Xu Yi-Jun, Au Ngan Pan Bennett, Ma Chi Him Eddie
Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
Front Aging Neurosci. 2022 May 26;14:896852. doi: 10.3389/fnagi.2022.896852. eCollection 2022.
Alzheimer's disease (AD) is a progressive neurodegenerative disease and is closely associated with the accumulation of β-amyloid (Aβ) and neurofibrillary tangles (NFTs). Apart from Aβ and NFT pathologies, AD patients also exhibit a widespread microglial activation in various brain regions with elevated production of pro-inflammatory cytokines, a phenomenon known as neuroinflammation. In healthy central nervous system, microglia adopt ramified, "surveying" phenotype with compact cell bodies and elongated processes. In AD, the presence of pathogenic proteins such as extracellular Aβ plaques and hyperphosphorylated tau, induce the transformation of ramified microglia into amoeboid microglia. Ameboid microglia are highly phagocytic immune cells and actively secrete a cascade of pro-inflammatory cytokines and chemokines. However, the phagocytic ability of microglia gradually declines with age, and thus the clearance of pathogenic proteins becomes highly ineffective, leading to the accumulation of Aβ plaques and hyperphosphorylated tau in the aging brain. The accumulation of pathogenic proteins further augments the neuroinflammatory responses and sustains the activation of microglia. The excessive production of pro-inflammatory cytokines induces a massive loss of functional synapses and neurons, further worsening the disease condition of AD. More recently, the identification of a subset of microglia by transcriptomic studies, namely disease-associated microglia (DAM), the progressive transition from homeostatic microglia to DAM is TREM2-dependent and the homeostatic microglia gradually acquire the state of DAM during the disease progression of AD. Recent in-depth transcriptomic analysis identifies ApoE and Trem2 from microglia as the major risk factors for AD pathogenesis. In this review, we summarize current understandings of the functional roles of age-dependent microglial activation and neuroinflammation in the pathogenesis of AD. To this end, the exponential growth in transcriptomic data provides a solid foundation for drug screening and gains further insight into the development of microglia-based therapeutic interventions for AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，与β-淀粉样蛋白（Aβ）的积累和神经原纤维缠结（NFTs）密切相关。除了Aβ和NFT病理改变外，AD患者在各个脑区还表现出广泛的小胶质细胞激活，促炎细胞因子的产生增加，这一现象被称为神经炎症。在健康的中枢神经系统中，小胶质细胞呈现出具有紧密细胞体和细长突起的分支状“监测”表型。在AD中，诸如细胞外Aβ斑块和过度磷酸化的tau等致病蛋白的存在，诱导分支状小胶质细胞转变为阿米巴样小胶质细胞。阿米巴样小胶质细胞是高度吞噬性的免疫细胞，并积极分泌一系列促炎细胞因子和趋化因子。然而，小胶质细胞的吞噬能力会随着年龄的增长而逐渐下降，因此致病蛋白的清除变得非常低效，导致衰老大脑中Aβ斑块和过度磷酸化的tau积累。致病蛋白的积累进一步增强了神经炎症反应，并维持小胶质细胞的激活。促炎细胞因子的过度产生导致功能性突触和神经元大量丢失，进一步恶化了AD的病情。最近，通过转录组学研究鉴定出了一小部分小胶质细胞，即疾病相关小胶质细胞（DAM），从稳态小胶质细胞向DAM的渐进性转变是TREM2依赖性的，并且在AD的疾病进展过程中，稳态小胶质细胞逐渐获得DAM状态。最近的深入转录组学分析确定小胶质细胞中的载脂蛋白E（ApoE）和触发受体表达于髓样细胞2（Trem2）是AD发病机制的主要危险因素。在这篇综述中，我们总结了目前对年龄依赖性小胶质细胞激活和神经炎症在AD发病机制中的功能作用的认识。为此，转录组学数据的指数增长为药物筛选提供了坚实的基础，并进一步深入了解基于小胶质细胞的AD治疗干预措施的开发。
