C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease
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
Digital Object Identifier (DOI)
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.