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

• 批准号: 10314478
• 负责人: Zena Chatila
• 金额: $ 4.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10314478
• 关键词: Acetyl Coenzyme A; Address; Adopted; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Anti-Inflammatory Agents; Area; Automobile Driving; Brain; Brain Pathology; Cell Death; Cell Line; Cells; 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; 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; Neuraxis; 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; XCL1 gene; age related neurodegeneration; alpha ketoglutarate; amyloid pathology; base; cytokine; established cell line; genetic variant; genome editing; genome sequencing; 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

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.

项目摘要 阿尔茨海默氏病（AD）是一种与年龄有关的神经退行性疾病，其特征是认知能力下降和 淀粉样病理的积累。人们认为强大的遗传驱动的先天免疫组件可以发挥作用 在AD中的致病作用，隐含小胶质功能障碍的核心作用。小胶质细胞是长寿的居民 中枢神经系统中的先天免疫细胞。其免疫和代谢途径的激活导致 先天免疫记忆（IIM），一个功能重编程过程，其中对初始刺激的响应 塑造长期的表观遗传修饰，为对随后的刺激的反应提供了依据。 IIM可能会导致 根据初始炎症的身份增强激活（训练）或抑制（公差） 刺激。由于持续变化，IIM已被证明会改变AD鼠标模型中的病理 在小胶质功能中。包括CD33在内的几种常见的AD风险变体会收敛以抑制小胶质细胞 激活，通过减少炎症信号传导或增加其抑制作用。根据我的整体假设 是由于抑制性遗传AD风险变体而改变的小胶质细胞IIM是一种关键机制 AD中观察到的小胶质细胞功能障碍。更具体地说，我假设抑制CD33广告风险 变体将减少细胞激活时发生的表观遗传和代谢重新布线，损害小胶质细胞 IIM。这种表观遗传水平的反应性的持续变化可能导致小胶质失败作为一个 AD中的致病机制。为了解决这些假设，我提议检查人类的机制 小胶质IIM响应AD相关的炎症刺激，包括淀粉样蛋白和TAU，以及 CD33在这个印迹过程中的风险变体。在AIM 1中，我将研究人类小胶质IIM表型 用CRISPR编辑的HMC3S（人类小胶质细胞系）的结果携带CD33 AD风险等位基因。我会测试 一系列与广告相关的炎症刺激是否产生了经过训练或耐受的IIM反应，以及如何产生 CD33基因型会影响这些结果。在AIM 2中，我将研究表观遗传和代谢机制 携带CD33风险或保护等位基因的HMC3中的IIM的基础IIM。这些研究将提供机械 深入了解小胶质细胞与局部脑病理学之间的纵向相互作用，以及CD33的风险如何 变体介导小胶质功能障碍并最终导致AD敏感性。重要的是，他们还将推动我们的 对人类小胶质细胞中的IIM的了解，其中知之甚少，以及他们为回应所采用的IIM表型 进行广告病理。因此，他们成功的结论可能为发展潜力开辟了新的途径 靶向AD中小胶质失调的疗法，并最终改善患者预后。