Cellular response toβ-amyloid neurotoxicity in Alzheimer's disease and implications in new therapeutics  

作　　者：Haolin Zhang Xianghua Li Xiaoli Wang Jiayu Xu Felice Elefant Juan Wang 

机构地区：[1]Faculty of Environment and Life,Beijing University of Technology,Beijing,China [2]Department of Biology,Drexel University,Philadelphia,Pennsylvania,USA

出　　处：《Animal Models and Experimental Medicine》2023年第1期3-9,共7页动物模型与实验医学（英文）

基　　金：National Institute of Neurological Disorders and Stroke,Grant/Award Number:2RF1NS095799;National Natural Science Foundation of China,Grant/Award Number:31970044 and 91854115;Beijing University of Technology Faculty of Environment and Life Seed Funding,Grant/Award Number:049000513202。

摘　　要：β-Amyloid(Aβ)is a specific pathological hallmark of Alzheimer's disease(AD).Because of its neurotoxicity,AD patients exhibit multiple brain dysfunctions.Disease-modifying therapy(DMT)is the central concept in the development of AD thera-peutics today,and most DMT drugs that are currently in clinical trials are anti-Aβdrugs,such as aducanumab and lecanemab.Therefore,understanding Aβ's neurotoxic mechanism is crucial for Aβ-targeted drug development.Despite its total length of only a few dozen amino acids,Aβis incredibly diverse.In addition to the well-known Aβ_(1-42),N-terminally truncated,glutaminyl cyclase(QC)catalyzed,and pyroglutamate-modified Aβ(pEAβ)is also highly amyloidogenic and far more cytotoxic.The extracel-lular monomeric Aβ_(x-42)(x=1-11)initiates the aggregation to form fibrils and plaques and causes many abnormal cellular responses through cell membrane receptors and receptor-coupled signal pathways.These signal cascades further influence many cel-lular metabolism-related processes,such as gene expression,cell cycle,and cell fate,and ultimately cause severe neural cell damage.However,endogenous cellular anti-Aβdefense processes always accompany the Aβ-induced microenvironment alterations.Aβ-cleaving endopeptidases,Aβ-degrading ubiquitin-proteasome system(UPS),and Aβ-engulfing glial cell immune responses are all essential self-defense mechanisms that we can leverage to develop new drugs.This review discusses some of the most recent advances in understanding Aβ-centric AD mechanisms and suggests prospects for promising anti-Aβstrategies.

关 键 词：Alzheimer's disease(AD) astrocytes ENDOPEPTIDASE glutaminyl cyclase(QC) microglia p75 neurotrophin receptor(p75NTR) proteolysis targeting chimeras(PROTACs) β-Amyloid(Aβ) 

分 类 号：R-332[医药卫生]