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: 10581646
• 负责人: Zhenyu Yue
• 金额: $ 84.22万
• 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/10581646
• 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; Disease associated microglia; EPHA1 gene; FRAP1 gene; Functional disorder; Genes; Gliosis; 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; glial activation; insight; metabolic fitness; mouse model; neuroinflammation; neuropathology; neuroprotection; neurotoxicity; new therapeutic target; pathogen; phagocytosis receptor; prevent; receptor; response to injury; restraint; 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.

我们的中心目标是确定小胶质细胞和自噬赋予的神经保护机制， 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病的发病机制 （AD）。来自人类遗传学和病理学研究的新证据表明， 小胶质细胞在AD发病机制中的作用小胶质细胞是机体内的固有免疫细胞， 个脑袋然而，小胶质细胞在AD发病机制中的确切作用仍然知之甚少。多行 研究揭示了小胶质细胞的保护功能，其抑制β-淀粉样蛋白的毒性积累， 预防疾病进展。然而，也有证据表明，过度的小胶质细胞活化可以 通过释放炎性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Aβ，斑块的主要成分，作为AD病理学的标志;单细胞RNAseq分析 显示疾病相关的小胶质细胞（DAM），其位于AD动物模型中的斑块处，与 TREM 2作为DAM活化的关键调节剂的作用。自噬是一种溶酶体清除途径 在代谢应激下维持体内平衡和神经保护中起重要作用。之甚少 了解神经胶质细胞自噬。以前对外周免疫细胞的研究表明， 免疫和炎症中的自噬。然而，小胶质细胞自噬是否起着这样的作用， 不太了解。我们最近分析了AD小鼠模型，观察了小胶质细胞的激活， 自噬我们发现DAM与自噬活性的强烈增加有关。我们还展示 小胶质细胞自噬失活导致与Aβ斑块相关的小胶质细胞数量减少， 增强AD模型中的神经毒性，其表型模拟了AD模型中Trem 2损失的作用。 因此，我们的总体假设是，自噬激活是DAM代谢适应性降低所必需的 Aβ和保护AD脑中的神经元。我们还假设小胶质细胞自噬控制炎症 通过在AD中具有神经保护作用的蛋白质受体选择性降解炎性小体。我们的具体 目的是（1）确定小胶质细胞自噬通过清除吞噬的Aβ在神经保护中的作用， 维持AD小鼠模型的代谢适应性;（2）剖析小胶质细胞自噬的机制， 控制AD小鼠模型中的炎症;（3）确定自噬是TREM 2介导的炎症的组成部分。 AD小鼠模型小胶质细胞的神经保护机制