Determining the neuroprotective mechanism for microglial autophagy in Alzheimer's disease

确定阿尔茨海默病中小胶质细胞自噬的神经保护机制

• 批准号: 10213290
• 负责人: Zhenyu Yue
• 金额: $ 84.36万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10213290
• 关键词: Alleles; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Animal Disease Models; Anti-Inflammatory Agents; Apoptotic; Autophagocytosis; Behavior; Brain; Cell Nucleus; Cells; Disease; Disease Progression; EPHA1 gene; FRAP1 gene; Functional disorder; Genes; Goals; Homeostasis; Human; Human Genetics; Immune; Immune system; Immunity; Immunologic Surveillance; Inflammasome; Inflammation; Inflammatory; Late Onset Alzheimer Disease; Link; Lysosomes; Mediating; Metabolic; Metabolic stress; Microglia; Morphology; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Peripheral; Phenocopy; Play; Prefrontal Cortex; Risk; Role; Surveys; Synapses; TREM2 gene; Testing; Up-Regulation; Variant; abeta accumulation; brain cell; cell type; cytokine; gender difference; genetic risk factor; genetic variant; genome wide association study; insight; metabolic fitness; mouse model; neuroinflammation; neuropathology; neuroprotection; neurotoxicity; new therapeutic target; pathogen; phagocytosis receptor; prevent; receptor; response to injury; single-cell RNA sequencing; transcriptomics

Our central goal is to determine neuroprotective mechanism conferred by microglia and autophagy, and understand how dysfunctional autophagy in microglia contributes to the pathogenesis of Alzheimer's disease (AD). Emerging evidence from human genetic and pathological studies has demonstrated the significance of microglia pathophysiology in the pathogenesis of AD. Microglia are the resident innate immune cells in the brain. The exact role for microglia in AD pathogenesis, however, remains poorly understood. Multiple lines of studies revealed the protective function of microglia that restrain the toxic accumulation of β-amyloid and prevent disease progression. However, evidence also exists suggesting excessive microglial activation can harm the neurons by releasing inflammatory factors and engulfing neuronal synapses. Microglia may phagocytose Aβ, the main component of plaques as a hallmark of AD pathology; single-cell RNAseq analysis showed the disease-associated microglia (DAM), which localizes at plaques in AD animal models, consistent with a role of TREM2 as a critical regulator of DAM activation. Autophagy is a lysosome clearance pathway that plays an important role in maintaining homeostasis under metabolic stress and neuroprotection. Little is known about glial autophagy. Previous studies from peripheral immune cells demonstrate a significant role of autophagy in immunity and inflammation. Whether microglial autophagy plays such a role, however, remains poorly understood. We recently analyzed AD mouse model and observed the activation of microglial autophagy. We found that DAM is associated with a robust increase of autophagic activity. We also showed that inactivation of microglial autophagy causes reduced number of microglia associated with Aβ plagues and enhanced neurotoxicity in AD models, which phenocopied the effect of the loss of Trem2 in AD models. Therefore, our overall hypothesis is that autophagy activation is required for DAM metabolic fitness to degrade Aβ and protect neurons in the AD brains. We also hypothesize that microglial autophagy controls inflammation by selective degradation of inflammasomes via protein receptors that are neuroprotective in AD. Our specific aims are to (1) determine the role for microglial autophagy in neuroprotection by clearing phagocytosed Aβ and maintaining metabolic fitness in AD mouse models; (2) dissect the mechanism of microglial autophagy that controls inflammation in AD mouse model; (3) determine that autophagy is an integral part of TREM2-mediated neuroprotection mechanism in microglia of AD mouse model.

我们的核心目标是确定由小胶质细胞和自噬所赋予的神经保护机制，以及 了解小胶质细胞中功能失调的自噬如何有助于阿尔茨海默氏病的发病机理 （广告）。来自人类遗传和病理研究的新兴证据表明 AD发病机理中的小胶质细胞生理学。小胶质细胞是居民先天免疫细胞 脑。然而，小胶质细胞在AD发病机理中的确切作用仍然鲜为人知。多行 研究表明，小胶质细胞的保护功能限制了β-淀粉样蛋白和 预防疾病进展。但是，也存在证据表明过量的小胶质激活可以 通过释放炎症因子和吞噬神经元突触来伤害神经元。小胶质细胞可能 吞噬细胞Aβ，斑块的主要成分是AD病理的标志；单细胞RNASEQ分析 显示了与疾病相关的小胶质细胞（DAM），该小胶质细胞（DAM）位于AD动物模型中的斑块上 以TREM2作为大坝激活的关键调节剂的作用。自噬是一种溶因体间隙途径 这在维持代谢压力和神经保护作用下保持体内稳态方面起着重要作用。几乎没有 关于神经胶质自噬的知名度。外周免疫细胞的先前研究表明 免疫和炎症自噬。然而，小胶质体的自噬是否扮演着这样的角色 理解不佳。我们最近分析了AD小鼠模型并观察到小胶质细胞的激活 自噬。我们发现大坝与自噬活性的强大增加有关。我们也表明 小胶质体自噬的失活导致与Aβ瘟疫相关的小胶质细胞数量减少 AD模型中的神经毒性增强了，这表现了AD模型中TREM2丢失的影响。 因此，我们的总体假设是大坝代谢适应性需要自噬激活才能降解 Aβ并保护广告大脑中的神经元。我们还假设小胶质体自噬控制注射 通过在AD中具有神经保护性的蛋白质受体的选择性降解。我们的具体 目的是（1）通过清除吞噬细胞Aβ和 在AD小鼠模型中保持代谢适应性； （2）剖析小胶质体自噬的机理 控制AD鼠标模型中的注射； （3）确定自噬是trem2介导的组成部分 AD小鼠模型小胶质细胞中的神经保护机制。