神经药理学报2025，Vol.15Issue(5)：16-25,10.DOI:10.3969/j.issn.2095-1396.2025.05.003
内质网应激在阿尔茨海默病中的作用机制及靶向治疗进展
The Research Progress on the Mechanism of Endoplasmic Reticulum Stress in Alzheimer's Disease and the Targeted Therapy for It
摘要
Abstract
Endoplasmic reticulum stress(ERS)regulates the expression and activity of beta-site APP-cleaving enzyme 1(BACE1)at multiple levels including transcription,translation and post-translation by activating the unfolded protein response pathway.This will further alleviate the pathological process of Aβ in Alzheimer's disease.The PERK-eIF2α-ATF4 axis is the key mechanism by which ERS upregulates BACE1.Continuous ERS could prompt PERK to phosphorylate eIF2α,which directly binds to the BACE1 promoter,increasing its transcriptional and protein levels and accelerating amyloid protein production.On the other hand,the IRE1-XBP1s and ATF6 pathways promote the degradation of BACE1 and APP non-amyloidogenic pathway cleavage by upregulating ERAD key factors in early ERS,which has an inhibitory effect on Aβ production.Therefore,the regulation of BACE1 by ERS is bidirectional through the PERK,IRE1 or ATF6 pathways.This article summarized the research progress of the relevant mechanisms,with the aim of seeking new strategies to restore protein homeostasis and slow down the pathological process of AD through intervention targeting ERS.关键词
阿尔茨海默病/内质网应激/BACE1/未折叠蛋白反应Key words
Alzheimer's disease/endoplasmic reticulum stress/beta-site APP-cleaving enzyme 1/unfolded protein response分类
医药卫生引用本文复制引用
张健东,谷泽龙,要祎冉,赵涵菲,王怡,牛丽娇,李炜..内质网应激在阿尔茨海默病中的作用机制及靶向治疗进展[J].神经药理学报,2025,15(5):16-25,10.基金项目
河北省神经损伤与修复重点实验室开放课题(No.NJKF202402) （No.NJKF202402）
河北北方学院面上项目(No.XJ2024021) （No.XJ2024021）
