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

Zhentao Zhang, Mingke Song, Xia Liu, Seong Su Kang, Duc M. Duong, Nicholas T. Seyfried, Xuebing Cao, Liming Cheng, Yi E. Sun (), Shan Ping Yu, Jianping Jia (), Allan I. Levey and Keqiang Ye ()
Additional contact information
Zhentao Zhang: Emory University School of Medicine
Mingke Song: Emory University School of Medicine
Xia Liu: Emory University School of Medicine
Seong Su Kang: Emory University School of Medicine
Duc M. Duong: Center for Neurodegenerative Diseases, Emory University School of Medicine
Nicholas T. Seyfried: Center for Neurodegenerative Diseases, Emory University School of Medicine
Xuebing Cao: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Liming Cheng: Translational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine
Yi E. Sun: Translational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine
Shan Ping Yu: Emory University School of Medicine
Jianping Jia: Xuan Wu Hospital of Capital Medical University
Allan I. Levey: Center for Neurodegenerative Diseases, Emory University School of Medicine
Keqiang Ye: Emory University School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: 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.

Date: 2015
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms9762 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9762

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms9762

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().