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Neuronal ApoE4 stimulates C/EBPβ activation, promoting Alzheimer's disease pathology in a mouse model.

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单位: [1]Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Laney Graduate School, Emory University, Atlanta, GA, 30322, USA [2]Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China [3]Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China [4]Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200065, China [5]Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education of the People’s Republic of China, Shanghai, 200072, China [6]Neuroscience Graduate Program, Laney Graduate School, Emory University, Atlanta, GA, 30322, USA [7]Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada [8]University of Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France [9]Department of Anaesthesiology, Emory University School of Medicine, Laney Graduate School, Emory University, Atlanta, GA, 30322, USA [10]Co-innovation Center of Neuroregeneration, Nantong University, JS, 226001, China [11]Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, Guangdong, China
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关键词: Alzheimer’s disease Transcription factor C/EBPβ ApoE4 Animal model

摘要:
ApoE4 is a major genetic risk determinant for Alzheimer's disease (AD) and drives its pathogenesis via Aβ-dependent and -independent pathways. C/EBPβ, a proinflammatory cytokine-activated transcription factor, is upregulated in AD patients and increases cytokines and δ-secretase expression. Under physiological conditions, ApoE is mainly expressed in glial cells, but its neuronal expression is highly elevated under pathological stresses. However, how neuronal ApoE4 mediates AD pathologies remains incompletely understood. Here we show that ApoE4 activates C/EBPβ that subsequently regulates APP, Tau and BACE1 mRNA expression in mouse neurons, driving AD-like pathogenesis. To interrogate the pathological roles of both human ApoE4 and C/EBPβ elevation in neurons in the aged brain, we develop neuronal specific Thy1-ApoE4/C/EBPβ double transgenic mice. Neuronal ApoE4 strongly activates C/EBPβ and augmented δ-secretase subsequently cleaves increased mouse APP and Tau, promoting AD-like pathologies. Notably, Thy1-ApoE4/C/EBPβ mice develop amyloid deposits, Tau aggregates and neurodegeneration in an age-dependent manner, leading to synaptic dysfunction and cognitive disorders. Thus, our findings demonstrate that neuronal ApoE4 triggers AD pathogenesis via activating the crucial regulator C/EBPβ.Copyright © 2021. Published by Elsevier Ltd.

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出版当年[2020]版
大类 | 1 区 医学
小类 | 1 区 神经科学
最新[2025]版
大类 | 2 区 医学
小类 | 2 区 神经科学
第一作者:
第一作者单位: [1]Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Laney Graduate School, Emory University, Atlanta, GA, 30322, USA [2]Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
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通讯作者:
通讯机构: [1]Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Laney Graduate School, Emory University, Atlanta, GA, 30322, USA [3]Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China [10]Co-innovation Center of Neuroregeneration, Nantong University, JS, 226001, China [11]Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, Guangdong, China [*1]Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, Guangdong, China. [*2]Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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