Alzheimer's Disease Genetic Risk and Microglial Innate Immune Memory

阿尔茨海默病遗传风险与小胶质细胞先天免疫记忆

基本信息

批准号：
10672444
负责人：
Zena Chatila
金额：
$ 5.27万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672444
关键词：
ATAC-seq Acetyl Coenzyme A Address Adopted Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Anti-Inflammatory Agents Area Automobile Driving Brain Brain Pathology Cell Death Cell Line Cells Central Nervous System Cholesterol Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Deoxyglucose Development Disease Disease susceptibility Dose Epigenetic Process Equilibrium Exposure to Failure Fumarates Functional disorder Gene Dosage Genetic Genetic Diseases Genetic Risk Genetic study Genotype Glutamates Glutamine Glycolysis Goals Heterozygote Human Immune Immune response Immunologic Memory Impaired cognition Impairment Individual Inflammation Inflammatory Knowledge Lead Link Malates Measures Mediating Memory Metabolic Metabolic Pathway Metabolic stress Metabolism Methods Microglia Modification NADP Natural Immunity Nature Outcome Pathogenesis Pathogenicity Pathology Patient-Focused Outcomes Phagocytosis Phenotype Play Process Production Pyruvate Receptor Signaling Research Personnel Role Shapes Signal Transduction Stimulus Supplementation Testing Therapeutic Therapeutic Intervention Training Variant age related neurodegeneration alpha ketoglutarate amyloid pathology cytokine established cell line genetic variant genome editing genome sequencing glial activation immune activation impaired capacity imprint improved insight interest monocyte mouse model neuroinflammation new therapeutic target novel novel strategies protective allele response risk variant tau Proteins transcriptome sequencing transcriptomics uptake

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by cognitive decline and an accumulation of amyloid pathology. A strong genetically-driven innate immune component is thought to play a pathogenic role in AD, implicating a central role for microglial dysfunction. Microglia are long-lived resident innate immune cells in the central nervous system. Activation of their immune and metabolic pathways lead to innate immune memory (IIM), a functional reprogramming process in which the response to an initial stimulus shapes long-lasting epigenetic modifications which inform the response to subsequent stimuli. IIM may result in enhanced activation (training) or suppression (tolerance) based on the identity of the initial inflammatory stimulus. IIM has been shown to alter pathology in AD mouse models, as a consequence of a sustained alteration in microglial functioning. Several common AD risk variants, including CD33, converge to suppress microglial activation, by decreasing inflammatory signaling or increasing its inhibition. Accordingly, my overall hypothesis is that altered microglial IIM as a result of suppressive genetic AD risk variants is a critical mechanism underlying the observed microglial dysfunction in AD. More specifically, I hypothesize that the suppressive CD33 AD-risk variant will reduce epigenetic and metabolic rewiring that occurs upon cellular activation, impairing microglial IIM. This sustained alteration of responsiveness at the epigenetic level may contribute to microglial failure as a pathogenic mechanism in AD. To address these hypotheses, I propose to examine the mechanisms of human microglial IIM in response to AD associated inflammatory stimuli, including amyloid and tau, and the effect of the CD33 risk variant on this imprinting process. In Aim 1, I will investigate human microglial IIM phenotypic outcomes in HMC3s (a human microglial cell line) edited with CRISPR to carry the CD33 AD risk allele. I will test whether a range of AD-associated inflammatory stimuli produce trained or tolerized IIM responses, and how CD33 genotype affects these outcomes. In Aim 2, I will investigate the epigenetic and metabolic mechanisms underlying IIM in HMC3s carrying the CD33 risk or protective alleles. These studies will provide mechanistic insight into longitudinal interactions between microglia and local brain pathology, as well as how the CD33 risk variant mediates microglial dysfunction and ultimately AD susceptibility. Importantly, they will also advance our understanding of IIM in human microglia, of which little is known, and the IIM phenotypes they adopt in response to AD pathologies. Their successful conclusion may thus open novel avenues for the development of potential therapeutics to target microglial dysregulation in AD, and to ultimately improve patient outcomes.

项目概要阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是认知能力下降和淀粉样蛋白病理学的积累被认为是一种强大的遗传驱动的先天免疫成分。 AD 中的致病作用，暗示小胶质细胞功能障碍的核心作用。中枢神经系统中的先天免疫细胞的免疫和代谢途径的激活。先天免疫记忆（IIM），一种功能重编程过程，其中对初始刺激的反应持久的表观遗传修饰可能会导致对后续刺激的反应。根据初始炎症的特性增强激活（训练）或抑制（耐受） IIM 刺激已被证明可以改变 AD 小鼠模型的病理学，这是持续改变的结果。几种常见的 AD 风险变异，包括 CD33，共同抑制小胶质细胞的功能。通过减少炎症信号或增加其抑制来激活，因此，我的总体假设是。抑制性 AD 风险基因变异导致小胶质细胞 IIM 的改变是潜在的关键机制更具体地说，我研究了抑制性 CD33 AD 风险。变体将减少细胞激活时发生的表观遗传和代谢重连，损害小胶质细胞 IIM。表观遗传水平上反应性的持续改变可能导致小胶质细胞失败。为了解决这些假设，我建议研究人类的发病机制。小胶质细胞 IIM 对 AD 相关炎症刺激（包括淀粉样蛋白和 tau 蛋白）的反应，以及在目标 1 中，我将研究人类小胶质细胞 IIM 表型。我将测试使用 CRISPR 编辑携带 CD33 AD 风险等位基因的 HMC3s（人类小胶质细胞系）的结果。一系列 AD 相关炎症刺激是否会产生训练有素或耐受的 IIM 反应，以及如何产生 CD33 基因型影响这些结果，在目标 2 中，我将研究表观遗传和代谢机制。携带 CD33 风险或保护性等位基因的 HMC3 中潜在的 IIM 这些研究将提供机制。深入了解小胶质细胞和局部脑病理学之间的纵向相互作用，以及 CD33 风险如何变异介导小胶质细胞功能障碍并最终介导AD易感性，重要的是，它们还将提高我们的水平。了解人类小胶质细胞中的 IIM（人们对此知之甚少）以及它们响应时采取的 IIM 表型因此，他们的成功结论可能为开发潜力开辟新途径。针对 AD 中小胶质细胞失调的治疗方法，并最终改善患者的治疗结果。