Targeting TREM2 AD/ADRD risk and immunometabolism in human microglia

项目摘要 创伤性脑损伤(TBI)和阿尔茨海默病(AD)会导致长期残疾和痴呆症 折磨着数百万人。TREM2基因的TBI和亚型变体都是由 大脑中的小胶质细胞，增加自发性阿尔茨海默病的风险。高迁移率族蛋白1是一种蛋白质 随着年龄的增长和脑外伤后启动小胶质细胞促炎信号的细胞外增加， 大脑的先天免疫细胞。这项提议将检验艾地苯酮恢复Aβ的中心假设 TREM2缺陷患者的吞噬能力、基线和HMGB1反应性转录特征 人类小胶质细胞通过挽救线粒体的生物能量功能。体内平衡功能需要TREM2 小胶质细胞的吞噬能力，包括它们清除与AD病理有关的淀粉样蛋白-β(Aβ)聚集体的能力。 然而，由于缺乏TREM2信号只是一个风险因素，终身环境因素，这可能 包括脑损伤和年龄相关改变，是AD表现所必需的。反应中的代谢变化 外源线索改变了包括小胶质细胞在内的各种免疫细胞类型与环境的相互作用方式。 这项建议的主要目的是：i)阐明线粒体呼吸链损伤的位点(S) TREM2信号缺陷的人诱导多能干细胞(IPSC)来源的小胶质细胞样细胞，II) 确定临床安全的复方艾地苯酮是否拯救线粒体的生物能量功能， 人类对衰老/脑外伤相关的HMGB1刺激或Aβ吞噬功能受损的转录反应 TREM2缺陷的小胶质细胞样细胞(以下简称小胶质细胞)，iii)开始评估个体 人类对脑外伤和AD相关炎症刺激的男性和女性小胶质细胞反应的变异性，以及 四)开始评估人类小胶质细胞将艾地苯酮酶促还原为 它的活性形式艾地苯酚。这些目标通过评估TBI合乎逻辑地建立在实验室之前的调查路线上- 人类细胞中相关的小胶质细胞免疫反应与阿尔茨海默病遗传风险因子的协同作用 临床安全的线粒体靶向干预可缓解相关的免疫代谢“程序性”缺陷 AD和AD相关痴呆症(ADRD)。目的1将检验线粒体缺陷(S)的预测 TREM2缺陷的IPSC来源的小胶质细胞发生在呼吸链复合体III的上游，可以被 艾地苯酮。目标2将测试艾地苯酮对基线和HMGB1刺激的正常化的预测 TREM2缺陷的人小胶质细胞转录特征和吞噬细胞Aβ清除率。我们的 研究将确定人类线粒体生物能量学缺陷的特定潜在机制(S) TREM2信号缺陷的小胶质细胞，可能揭示预防AD的新干预策略 由于遗传风险或环境因素(如脑外伤)而导致的发育。此外，我们的研究将开始解决 个体遗传变异如何影响艾地苯酮作为治疗策略的使用。

Project Summary Traumatic brain injury (TBI) and Alzheimer’s disease (AD) cause long-term disability and dementia that afflict millions of individuals. Both TBI and hypomorphic variants of TREM2, a gene exclusively expressed by microglia in the brain, increase spontaneous AD risk. High Mobility Group Box 1 (HMGB1) protein is a protein that increases extracellularly with age and following TBI that initiates pro-inflammatory signaling in microglia, the innate immune cells of the brain. This proposal will test the central hypothesis that idebenone restores Aβ phagocytosis capacity and the baseline and HMGB1-reactive transcriptomic signatures of TREM2-deficient human microglia by rescuing mitochondrial bioenergetic function. TREM2 is required for homeostatic functions of microglia, including their phagocytic capacity for clearing amyloid-β (Aβ) aggregates linked to AD pathology. However, because deficient TREM2 signaling is only a risk factor, lifetime environmental factors, which may include TBI and age-associated changes, are required for AD manifestation. Metabolic alterations in response to exogenous cues rewire how various immune cell types, including microglia, interact with their environment. The primary goals of this proposal are to: i) elucidate site(s) of mitochondrial respiratory chain impairment in human induced pluripotent stem cell (iPSC)-derived microglia-like cells that are TREM2 signaling-deficient, ii) determine whether the clinically safe compound idebenone rescues mitochondrial bioenergetic function, the transcriptional response to aging/TBI-relevant HMGB1 stimulation, or impaired Aβ phagocytosis in human TREM2-deficient microglia-like cells (hereafter referred to simply as microglia), iii) begin to evaluate individual human variability in male and female microglial responses to TBI- and AD-relevant inflammatory stimulation, and iv) begin to evaluate individual variability in the ability of human microglia to enzymatically reduce idebenone to its active form, idebenol. These goals logically build on the lab’s previous lines of investigation by evaluating TBI- relevant microglial immune responses in tandem with a genetic AD risk factor in human cells and testing whether a clinically safe mitochondria-targeted intervention mitigates immunometabolic “programming” deficits relevant to AD and AD-related dementias (ADRD). Aim 1 will test the predictions that the mitochondrial defect(s) of TREM2 deficient iPSC-derived microglia occur upstream of respiratory chain Complex III and can be rescued by idebenone. Aim 2 will test the predictions that idebenone normalizes both the baseline and HMGB1-stimulated TREM2-deficient human microglial transcriptomic signatures and the rate of phagocytic Aβ clearance. Our studies will determine specific underlying mechanism(s) of mitochondrial bioenergetics deficits in human microglia with deficient TREM2 signaling, potentially revealing novel intervention strategies to forestall AD development due to genetic risk or environmental factors like TBI. In addition, our studies will begin to address how individual genetic variability influences the use of idebenone as a treatment strategy.