Examining the Effects of the Neuroprotective APOE2 Allele on Peripheral Immunometabolism

神经保护性载脂蛋白2等位基因对外周免疫代谢的影响 载脂蛋白E(ApoE)是一种参与胆固醇和磷脂转运的载脂蛋白。 大脑，通过调节胆固醇、甘油三酯和磷脂代谢来促进脂质动态平衡 在全身运输。载脂蛋白E存在三种亚型(E2、E3和E4)，并为 阿尔茨海默病(AD)。在大约14%的人群中发现的APOE4等位基因提供了最大的 阿尔茨海默病的风险机制尚不完全清楚。有趣的是，APOE2等位基因，在大约8%的 人口，具有神经保护作用。APOE2与AD风险降低、认知功能减退和 延长了寿命。支持这一项目的父母拨款集中在寻找新的生物标记物来预测潜伏期 为AD的防治提供了新的分子靶点。这个受资助的项目使 使用间接量热法测量的全身能量消耗来研究潜在的代谢 载脂蛋白E亚型之间的差异及其与认知功能的关系。与 在AD患者和认知健康的E4个体中观察到的代谢变化增加了神经炎症 最近还描述了异常的免疫反应。这为 目前的建议，其中我们的目标是寻找关于潜在疾病的有意义的外周生物标记物 与载脂蛋白4携带者相关的免疫功能障碍。这个项目的目标是阐明不同之处。 E2个体外周血单个核细胞(PBMC)免疫细胞间的比较 风险较高的E3和E4。众所周知，先天免疫反应会引起新陈代谢重新编程。 在小胶质细胞中，我们的实验室观察到了脑源性小胶质细胞和外周血细胞之间的代谢变化 来自不同APOE基因的巨噬细胞。我们实验室之前的研究发现， E4星形胶质细胞从氧化磷酸化到有氧糖酵解的代谢偏好，这种代谢转变 可以增加像乳酸这样的炎症介质，为检查免疫代谢提供了进一步的理由 在人类载脂蛋白E的背景下。利用转录和代谢组学方法，目前的项目将 使用从APOE基因分型研究参与者的血液中分离的PBMC来阐明其机制 哪些E4个体对炎症刺激的反应假设为E4外周免疫细胞表现出 与小胶质细胞类似的促炎表型，导致细胞内的代谢向有氧代谢转变 糖酵解，而E2细胞倾向于氧化磷酸化。

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.