早老素与阿尔茨海默病:钙信号通路机制  

Presenilin and Alzheimer's disease:calcium signaling pathway

作　　者：郝晓丽 刘慧[1] 沈璐[1,2] 焦彬 Hao Xiaoli;Liu Hui;Shen Lu;Jiao Bin(Department of Neurology,Xiangya Hospital of Central South University,Changsha 410008,China;National Clinical Research Center for Geriatric Diseases(Xiangya Hospital),Changsha 410000,China)

机构地区：[1]中南大学湘雅医院神经内科,长沙410008 [2]国家老年疾病临床医学研究中心(湘雅医院),长沙410000

出　　处：《中华行为医学与脑科学杂志》2021年第6期566-571,共6页Chinese Journal of Behavioral Medicine and Brain Science

基　　金：国家自然科学基金项目(82071216)。

摘　　要：早老素(presenilin,PS)基因是家族性阿尔茨海默病(Alzheimer's disease,AD)的主要致病基因。PS基因突变可以促使淀粉样前体蛋白(amyloid precursor protein,APP)加工成有毒形式的β淀粉样蛋白(amyloid beta protein,Aβ),在AD发病机制中发挥重要作用。然而,目前针对Aβ的靶向治疗对AD尚未能产生良好的效果,这表明可能存在其他的致病机制。近年来,钙稳态异常及其在AD中的病理作用引起了人们的关注。钙信号通路受PS的调节,PS基因突变的神经元中钙调节受损,导致其处理氧化应激的能力降低,从而导致细胞死亡促进AD的发生。PS基因突变引起内质网钙含量的部分耗尽也会导致自噬功能受损。此外,最近的研究表明PS基因突变导致的Ca2+稳态失衡会引起线粒体代谢受损及大脑网络活动缺陷。本文以钙信号通路为中心,从自噬受损、内质网应激、线粒体功能障碍、细胞凋亡及大脑网络活动缺陷等方面综述PS通过调节钙信号参与AD的致病机制,为AD的病因学研究及药物靶点的发现提供思路。Presenilin(PS)is the main pathogenic gene of familial Alzheimer's disease(AD).Mutations of PS gene can promote the processing of amyloid precursor protein(APP)into a toxic form of amyloid beta protein(Aβ),which plays an important role in the pathogenesis of AD.However,the current targeted therapy for Aβhas not yet produced a good effect on AD,suggesting the existence of additional pathogenic mechanisms.In recent years,the abnormal calcium homeostasis and its pathological role in AD have attracted people's attention.The calcium signaling pathway is regulated by presenilin.And the calcium regulation of PS gene mutant neurons is impaired,resulting in reduced ability to deal with oxidative stress,which leads to cell death and promotes the occurrence of AD.In addition,damage to neuronal autophagy induced by PS gene mutations also depends on the ability to partially deplete endoplasmic reticulum calcium content.Recent studies have shown that abnormal Ca2+homeostasis caused by PS gene mutations can lead to impaired mitochondrial metabolism and defects in brain network activity.This review will focus on the calcium signaling pathway,and explore the pathogenesis of presenilin in AD through the regulation of calcium signals from the perspectives of impaired autophagy,endoplasmic reticulum stress,mitochondrial dysfunction,apoptosis and defects in brain network activity,so as to provide ideas for the etiology of AD and the discovery of drug targets.

关 键 词：阿尔茨海默病 早老素 钙信号 自噬 内质网应激 线粒体功能障碍 凋亡 大脑网络活动 

分 类 号：R749.16[医药卫生—神经病学与精神病学]