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

Author

Listed:
  • Zhentao Zhang

    (Emory University School of Medicine
    Renmin Hospital of Wuhan University)

  • 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
    Center for Neurodegenerative Diseases, Emory University School of Medicine)

  • Nicholas T. Seyfried

    (Center for Neurodegenerative Diseases, Emory University School of Medicine
    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
    UCLA 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)

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.

Suggested Citation

  • 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, 2015. "Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease," Nature Communications, Nature, vol. 6(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9762
    DOI: 10.1038/ncomms9762
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    Cited by:

    1. Yiyuan Xia & Yifan Xiao & Zhi-Hao Wang & Xia Liu & Ashfaqul M. Alam & John P. Haran & Beth A. McCormick & Xiji Shu & Xiaochuan Wang & Keqiang Ye, 2023. "Bacteroides Fragilis in the gut microbiomes of Alzheimer’s disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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