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 （公元）。来自人类遗传和病理学研究的新证据证明了 AD 发病机制中的小胶质细胞病理生理学。小胶质细胞是体内常驻的先天免疫细胞 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，可抑制β-淀粉样蛋白的毒性积累， 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 Aβ，斑块的主要成分，是 AD 病理学的标志；单细胞RNA测序分析 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 的作用是 DAM 激活的关键调节因子。自噬是一种溶酶体清除途径 这在代谢应激和神经保护下维持体内平衡发挥着重要作用。小的是 了解神经胶质细胞自噬。先前的外周免疫细胞研究表明， 免疫和炎症中的自噬。然而，小胶质细胞自噬是否发挥这样的作用仍然存在 不太了解。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 DAM 与自噬活性的强劲增加有关。我们还展示了 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。我们还假设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。我们的具体 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 维持 AD 小鼠模型的代谢健康； (2) 剖析小胶质细胞自噬的机制 控制 AD 小鼠模型的炎症； (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。

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.