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

我们的中心目标是确定小胶质细胞和自噬所赋予的神经保护机制，以及 了解小胶质细胞功能障碍自噬如何在阿尔茨海默病的发病机制中起作用 (Ad)。来自人类遗传学和病理学研究的新证据表明， 小胶质细胞病理生理学在阿尔茨海默病发病中的作用小胶质细胞是脑内固有的免疫细胞。 大脑。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，抑制了β-淀粉样蛋白和 防止疾病进展。然而，也有证据表明，过度的小胶质细胞激活可能 通过释放炎症因子和吞噬神经元突触来损害神经元。小胶质细胞可能 吞噬细胞β，斑块的主要成分，是AD病理的标志；单细胞RNA序列分析 结果显示，在AD动物模型中定位于斑块的疾病相关小胶质细胞(DAM)与 TREM2作为大坝激活的关键调节因子发挥作用。自噬是一种溶酶体清除途径 这在维持代谢应激状态下的动态平衡和神经保护方面起着重要作用。小才是 已知神经胶质细胞自噬。先前来自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发挥了这样的作用仍然存在。 人们对此知之甚少。我们最近对AD小鼠模型进行了分析，观察了小胶质细胞的激活情况 自噬。我们发现，水坝与自噬活动的强劲增长有关。我们还展示了 小胶质细胞自噬的失活导致与Aβ瘟疫和 增强AD模型的神经毒性，表现为TREM2缺失在AD模型中的作用。 因此，我们的总体假设是，自噬激活是dam代谢适应性降级所必需的。 Aβ和保护AD大脑中的神经元。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地降解炎性小体。我们的特定 目的是(1)通过清除吞噬的Aβ和 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小鼠模型的炎症反应；(3)确定自噬是TREM2介导的一个组成部分 阿尔茨海默病模型小胶质细胞的神经保护机制。

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.