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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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，以及了解小胶质细胞功能失调的自噬如何导致阿尔茨海默病的发病机制 (AD) 人类遗传和病理学研究的新证据证明了这一点的重要性。 AD 发病机制中的小胶质细胞病理生理学小胶质细胞是常驻的先天免疫细胞。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。研究揭示了小胶质细胞的保护功能，可抑制β-淀粉样蛋白的毒性积累，然而，也有证据表明过度的小胶质细胞激活可以预防疾病进展。可能通过释放炎症因子和吞噬神经元突触来伤害神经元。吞噬 Aβ，斑块的主要成分，是 AD 病理学的标志；研究表明，在 AD 动物模型中，与疾病相关的小胶质细胞 (DAM) 位于斑块上，与此一致 TREM2 作为 DAM 激活的关键调节因子，自噬是溶酶体清除途径。在代谢压力下维持体内平衡和神经保护方面发挥着重要作用。先前对外周免疫细胞的研究表明，神经胶质细胞自噬具有重要作用。然而，小胶质细胞自噬是否在免疫和炎症中发挥这样的作用仍然存在。我们最近分析了 AD 小鼠模型并观察了小胶质细胞的激活。我们还发现 DAM 与自噬活性的强劲增加有关。小胶质细胞自噬失活会导致与 Aβ 瘟疫相关的小胶质细胞数量减少增强了 AD 模型中的神经毒性，其表型模仿了 AD 模型中 Trem2 缺失的影响。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 并保护 AD 大脑中的神经元我们还认为小胶质细胞自噬控制炎症。通过对 AD 具有神经保护作用的蛋白质受体选择性降解炎症小体。目的是 (1) 通过清除吞噬的 Aβ 和确定小胶质细胞自噬在神经保护中的作用 (2) 剖析小胶质细胞自噬机制 (3)确定自噬是TREM2介导的一个组成部分 AD小鼠模型小胶质细胞的神经保护机制。