title: Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Mingke
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Seong
authors.initials: S
authors.lastname: Su Kang
authors.affiliation: Department of Neurology, Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Department of Biochemistry, Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Duc M
authors.initials: DM
authors.lastname: Duong
authors.affiliation: Department of Neurology, Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Department of Biochemistry, Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Seyfried
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Cao
authors.affiliation: Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China.|Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, California 90095, USA.
authors.forename: Yi E
authors.initials: YE
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Ping Yu
authors.affiliation: Department of Neurology, Xuan Wu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Neurology, Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D054351:Electrical Synapses; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017774:Long-Term Potentiation; D008297:Male; D013058:Mass Spectrometry; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000378:metabolism; D000099240:Asparaginyl Endopeptidase
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003546:Cysteine Endopeptidases; D000099240:Asparaginyl Endopeptidase