Examining the Effects of the Neuroprotective APOE2 Allele on Peripheral Immunometabolism

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Examining the Effects of the Neuroprotective APOE2 Allele on Peripheral Immunometabolism Apolipoprotein E (APOE) is an apolipoprotein involved in the transport of cholesterol and phospholipids in the brain, contributing to lipid homeostasis by regulating cholesterol, triglycerides, and phospholipid metabolism and transport throughout the body. Three isoforms of APOE exist (E2, E3, and E4) and confer various risks for Alzheimer’s disease (AD). The APOE4 allele, found in approximately 14% of the population, provides the largest risk for AD through mechanisms not completely known. Interestingly, the APOE2 allele, found in about 8% of the population, is neuroprotective. APOE2 is associated with reduced AD risk, slower cognitive decline, and increased longevity. The parent grant to support this project focuses on finding novel biomarkers to predict latent disease and provide new molecular targets for the prevention and treatment of AD. The funded project makes use of whole-body energy expenditure measured by indirect calorimetry to investigate the underlying metabolic differences between APOE isoforms and how they associate with cognitive function. In conjunction with the metabolic changes observed in AD patients and cognitively healthy E4 individuals, increased neuroinflammation and abnormal immunological responses have also recently been described. This provides the impetus for the current proposal, in which we aim to find meaningful peripheral biomarkers of latent disease with respect to immunological dysfunctions associated with APOE4 carriage. The goal of this project is to elucidate differences between immune cells known as peripheral blood mononuclear cells (PBMCs) of E2 individuals in comparison to higher risk E3 and E4. It is well established that innate immune responses invoke metabolic reprogramming in microglia and our lab has observed metabolic changes between both brain-derived microglia and peripheral macrophages from the different APOE genotypes. Previous research in our laboratory identified a shift in the metabolic preference of E4 astrocytes from oxidative phosphorylation to aerobic glycolysis, a metabolic shift that can increase inflammatory mediators like lactate, providing further justification to examine immunometabolism in the context of APOE in humans. Using transcriptomic and metabolomics approaches, the current project will use PBMCs isolated from the blood of APOE genotyped study participants to shed light on the mechanisms by which E4 individuals respond to inflammatory stimuli with the hypothesis that E4 peripheral immune cells exhibit similar pro-inflammatory phenotypes as microglia, causing a metabolic shift within the cell toward aerobic glycolysis while E2 cells favor oxidative phosphorylation.