C/EBPβ is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer's disease

• Published in: Molecular psychiatry Vol. 26; no. 10; pp. 6002 - 6022
• Main Authors: Xia, Yiyuan, Wang, Zhi-Hao, Zhang, Jichun, Liu, Xia, Yu, Shan Ping, Ye, Karen X, Wang, Jian-Zhi, Ye, Keqiang, Wang, Xiao-Chuan
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2021; Nature Publishing Group UK
• Subjects: Aging; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animal models; Animals; Apolipoprotein E; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoproteins E; Brain - metabolism; CCAAT-Enhancer-Binding Protein-beta - genetics; Gene expression; Mice; Mice, Knockout; Monoclonal antibodies; Neurodegenerative diseases; Neurofibrillary tangles; Risk factors; Tau protein; Transcription factors; β-Amyloid
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-020-00956-4

The apolipoprotein E ε4 (APOE4) allele is a major genetic risk factor for Alzheimer's disease (AD), and its protein product, ApoE4, exerts its deleterious effects mainly by influencing amyloid-β (Aβ) and Tau (neurofibrillary tangles, NFTs) deposition in the brain. However, the molecular mechanism dictating its expression during ageing and in AD remains incompletely clear. Here we show that C/EBPβ acts as a pivotal transcription factor for APOE and mediates its mRNA levels in an age-dependent manner. C/EBPβ binds the promoter of APOE and escalates its expression in the brain. Knockout of C/EBPβ in AD mouse models diminishes ApoE expression and Aβ pathologies, whereas overexpression of C/EBPβ accelerates AD pathologies, which can be attenuated by anti-ApoE monoclonal antibody or deletion of ApoE via its specific shRNA. Remarkably, C/EBPβ selectively promotes more ApoE4 expression versus ApoE3 in human neurons, correlating with higher activation of C/EBPβ in human AD brains with ApoE4/4 compared to ApoE3/3. Therefore, our data support that C/EBPβ is a crucial transcription factor for temporally regulating APOE gene expression, modulating ApoE4's role in AD pathogenesis.