抑制NLRP3炎症小体激活通路治疗阿尔茨海默病的研究进展

Research Progress on Inhibiting the NLRP3 Inflammasome Activation Pathway in the Treatment of Alzheimer’s Disease

摘要: 阿尔茨海默病(Alzheimer’s Disease, AD)是一种隐匿性起病、慢性进行性发展的神经退行性疾病，被认为是老年人失能的主要原因之一。AD发病机制复杂，目前仅有几种药物被批准用于临床治疗，且作用机制较为单一，因此，寻找新的治疗靶点亟不可待。最新研究表明神经炎症反应在AD的发病机制中具有重要作用，神经炎症是中枢神经系统中由胶质细胞激活的免疫应答，通常在神经损伤、感染和毒素等刺激下或在自身免疫作用下出现，随后激活小胶质细胞，并伴随着Aβ沉积的出现，在AD晚期，Aβ清除率下降，结合tau蛋白聚集，会破坏小胶质细胞的防御能力。其中，核苷酸结合寡聚化结构域样受体蛋白3 (NLRP3)炎症小体信号转导通路的激活是关键环节，不但会增加大脑神经炎症反应，而且还会干预小胶质细胞极化、β淀粉样蛋白(β amyloid protein, Aβ)沉积、微管相关蛋白(Tau蛋白)磷酸化、细胞自噬以及大脑内稳态等。本文以NLRP3为关键点，总结近年来针对AD发病机制的上下游信号通路、靶点作用方式、相关的治疗药物研发进展以及防治AD的最新研究成果。

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease with insidious onset and chronic progressive development. It is considered to be one of the main causes of disability in the elderly. The pathogenesis of AD is complex. Currently, only a few drugs have been approved for clinical treatment, and their mechanisms of action are relatively simple. Therefore, it is urgent to find new therapeutic targets. The latest studies have shown that neuroinflammatory response plays an important role in the pathogenesis of AD. Neuroinflammation is an immune response activated by glial cells in the central nervous system. It usually occurs under stimulation such as nerve damage, infection and toxins, or under autoimmunity. It then activates microglia and is accompanied by the appearance of Aβ deposition. In the late stage of AD, the clearance rate of Aβ decreases, combined with tau protein aggregation, which will destroy the defense ability of microglia. Among them, the activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome signal transduction pathway is a key link, which not only increases the brain’s neuroinflammatory response, but also interferes with microglial polarization, β-amyloid protein (Aβ) deposition, microtubule-associated protein (Tau protein) phosphorylation, cell autophagy, and brain homeostasis. This article takes NLRP3 as the key point to summarize the upstream and downstream signaling pathways, target action modes, related therapeutic drug development progress, and the latest research results on the prevention and treatment of AD in recent years.