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

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

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