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

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 () and Keqiang Ye ()
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Zhi-Hao Wang: Emory University School of Medicine
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

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04120-z

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