线粒体自噬、铁死亡、铜死亡和双硫死亡在阿尔茨海默病中的作用机制及进展

Mechanism of action and progress of mitophagy,ferroptosis,cuproptosis,and disulfidptosis in Alzheimer’s disease

背景:近年来,随着对细胞程序性死亡的深入研究,阿尔茨海默病损伤涉及的新型程序性死亡模型(线粒体自噬、铁死亡、铜死亡及双硫死亡)正逐渐兴起并且未来具有较大研究空间。目的:对新型程序性细胞死亡模式(线粒体自噬、铁死亡、铜死亡和双硫死亡)的分子机制、新型细胞死亡模式的串扰机制、临床转化等在阿尔茨海默病的研究进展进行综述,为探索新型细胞死亡模式在阿尔茨海默病中的作用机制和药物靶点提供新视角。方法:由第一作者应用计算机检索1991-2024年中国知网和PubMed数据库收录的文献,最终纳入101篇文章进行综述分析。结果与结论:①细胞程序性死亡作为维持细胞正常更新和内环境稳态的必要调节途径,其中线粒体自噬、铁死亡、铜死亡和双硫死亡等新型细胞程序性死亡是目前生命科学的热门研究领域。②线粒体自噬能够清除阿尔茨海默病神经元中受损线粒体,降低细胞内活性氧,恢复阿尔茨海默病中神经元细胞的能量代谢和信号转导,在调控神经元健康和功能中起着至关重要的作用。③铁死亡在阿尔茨海默病中的研究备受关注,能够通过胱氨酸/谷氨酸、铁代谢及多不饱和脂肪酸等多种途径调控阿尔茨海默病,从而影响Aβ沉积及Tau蛋白磷酸化,近期研究显示天然多酚、酸枣仁汤、茯苓酸和维生素E等可在阿尔茨海默病中抑制铁死亡。④铜死亡是涉及铜的依赖、脂酰化蛋白的积累以及铁硫簇蛋白减少的一种新型独特细胞死亡形式,其过量铜暴露可能会直接与Aβ斑块和淀粉样蛋白前体蛋白相互作用,加重阿尔茨海默病的认知障碍,目前铜死亡研究领域正兴起,作用机制尚未完全阐明。⑤双硫死亡作为一种新兴细胞程序死亡形式,由胱氨酸过量积累以及葡萄糖饥饿引起二硫化物应激,导致对与阿尔茨海默病有关的肌动蛋白骨架受损。⑥各类细胞程序性死亡模式在阿尔茨海默病发病机制中存在串联机制,形成了以自噬为核心的各类程序性死亡的相互作用网络,为多层次、多靶点调控阿尔茨海默病提供了巨大潜力,“自噬-坏死性凋亡-焦亡/铁死亡”之间的串扰网络机制共同调控阿尔茨海默病。⑦铜死亡和双硫死亡作为一种新的程序性死亡方式,目前在阿尔茨海默病中报导不够深入,未来仍然需要进一步的研究及持续关注。⑧由于线粒体自噬、铁死亡、铜死亡和双硫死亡大多数研究都基于基础实验或生物信息学分析,缺乏大规模及长期的临床研究验证,未来需进一步深入探讨,以期为治疗阿尔茨海默病提供新思路和有效策略。

BACKGROUND:In recent years,with the in-depth study of programmed cell death,new models of programmed cell death(mitophagy,ferroptosis,cuproptosis,and disulfidptosis)involved in Alzheimer’s disease injury are gradually emerging and have large research space in the future.OBJECTIVE:To review the molecular mechanism of novel programmed cell death mode(mitophagy,ferroptosis,cuproptosis,and disulfidptosis),the crosstalk mechanism of novel cell death mode,and clinical transformation in Alzheimer’s disease,aiming to provide a new perspective for exploring the mechanism of action and drug targets in Alzheimer’s disease.METHODS:The first author used the computer to search the literature published between 1991 and 2024.101 articles were finally included according to the inclusion criteria.RESULTS AND CONCLUSION:(1)Programmed cell death is a necessary regulatory pathway to maintain normal cell renewal and homeostasis.Among them,new types of programmed cell death such as mitophagy,ferroptosis,cuproptosis,and disulfidptosis are hot research fields in life science.(2)Mitophagy can clear damaged mitochondria in Alzheimer’s disease neurons,reduce intracellular reactive oxygen species,restore the energy metabolism and signal transduction of neurons in Alzheimer’s disease,and play a crucial role in regulating the health and function of neurons.(3)Studies on ferroptosis in Alzheimer’s disease have attracted much attention.It can regulate Alzheimer’s disease through various ways such as cystine/glutamate,iron metabolism,and polyunsaturated fatty acids,thus affecting Aβ deposition and Tau protein phosphorylation.Recent studies have shown that natural polyphenols,Suanzoren decoction,poria acid,and vitamin E can resist ferroptosis in Alzheimer’s disease.(4)Cuproptosis is a new and unique form of cell death involving copper dependence,accumulation of fatty acylated proteins,and reduction of iron-sulfur tufting proteins.Excessive copper exposure may directly interact with Aβ plaques and amyloid precursor proteins,exacerbating cognitive impairment in Alzheimer’s disease.Currently,the research field of cuproptosis is emerging,and the mechanism of action has not been fully clarified.(5)Disulfidptosis,as an emerging form of programmed cell death,is caused by disulfide stress due to excessive cystine accumulation and glucose starvation,resulting in damage to the actin skeleton associated with Alzheimer’s disease.(6)Various patterns of programmed cell death have a tandem mechanism in the pathogenesis of Alzheimer’s disease,forming an interaction network of various programmed cell death with autophagy as the core,providing great potential for multi-level and multi-target regulation of Alzheimer’s disease.The crosstalk network mechanism between autophagy,necroptosis,and pyroptosis/ferroptosis co-regulates Alzheimer’s disease.(7)Cuproptosis and disulfidptosis,as a new mode of programmed death,have not been reported deeply enough in Alzheimer’s disease,and further research and continuous attentions are still needed in the future.(8)Since most studies on mitophagy,ferroptosis,cuproptosis,and disulfidptosis are based on basic experiments or biogenic analysis,there is a lack of large-scale and long-term clinical research validation.Further in-depth studies are needed in the future to provide new ideas and effective strategies for the treatment of Alzheimer’s disease.