载脂蛋白E
转录因子
阿尔茨海默病
生物
发病机制
基因表达
基因敲除
细胞生物学
内分泌学
分子生物学
内科学
医学
基因
遗传学
免疫学
疾病
作者
Yiyuan Xia,Zhi-Hao Wang,Jichun Zhang,Xia Liu,Shan Ping Yu,Keqiang Ye,Jian‐Zhi Wang,Keqiang Ye,Xiaochuan Wang
标识
DOI:10.1038/s41380-020-00956-4
摘要
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.
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