabolic activity and oxidative stress. To achieve this goal, this work will utilized three viral constructs expressing either wildtype ACBP, a mutant ACBP incapable of binding lipids, or a mutant ACBP inactive at the ODN receptor to isolate the impact of each signaling mechanism on the metabolic, inflammatory, and behavioral responses to AD modeled stress ex vivo and in vivo. These experiments and data analyses aim to provide evidence for the protective role of astrocyte ACBP lipid binding to combat metabolic perturbations of AD and demonstrate clinical relevance of ACBP lipometabolic regulation to AD pathogenesis. Project Number: 5P20GM148326-04 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Caroline Geisler | Institution: UNIVERSITY OF KENTUCKY, LEXINGTON, KY | Award Amount: $260,873 | Activity Code: P20 | Study Section: ZGM1-RCB-4(C1) View on NIH RePORTER: https://reporter.nih.gov/project-details/11506431