Kurmi Shubham, Doshi Gaurav, Parab Siddhi Bagwe
Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle (W), Mumbai, India.
CNS Neurol Disord Drug Targets. 2025 May 21. doi: 10.2174/0118715273377780250505115039.
Alzheimer's disease (AD) is the primary cause of dementia in elderly individuals, characterized by progressive memory loss, cognitive decline, and impaired daily functioning. Pathologically, AD is associated with the accumulation of amyloid-β (Aβ) plaques, tau tangles, mitochondrial dysfunction, and chronic neuroinflammation. The activation of the NOD-like receptor pyrin domain- containing 3 (NLRP3) inflammasome by Aβ clusters triggers microglial activation, leading to a cascade of inflammatory responses. Similarly, tau tangles stimulate neuronal and glial cells, further amplifying NLRP3 activation and perpetuating a cycle of chronic inflammation. Mitochondrial dysfunction exacerbates this process by increasing oxidative stress and inflammasome activation. Additionally, purinergic receptor P2X7 (P2X7R) activation in microglia plays a crucial role in initiating neuroinflammation, making it a potential therapeutic target. Despite extensive research, current AD therapies remain symptomatic rather than disease-modifying. Targeting the NLRP3 inflammasome offers a promising strategy for mitigating AD progression. Various small-molecule inhibitors, monoclonal antibodies, and repurposed drugs have been explored to inhibit NLRP3 activation and its downstream signaling pathways. Preclinical studies suggest that NLRP3 inhibitors effectively reduce Aβ- and tau-induced neuroinflammation while improving mitochondrial function and overall neuronal survival. This review summarizes NLRP3 inflammasome priming, activation, and the therapeutic potential of its inhibitors in AD, highlighting challenges such as tau pathology, biomarker limitations, and treatment optimization. While NLRP3 remains a promising target, most inhibitors are in the early stages with uncertain long-term efficacy and BBB penetration. Future research should explore genetic variability, sex differences, and alternative approaches to enhance neuroprotective strategies.
阿尔茨海默病（AD）是老年人痴呆的主要病因，其特征为进行性记忆丧失、认知衰退及日常功能受损。在病理上，AD与β-淀粉样蛋白（Aβ）斑块的积累、tau缠结、线粒体功能障碍及慢性神经炎症相关。Aβ聚集体激活含NOD样受体吡咯结构域3（NLRP3）炎性小体，触发小胶质细胞活化，导致一系列炎症反应。同样，tau缠结刺激神经元和神经胶质细胞，进一步放大NLRP3激活并使慢性炎症循环持续。线粒体功能障碍通过增加氧化应激和炎性小体激活加剧这一过程。此外，小胶质细胞中嘌呤能受体P2X7（P2X7R）的激活在引发神经炎症中起关键作用，使其成为一个潜在的治疗靶点。尽管进行了广泛研究，但目前的AD疗法仍为对症治疗而非疾病修饰治疗。靶向NLRP3炎性小体为减轻AD进展提供了一种有前景的策略。已探索了各种小分子抑制剂、单克隆抗体及重新利用的药物来抑制NLRP3激活及其下游信号通路。临床前研究表明，NLRP3抑制剂可有效减少Aβ和tau诱导的神经炎症，同时改善线粒体功能和整体神经元存活。本综述总结了NLRP3炎性小体的启动、激活及其抑制剂在AD中的治疗潜力，强调了tau病理学、生物标志物局限性及治疗优化等挑战。虽然NLRP3仍然是一个有前景的靶点，但大多数抑制剂尚处于早期阶段，长期疗效和血脑屏障穿透性不确定。未来研究应探索基因变异性、性别差异及替代方法，以加强神经保护策略。
