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Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease.

Zhang, Zhentao, Song, Mingke, Liu, Xia, Su Kang, Seong, Duong, Duc M., Seyfried, Nicholas T., Cao, Xuebing, Cheng, Liming, Sun, Yi E., Ping Yu, Shan, Jia, Jianping, Levey, Allan I., Ye, Keqiang·2015·Nature Communications
DOI 10.1038/ncomms9762PMC PMC4659940
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Abstract

The age-dependent deposition of amyloid-β 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 δ-secretase, contributing to the age-dependent pathogenic mechanisms in AD.

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Authors
Zhang, Z., Song, M., Liu, X., Su Kang, S., Duong, D. M., Seyfried, N. T., Cao, X., Cheng, L., Sun, Y. E., Ping Yu, S., Jia, J., Levey, A. I., & Ye, K.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2015-11-09
Volume
6
Issue
1
ISSN
2041-1723
DOI
10.1038/ncomms9762
PMC
PMC4659940
Cited by
277
References
10
Language
en
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