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C/EBP beta regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease

  1. Author:
    Wang, Zhi-Hao
    Gong, Ke
    Liu, Xia
    Zhang, Zhentao
    Sun, Xiaoou
    Wei, Zheng Zachory
    Yu, Shan Ping
    Manfredsson, Fredric P.
    Sandoval, Ivette M.
    Johnson, Peter
    Jia, Jianping
    Wang, Jian-Zhi
    Ye, Keqiang

  2. Author Address

    Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA.Huazhong Univ Sci & Technol, Tongji Med Coll, Minist Educ Neurol Dis, Dept Pathophysiol,Key Lab, Wuhan 430030, Hubei, Peoples R China.Emory Univ, Sch Med, Dept Anesthesiol, Atlanta, GA 30322 USA.Michigan State Univ, Dept Translat Sci & Mol Med, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA.NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA.Capital Med Univ, Xuanwu Hosp, Dept Neurol, Beijing 100053, Peoples R China.Tongji Univ, Sch Med, Tongji Hosp, Translat Ctr Stem Cell Res, Shanghai 200065, Peoples R China.
    1. Year: 2018
    2. Date: May 3
  2. Journal: NATURE COMMUNICATIONS
  3. NATURE PUBLISHING GROUP,
    1. 9
  5. Type of Article: Article
  6. Article Number: 1784
  7. ISSN: 2041-1723
  1. 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/EBP beta),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/EBP beta regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBP beta in young 3x Tg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBP beta from old 3x Tg 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/EBP beta plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.

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  1. Keywords:

External Sources

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  2. DOI: 10.1038/s41467-018-04120-z
  3. PMID: 29725016
  4. View record in Web of Science®
  5. WOS: 000431298400009

Library Notes

  1. Fiscal Year: FY2017-2018
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