受体相互作用蛋白激酶1介导的细胞程序性坏死与阿尔茨海默病

Necroptosis mediated by receptor-interacting serine/threonine-protein kinase 1 and Alzheimer's disease

阿尔茨海默病(Alzheimer''s disease, AD)是一种难治型神经退行性疾病, 临床表现为记忆丧失、认知及行为功能障碍。AD主要病理特征包括神经元丢失、β-淀粉样蛋白(β-amyloid protein, Aβ)沉积和tau蛋白诱导的过度磷酸化神经原纤维缠结(neurofibrillary tangles, NFTs)。研究证明这些病理改变可能由神经元死亡和神经炎性反应所触发。受体相互作用蛋白激酶1(receptor-interacting serine/threonine-protein kinase 1, RIPK1)是一种存在于细胞死亡和炎性反应信号通路交叉点的丝氨酸/苏氨酸(serine / threonine, Ser/Thr)激酶, 近几年研究揭示RIPK1在AD进展中发挥重要作用。本文将主要从神经元死亡、炎性小体激活、血脑屏障破裂和线粒体功能障碍等方面综述RIPK1介导的细胞程序性坏死与AD之间的联系, 并对靶向RIPK1的AD治疗方法、RIPK1抑制剂的新发现以及正在进行的临床试验进行归纳总结, 旨在为AD的治疗提供新思路。

Alzheimer's disease(AD)is a refractory neurodegenerative disease clinically characterized by memory loss and cognitive and behavioral dysfunction.The main pathological features of AD include neuronal loss,β-amyloid protein(Aβ)deposition and neurofibrillary tangles(NFTs),and numerous studies have shown that these may be triggered by neuronal death and neuroinflammation Receptor-interacting serine/threonine-protein kinase 1(RIPK1)is a serine/threonine kinase present at the intersection of cell death and inflammatory signaling pathways.Studies in recent years have revealed a potential role of RIPK1 on the progress of AD.In this paper,we summarized the links between RIPK1-mediated necroptosis and AD treatment from the aspects of neuronal death,inflammasome activation,blood-brain barrier breakdown and mitochondrial dysfunction,and the targeted treatment of RIPK1,the new findings of RIPK1 inhibitors and ongoing clinical trials,aiming to provide new ideas for the treatment of AD.