Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention

Humans possess three genetic isoforms of apolipoprotein E (ApoE)—ApoE2, ApoE3, and ApoE4—that confer differential risk for Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. This study sought to investigate the impact of human ApoE isoforms on brain energy metabolism, an area significantly perturbed in preclinical AD. A TaqMan custom array was performed to examine the expression of a total of 43 genes involved in glucose and ketone body transport and metabolism, focusing on pathways leading to the generation of acetyl-CoA, in human ApoE gene-targeted replacement female mice. Consistent with our previous findings, brains expressing ApoE2 exhibited the most robust profile, whereas brains expressing ApoE4 displayed the most deficient profile on the uptake and metabolism of glucose, the primary fuel for the brain. Specifically, the three ApoE brains differed significantly in facilitated glucose transporters, which mediate the entry of glucose into neurons, and hexokinases, which act as the "gateway enzyme" in glucose metabolism. Interestingly, on the uptake and metabolism of ketone bodies, the secondary energy source for the brain, ApoE2 and ApoE4 brains showed a similar level of robustness, whereas ApoE3 brains presented a relatively deficient profile. Further, ingenuity pathway analysis indicated that the PPAR-/PGC-1α signaling pathway could be activated in the ApoE2 brain and inhibited in the ApoE4 brain. Notably, PGC-1α overexpression ameliorated ApoE4-induced deficits in glycolysis and mitochondrial respiration. Overall, our data provide additional evidence that human ApoE isoforms differentially modulate brain bioenergetic metabolism, which could serve as a potential mechanism contributing to their discrete risk impact in AD.

SIGNIFICANCE STATEMENT We uncovered hexokinase as a key cytosolic point in the glucose metabolism that is differentially modulated by the three ApoE genotypes. The differences in hexokinase expression and activity exhibited in the three ApoE brains may underlie their distinct impact on brain glucose utilization and further susceptibility to AD. Therefore, a therapeutic approach that could circumvent the deficiencies in the cytosolic metabolism of glucose by providing glucose metabolizing intermediates, e.g., pyruvate, may hold benefits for ApoE4 carriers, who are at high risk for AD. The bioenergetic robustness may translate into enhanced synaptic activity and, ultimately, reduces the risk of developing AD and/or delays the onset of clinical manifestation.