C/EBPβ is a Key Transcription Factor for APOE and Preferentially Mediates ApoE4 Expression in Alzheimer's Disease

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2020 Dec 19

PMID 33339957

Citations 28

Authors

Yiyuan Xia

Zhi-Hao Wang

Jichun Zhang

Xia Liu

Shan Ping Yu

Karen X Ye

Jian-Zhi Wang

Keqiang Ye

Xiao-Chuan Wang

Affiliations

Soon will be listed here.

Abstract

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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