P1‐195: APOE ISOFORMS DIFFERENTIATE NEURONAL AND ASTROCYTIC MITOCHONDRIAL BIOENERGETIC CAPACITY AND FUEL DEPENDENCY

Abstract

Late-onset Alzheimer's disease (LOAD) has a multifactorial nature and is associated with an early decline in brain glucose metabolism and a less efficient mitochondrion population. As the greatest genetic risk factor for LOAD, APOE4 allele has been found to impair amyloid-β (Aβ) clearance, promote its aggregation, affect energy metabolism, and mitochondrial function. While the exaggeration of age-related brain hypometabolism and mitochondrial inefficiency by APOE4 is well established in both AD patients and animal models of late stage AD, mixed results have thus far been reported regarding APOE4 effect on brain bioenergetics in young animals or in vitro models. We propose that such a discrepancy is partially due to the heterogeneous cellular composition of the brain and the distinct capacity of these cells to metabolize various energy substrates. Primary neurons and astrocytes were isolated from forebrains of humanized APOE4 and APOE3 mice. Mitochondrial bioenergetic profile and their dependency and capacity of metabolizing different substrates were characterized. As expected, both APOE3 and APOE4 embryonic neurons relied primarily on glucose than other fuels in terms of both dependency and capacity, whereas astrocytes could metabolize more fatty acids than neurons. APOE4 neurons and young adult astrocytes exhibited higher basal respiration but lower maximum-to-basal respiration ratio compared to APOE3 cells. Across energy fuels, APOE4 astrocytes had higher capacity metabolizing glucose than fatty acids upon high energetic demand while such a fuel preference was much less significant in APOE3 astrocytes. Consistently, the maximal capacity in metabolizing fatty acids was significantly lower in APOE4 astrocytes when compared to APOE3 astrocytes. Our findings indicated that the impact of APOE genotype on brain bioenergetics is cell type, AD, and stage-dependent. It was suggested that the development of strategies to restore brain energy metabolism against AD should consider APOE genotype, age and disease-stage, and the fuel preference of different cell types in the brain. This work was supported by NIA P01AG026572 to RDB (Project 1 to RDB & FY, Analytic Core to FY), University of Arizona Center for Innovation in Brain Science startup fund to FY, and Arizona Alzheimer's Consortium Pilot Project grants to RDB and to FY.