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C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease

Author

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  • Zhi-Hao Wang

    (Emory University School of Medicine
    Huazhong University of Science and Technology)

  • Ke Gong

    (Emory University School of Medicine)

  • Xia Liu

    (Emory University School of Medicine)

  • Zhentao Zhang

    (Emory University School of Medicine)

  • Xiaoou Sun

    (Emory University School of Medicine)

  • Zheng Zachory Wei

    (Emory University School of Medicine)

  • Shan Ping Yu

    (Emory University School of Medicine)

  • Fredric P. Manfredsson

    (Michigan State University)

  • Ivette M. Sandoval

    (Michigan State University)

  • Peter F. Johnson

    (National Cancer Institute)

  • Jianping Jia

    (Xuanwu Hospital of Capital Medical University)

  • Jian-Zhi Wang

    (Huazhong University of Science and Technology)

  • Keqiang Ye

    (Emory University School of Medicine
    Tongji University School of Medicine)

Abstract

Delta-secretase cleaves both APP and Tau to mediate the formation of amyloid plaques and neurofibrillary tangle in Alzheimer’s disease (AD). However, how aging contributes to an increase in delta-secretase expression and AD pathologies remains unclear. Here we show that a CCAAT-enhancer-binding protein (C/EBPβ), an inflammation-regulated transcription factor, acts as a key age-dependent effector elevating both delta-secretase (AEP) and inflammatory cytokines expression in mediating pathogenesis in AD mouse models. We find that C/EBPβ regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBPβ in young 3xTg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBPβ from old 3xTg or 5XFAD mice diminishes delta-secretase and reduces AD pathologies, leading to amelioration of cognitive impairment in these AD mouse models. Thus, our findings support that C/EBPβ plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.

Suggested Citation

  • Zhi-Hao Wang & Ke Gong & Xia Liu & Zhentao Zhang & Xiaoou Sun & Zheng Zachory Wei & Shan Ping Yu & Fredric P. Manfredsson & Ivette M. Sandoval & Peter F. Johnson & Jianping Jia & Jian-Zhi Wang & Keqia, 2018. "C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04120-z
    DOI: 10.1038/s41467-018-04120-z
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    Cited by:

    1. Jing Xiong & Jianming Liao & Xia Liu & Zhaohui Zhang & Jonathan Adams & Roberto Pacifici & Keqiang Ye, 2022. "A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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