The age-dependent deposition of amyloid-beta peptides, derived from amyloid precursor protein (APP), is a neuropathological hallmark of Alzheimer's disease (AD). Despite age being the greatest risk factor for AD, the molecular mechanisms linking ageing to APP processing are unknown. Here we show that asparagine endopeptidase (AEP), a pH-controlled cysteine proteinase, is activated during ageing and mediates APP proteolytic processing. AEP cleaves APP at N373 and N585 residues, selectively influencing the amyloidogenic fragmentation of APP. AEP is activated in normal mice in an age-dependent manner, and is strongly activated in 5XFAD transgenic mouse model and human AD brains. Deletion of AEP from 5XFAD or APP/PS1 mice decreases senile plaque formation, ameliorates synapse loss, elevates long-term potentiation and protects memory. Blockade of APP cleavage by AEP in mice alleviates pathological and behavioural deficits. Thus, AEP acts as a delta-secretase, contributing to the age-dependent pathogenic mechanisms in AD.
基金：
NIH [NS045627, 060680]; ADRC Center Grant [NIH/NIAP50 AG025688]; National Natural Science Foundation of China [81100958, 81571249]; National Key Basic Research Program of China [2010CB945202]; National Science Foundation of China [81330030]
第一作者单位：[1]Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA[2]Wuhan Univ, Renmin Hosp, Dept Neurol, Wuhan 430060, Peoples R China
通讯作者：
通讯机构：[7]Tongji Univ, Tongji Hosp, Dept Regenerat Med, Translat Ctr Stem Cell Res,Sch Med, Shanghai 200065, Peoples R China[8]Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA
推荐引用方式(GB/T 7714)：
Zhang Zhentao,Song Mingke,Liu Xia,et al.Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease[J].NATURE COMMUNICATIONS.2015,6:doi:10.1038/ncomms9762.
APA：
Zhang, Zhentao,Song, Mingke,Liu, Xia,Kang, Seong Su,Duong, Duc M....&Ye, Keqiang.(2015).Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease.NATURE COMMUNICATIONS,6,
MLA：
Zhang, Zhentao,et al."Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease".NATURE COMMUNICATIONS 6.(2015)
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