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

• Type of Material: Article
• Authors: Zhihao Wang, Emory University; Ke Gong, Emory University; Xia Liu, Emory University; Zhentao Zhang, Emory University; Xiaoou Sun, Emory University; Zheng Zachory Wei, Emory University; Shan Ping Yu, Emory University; Fredric P. Manfredsson, Michigan State University; Ivette M. Sandoval, Michigan State University; Peter F. Johnson, National Cancer Institute; Jianping Jia, Capital Medical University; Jian-Zhi Wang, Huazhong University of Science and Technology; Keqiang Ye, Emory University
• Language: English
• Date: 2018-05-03
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-04120-z
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Start Page: 1784
• End Page: 1784
• Grant/Funding Information: The research of P.F.J. was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.; This study was supported in part by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.; Further support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.; This work was supported by grants from NIH RO1 (NS02338; AG051538) to K.Y., and NSFC grant (no. 81528007) to K.Y. and J.Z.W.; Additional support was provided by the Emory Neuroscience NINDS Core Facilities (P30NS055077).
• Keywords: MEMORY; HIPPOCAMPUS; ENHANCER-BINDING-PROTEIN; Science & Technology - Other Topics; ASPARAGINE ENDOPEPTIDASE; BRAIN-INJURY; GENE; KNOCKOUT MICE; Multidisciplinary Sciences; Science & Technology; DAMAGE; INFLAMMATION; TRANSCRIPTION FACTORS
• Research Categories: Biology, Genetics; Biology, Neuroscience; Health Sciences, Pathology

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.