NLRP3炎症小体在阿尔兹海默症中的作用及潜在治疗靶点

The Role of NLRP3 Inflammasome in Alzheimer’s Disease andPotential Therapeutic Targets

阿尔兹海默症(Alzheimer’s disease,AD)是常见的神经退行性疾病,严重影响患者的生存质量。目前尚无有效的针对性治疗措施。AD发病机制复杂,是环境、遗传和年龄影响因素共同作用的结果。大脑中β-淀粉样蛋白(β-amyloid,Aβ)沉积、微管相关蛋白tau过度磷酸化形成的神经纤维缠结及神经元丢失是AD典型病理特征,大量研究证明,Aβ、tau蛋白聚集诱导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 pyrin domain-containing 3,NLRP3)炎症小体活化是AD炎性机制的核心环节,且以其和上下游分子为靶点的抑制剂和化合物治疗在细胞和动物模型中均发挥神经保护作用,改善空间记忆功能障碍,但临床疗效和安全性仍待研究。因此,抑制NLRP3炎症小体的活化可能是AD的潜在治疗靶点。本文以NLRP3炎症小体的活化机制和影响因素及与AD关系进行综述,并总结以NLRP3炎症小体为靶点的AD治疗药物,以期为AD等NLRP3炎症小体相关疾病提供新的治疗方向。

Alzheimer’s disease is a common neurodegenerative disease that seriously affects the quality of life of patients.At present,there is no effective targeted treatment.The pathogenesis of AD is complex and results from the combined effects of environmental,genetic and age factors.The typical pathological features of AD are the deposition ofβ-amyloid(Aβ),neurofibrillary tangles formed by hyperphosphorylation of microtubule-associated protein tau,and neuronal loss.A large number of studies have demonstrated that the aggregation of Aβand tau proteins induces nucleotide-binding oligomerization domain-like receptors containing Pyrin-domain protein-3(NLRP3)inflammasome activation,which is the core of the inflammatory mechanism of AD.Moreover,inhibitors and compounds targeting NLRP3 inflammasome and its upstream and downstream molecules can play a neuroprotective role in cells and animal models and improve spatial memory dysfunction,but clinical efficacy and safety remain to be studied.Therefore,inhibition of NLRP3 inflammasome activation may be a potential therapeutic target for AD.In this paper,the activation mechanism and influencing factors of NLRP3 inflammasome as well as its relationship with AD are reviewed,and the therapeutic drugs targeting NLRP3 inflammasome for AD are summarized in order to provide a new direction for NLRP3 inflammasome related diseases such as AD.