机构：[1]Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.[2]Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China.[3]Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.[4]Department of Translational Science & Molecular Medicine, Michigan State University, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.[5]Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.[6]Department of Neurology, Xuanwu Hospital of Capital Medical University, 100053 Beijing, China.神经内科首都医科大学宣武医院[7]Translational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine, 200065 Shanghai, China.
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/EBP beta),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/EBP beta regulates delta-secretase transcription and protein levels in an age-dependent manner. Overexpression of C/EBP beta in young 3x Tg mice increases delta-secretase and accelerates the pathological features including cognitive dysfunctions, which is abolished by inactive AEP C189S. Conversely, depletion of C/EBP beta from old 3x Tg 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/EBP beta plays a pivotal role in AD pathogenesis via increasing delta-secretase expression.
基金：
NIH RO1 (NS02338; AG051538)
NSFC grant (no. 81528007)
the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.
第一作者机构：[1]Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.[2]Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.[2]Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China.[6]Department of Neurology, Xuanwu Hospital of Capital Medical University, 100053 Beijing, China.[7]Translational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine, 200065 Shanghai, China.
推荐引用方式(GB/T 7714)：
Zhi-Hao Wang,Ke Gong,Xia Liu,et al.C/EBP beta regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease[J].NATURE COMMUNICATIONS.2018,9(1):1784.doi:10.1038/s41467-018-04120-z.
APA：
Zhi-Hao Wang,Ke Gong,Xia Liu,Zhentao Zhang,Xiaoou Sun...&Keqiang Ye.(2018).C/EBP beta regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease.NATURE COMMUNICATIONS,9,(1)
MLA：
Zhi-Hao Wang,et al."C/EBP beta regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease".NATURE COMMUNICATIONS 9..1(2018):1784
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