核苷酸结合寡聚化结构域样受体3炎症小体：阿尔茨海默病发病机制与靶向治疗

Nucleotide-Binding Oligomerization Domain-Like Receptor 3 Inflammatory Corpuscles: Pathogenesis and Targeted Therapy of Alzheimer’s Disease

摘要: 作为固有免疫应答的重要效应器，核苷酸结合寡聚化结构域样受体含pyrin结构域蛋白3 (Nucleotide-binding oligomerization domain-like receptor protein 3, NLRP3)炎症小体通过感知病原相关分子模式和损伤相关分子模式等危险信号分子，在神经炎症调控网络中发挥核心作用。阿尔茨海默病(Alzheimer’s disease, AD)主要病理特征表现为β淀粉样蛋白(Amyloid beta peptide, Aβ)在细胞外沉积所形成的老年斑及过度磷酸化的tau蛋白在神经元聚集形成的神经纤维缠结这两种病理性蛋白异常聚集可诱导细胞内NLRP3炎症小体的构象变化与功能激活。活化的炎症复合体通过caspase-1通路促进炎症因子的分泌，这种级联反应与AD典型病理改变形成正反馈调节环路，加速神经退行性进程。生理状态下存在精细的神经炎症调节网络，但在AD中这些调控往往出现功能障碍，导致神经免疫稳态失衡。针对NLRP3炎症小体的靶向治疗为AD病因学干预提供了新方向，包括人工合成拮抗剂、药物靶向重构和天然成分等。本文综述NLRP3结构及激活，并探索与AD病理蛋白相关性，旨在为AD治疗提供理论依据。

Abstract: As an important effector of innate immune response, nucleotide-binding oligomerization domain-like receptor containing pyrin domain-like receptor protein 3 (NLRP3) inflammatory corpuscles play a core role in the neuroinflammatory regulatory network by sensing dangerous signal molecules such as pathogen-related molecular patterns and injury-related molecular patterns. The main pathological feature of Alzheimer’s disease (AD) is that the abnormal aggregation of senile plaques formed by extracellular deposition of amyloid β-protein (Aβ) and neurofibrillary tangles formed by hyperphosphorylated tau protein in neurons can induce the conformational changes and functional activation of NLRP3 inflammatory corpuscles in cells. The activated inflammatory complex promotes the secretion of inflammatory factors through caspase-1 pathway, and this cascade reaction forms a positive feedback regulation loop with typical pathological changes of AD, which accelerates the process of neurodegeneration. There are fine neuroinflammatory regulatory networks in physiological state, but in AD, these regulatory networks often appear dysfunction, which leads to the imbalance of neuroimmune homeostasis. Targeted therapy for NLRP3 inflammatory corpuscles provides a new direction for AD etiological intervention, including synthetic antagonists, drug targeted reconstruction and natural components. In this paper, the structure and activation of NLRP3 are reviewed, and the correlation between NLRP 3 and pathological proteins of AD is explored, so as to provide theoretical basis for the treatment of AD.