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

Authors

• Zhi-Hao Wang, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
• Ke Gong, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
• Xia Liu, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
• Zhentao Zhang, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
• Xiaoou Sun, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
• Zheng Zachory Wei, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
• Shan Ping Yu, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
• Fredric P. Manfredsson, Department of Translational Science & Molecular Medicine, Michigan State University, 333 Bostwick Ave NE, Grand Rapids, MI, 49503, USA.Follow
• Ivette M. Sandoval, Department of Translational Science & Molecular Medicine, Michigan State University, 333 Bostwick Ave NE, Grand Rapids, MI, 49503, USA.
• Peter F. Johnson, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA.
• Jianping Jia, Department of Neurology, Xuanwu Hospital of Capital Medical University, 100053, Beijing, China. jiajp@vip.126.com.
• Jian-Zhi Wang, Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China. wangjz@mails.tjmu.edu.cn.
• Keqiang Ye, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA. kye@emory.edu.

Document Type

Article

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.

Medical Subject Headings

Alzheimer Disease (enzymology, metabolism, pathology); Amyloid Precursor Protein Secretases (metabolism); Animals; CCAAT-Enhancer-Binding Protein-beta (metabolism); Cells, Cultured; Central Nervous System (metabolism); Cognition Disorders (pathology); Cysteine Endopeptidases (genetics); Disease Models, Animal; Female; Glucose (metabolism); HEK293 Cells; Humans; Inflammation (pathology); Male; Mice, Inbred C57BL; Mice, Knockout; Neurons (pathology); Oxygen (metabolism); RNA, Messenger (genetics); Rats; Transcription, Genetic; Up-Regulation

Publication Date

5-3-2018

Publication Title

Nature communications

E-ISSN

2041-1723

Volume

9

Issue

1

First Page

1784

PubMed ID

29725016

Digital Object Identifier (DOI)

10.1038/s41467-018-04120-z

Recommended Citation

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 F.; Jia, Jianping; Wang, Jian-Zhi; and Ye, Keqiang, "C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease" (2018). Translational Neuroscience. 2018.
https://scholar.barrowneuro.org/neurobiology/2018