Targeting TREM2 AD/ADRD risk and immunometabolism in human microglia

靶向人类小胶质细胞中的 TREM2 AD/ADRD 风险和免疫代谢

基本信息

批准号：
10726661
负责人：
BRIAN M POLSTER
金额：
$ 42.49万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726661
关键词：
Abeta clearance Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Animals Attenuated Bioenergetics Brain Cells Clinical Clinical Trials Coenzyme Q10 Complex Consumption Country Cues Data Defect Dementia Development Disease Electron Transport Complex III Energy Metabolism Environment Environmental Risk Factor Enzymes Evaluation Extracellular Space Female Genes Genetic Genetic Transcription Genus Hippocampus Glycolysis Goals HMGB1 gene Heritability Heterozygote Human Immune Immune response Immunologic Receptors Impairment Individual Inflammatory Intervention Investigation Knock-out Late Onset Alzheimer Disease Link Measures Metabolic Microglia Mitochondria Modeling Molecular Mus NOS2A gene Nitric Oxide Oxidoreductase Pattern Persons Phagocytes Phagocytosis Pharmaceutical Preparations Phenotype Proteins Quinones Respiratory Chain Risk Risk Factors Signal Transduction Single Nucleotide Polymorphism Site TLR4 gene TREM2 gene Testing Therapeutic Intervention Traumatic Brain Injury Variant abeta accumulation aged analog apolipoprotein E-4 brain cell cell type dementia risk disability experimental study extracellular genetic risk factor genetic variant human subject idebenone in vivo individual variation induced pluripotent stem cell innovation male nano-string neuroinflammation novel preservation receptor for advanced glycation endproducts respiratory response risk variant transcriptomics translational potential treatment strategy

项目摘要

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.

项目概要创伤性脑损伤 (TBI) 和阿尔茨海默病 (AD) 会导致长期残疾和痴呆， TBI 和 TREM2（一种仅由 TREM2 表达的基因）的亚型变体都困扰着数以百万计的人。大脑中的小胶质细胞会增加自发性 AD 风险，高迁移率族蛋白 1 (HMGB1) 是一种蛋白质。随着年龄的增长和 TBI 后在细胞外的增加，TBI 会启动小胶质细胞中的促炎症信号传导，该提案将检验艾地苯醌恢复 Aβ 的中心假设。 TREM2 缺陷的吞噬能力以及基线和 HMGB1 反应性转录组特征人类小胶质细胞通过拯救线粒体生物能量功能来维持稳态功能。小胶质细胞的功能，包括其清除与 AD 病理相关的淀粉样蛋白-β (Aβ) 聚集体的吞噬能力。然而，由于 TREM2 信号传导缺陷只是一个危险因素，终生环境因素，可能包括 TBI 和年龄相关的变化，是 AD 表现所需要的代谢改变。外源线索重新连接了包括小胶质细胞在内的各种免疫细胞类型如何与其环境相互作用。该提案的主要目标是： i) 阐明线粒体呼吸链损伤的位点人类诱导多能干细胞 (iPSC) 衍生的 TREM2 信号传导缺陷的小胶质细胞样细胞，ii) 确定临床安全的化合物艾地苯醌是否可以挽救线粒体生物能功能，对衰老/TBI 相关的 HMGB1 刺激或人类 Aβ 吞噬作用受损的转录反应 TREM2 缺陷型小胶质细胞样细胞（以下简称小胶质细胞），iii) 开始评估个体男性和女性小胶质细胞对 TBI 和 AD 相关炎症刺激反应的人类差异，以及 iv) 开始评估人类小胶质细胞酶促还原艾地苯醌的能力的个体差异这些目标逻辑上建立在实验室之前通过评估 TBI 进行的研究基础上。相关的小胶质细胞免疫反应与人类细胞中的遗传 AD 危险因素相结合，并测试是否临床安全的线粒体靶向干预可减轻免疫代谢“编程”缺陷 AD 和 AD 相关痴呆 (ADRD) 的目标 1 将测试线粒体缺陷的预测。 TREM2 缺陷 iPSC 衍生的小胶质细胞出现在呼吸链复合物 III 的上游，可以通过目标 2 将测试艾地苯醌标准化基线和 HMGB1 刺激的预测。 TREM2 缺陷的人类小胶质细胞转录组特征和吞噬 Aβ 清除率。研究将确定人类线粒体生物能量缺陷的具体潜在机制 TREM2 信号传导缺陷的小胶质细胞，可能揭示预防 AD 的新干预策略此外，我们的研究将开始解决由于遗传风险或环境因素（如 TBI）而导致的发育。个体遗传变异如何影响艾地苯醌作为治疗策略的使用。