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; Keqiang Ye

doi:10.1038/ncomms9762

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

Nat Commun. 2015 Nov 9:6:8762. doi: 10.1038/ncomms9762.

Authors

Zhentao Zhang^{1

2}, Mingke Song³, Xia Liu¹, Seong Su Kang¹, Duc M Duong^{4

5}, Nicholas T Seyfried^{4

5}, Xuebing Cao⁶, Liming Cheng⁷, Yi E Sun^{7

8}, Shan Ping Yu³, Jianping Jia⁹, Allan I Levey⁴, Keqiang Ye¹

Affiliations

¹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
² Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
³ Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
⁴ Department of Neurology, Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
⁵ Department of Biochemistry, Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
⁶ Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
⁷ Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China.
⁸ Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, California 90095, USA.
⁹ Department of Neurology, Xuan Wu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Aging*
Alzheimer Disease / enzymology
Alzheimer Disease / genetics*
Amyloid Precursor Protein Secretases / genetics
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / metabolism*
Amyloid beta-Protein Precursor / metabolism*
Animals
Blotting, Western
Brain / metabolism*
Brain / pathology
Cysteine Endopeptidases / genetics*
Cysteine Endopeptidases / metabolism
Electrical Synapses
Enzyme-Linked Immunosorbent Assay
Female
Fluorescent Antibody Technique
HEK293 Cells
Hippocampus / metabolism*
Hippocampus / physiopathology
Humans
Immunohistochemistry
Immunoprecipitation
Long-Term Potentiation
Male
Mass Spectrometry
Memory
Mice
Mice, Knockout
Mice, Transgenic
Microscopy, Electron
Middle Aged
Plaque, Amyloid / metabolism

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Amyloid Precursor Protein Secretases
Cysteine Endopeptidases
asparaginylendopeptidase

Abstract

Publication types

MeSH terms

Substances

Grants and funding