Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, United States.
Front Immunol. 2020 Apr 23;11:724. doi: 10.3389/fimmu.2020.00724. eCollection 2020.
Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.
淀粉样斑块主要由脑实质中异常聚集的淀粉样 β 蛋白（Aβ）组成，神经原纤维缠结（NFTs）由神经元中过度磷酸化的tau 蛋白聚集组成，是阿尔茨海默病（AD）的两种病理标志物。大脑中的 Aβ 纤维和 tau 聚集物与神经炎症和突触丧失密切相关，其特征是小胶质细胞激活和树突变形。全基因组遗传关联研究通过识别十几个调节固有免疫活性的遗传风险位点，揭示了固有免疫细胞在晚发性 AD 发病机制中的重要作用。此外，脑内固有免疫细胞小胶质细胞，通过清除毒性 Aβ 聚集物和增强神经元可塑性或产生促炎细胞因子、活性氧和突触毒性，在 AD 发病机制中发挥关键的、相反的作用，越来越受到重视。聚集的 Aβ 与 Toll 样受体 4（TLR4）结合并激活小胶质细胞，导致吞噬作用和细胞因子产生增加。补体成分与淀粉样斑块和 NFTs 相关。聚集的 Aβ 可以激活补体，导致通过小胶质细胞吞噬作用进行突触修剪和丧失。全身炎症可以激活小胶质细胞 TLR4、NLRP3 炎性小体和脑内补体，导致神经炎症、Aβ 积累、突触丧失和神经退行性变。宿主免疫反应已被证明通过 TLR、补体和炎性小体信号通路之间的复杂串扰发挥作用。因此，针对 TLR-补体-NLRP3 炎性小体信号通路的分子机制可能是预防和治疗 AD 的一种方法。
