| First Author | Xia Y | Year | 2021 |
| Journal | Mol Psychiatry | Volume | 26 |
| Issue | 10 | Pages | 6002-6022 |
| PubMed ID | 33339957 | Mgi Jnum | J:368819 |
| Mgi Id | MGI:8215667 | Doi | 10.1038/s41380-020-00956-4 |
| Citation | Xia Y, et al. (2021) C/EBPbeta is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer's disease. Mol Psychiatry 26(10):6002-6022 |
| abstractText | The apolipoprotein E epsilon4 (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-beta (Abeta) 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/EBPbeta acts as a pivotal transcription factor for APOE and mediates its mRNA levels in an age-dependent manner. C/EBPbeta binds the promoter of APOE and escalates its expression in the brain. Knockout of C/EBPbeta in AD mouse models diminishes ApoE expression and Abeta pathologies, whereas overexpression of C/EBPbeta accelerates AD pathologies, which can be attenuated by anti-ApoE monoclonal antibody or deletion of ApoE via its specific shRNA. Remarkably, C/EBPbeta selectively promotes more ApoE4 expression versus ApoE3 in human neurons, correlating with higher activation of C/EBPbeta in human AD brains with ApoE4/4 compared to ApoE3/3. Therefore, our data support that C/EBPbeta is a crucial transcription factor for temporally regulating APOE gene expression, modulating ApoE4's role in AD pathogenesis. |
