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， 折磨着数百万人TBI和TREM 2的亚晶变体，TREM 2是一种仅由TBI表达的基因， 大脑中的小胶质细胞，增加自发性AD风险。高迁移率族蛋白1（HMGB 1）蛋白是一种蛋白质， 随着年龄的增长和TBI后细胞外增加，TBI启动了小胶质细胞中的促炎信号， 大脑的先天免疫细胞。这项提议将检验艾地苯醌恢复Aβ的中心假设 TREM 2缺陷型小鼠的吞噬能力以及基线和HMGB 1反应性转录组特征 人类小胶质细胞通过挽救线粒体生物能量功能。TREM 2是体内平衡功能所必需的 小胶质细胞，包括其清除与AD病理学相关的淀粉样蛋白-β（Aβ）聚集体的吞噬能力。 然而，由于缺乏TREM 2信号传导只是一个风险因素，因此可能导致糖尿病的终生环境因素， 包括TBI和年龄相关变化。代谢改变的反应 外源性信号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。 该提案的主要目标是：i）阐明线粒体呼吸链损伤的位点， TREM 2信号传导缺陷的人诱导多能干细胞（iPSC）衍生的小胶质细胞样细胞，ii） 确定临床上安全的化合物艾地苯醌是否挽救线粒体生物能功能， 人类对衰老/TBI相关HMGB 1刺激或Aβ吞噬功能受损的转录反应 iii）开始评估TREM 2缺陷型小胶质细胞样细胞（下文简称为小胶质细胞）， 男性和女性小神经胶质细胞对TBI和AD相关炎症刺激的反应的人类变异性，以及 iv）开始评估人小胶质细胞酶促还原艾地苯醌至 其活性形式艾地烯醇。这些目标逻辑上建立在实验室以前的调查路线，通过评估TBI- 相关的小胶质细胞免疫反应与人类细胞中的遗传性AD风险因子串联，并测试是否 临床安全的靶向干预可减轻免疫代谢“编程”缺陷， AD和AD相关痴呆（ADRD）。目的1将测试的预测，线粒体缺陷（S）的 TREM 2缺陷型iPSC衍生的小胶质细胞出现在呼吸链复合物III的上游，并且可以通过以下方式拯救： 艾地苯醌目标2将测试艾地苯醌使基线和HMGB 1刺激的 TREM 2缺陷型人小胶质细胞转录组特征和吞噬Aβ清除率。我们 研究将确定人类线粒体生物能量学缺陷的具体潜在机制， TREM 2信号传导缺陷的小胶质细胞，可能揭示预防AD的新干预策略 由于遗传风险或TBI等环境因素而导致的发展。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醌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.