Activation of Estrogen Receptor α Increases and Estrogen Receptor β Decreases Apolipoprotein E Expression in Hippocampus in vitro and in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 45; pp. 16983 - 16988
• Main Authors: Wang, Jun Ming, Irwin, Ronald W., Brinton, Roberta Diaz
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.11.2006; National Acad Sciences
• Subjects: Agonists; Alleles; Alzheimer Disease - etiology; Animals; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Biological Sciences; Cells, Cultured; Down-Regulation - drug effects; Estradiol - pharmacology; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; Female; Gene expression regulation; Hippocampus - drug effects; Hippocampus - metabolism; Humans; In Vitro Techniques; Ligands; Messenger RNA; Mice; Neurons; Nitriles - pharmacology; Phenols; Propionates - pharmacology; Protein isoforms; Pyrazoles - pharmacology; Rats; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Reverse transcriptase polymerase chain reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transfection; Up-Regulation - drug effects; Vehicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0608128103

Previous evidence indicates that, in carriers of apolipoprotein E4 (ApoE4), estrogen therapy increased the risk of late-onset Alzheimer's disease (AD), whereas in individuals carrying ApoE2/3, estrogen therapy reduced the risk of AD [Cauley JA, Zmuda JM, Yaffe K, Kuller LH, Ferrell RE, Wisniewski SR, Cummings SR (1999) J Bone Miner Res 14:1175-1181; Yaffe K, Haan M, Byers A, Tangen C, Kuller L (2000) Neurology 54:1949-1954]. Estrogen mechanisms of action are mediated by two estrogen receptors (ERs), ERα and ERPβ. In this study, we determined the relationship between ER subtype and estrogen regulation of ApoE expression in HT-22 cells ectopically transfected with ERa or ERf3, in primary cultured rat hippocampal neurons in vitro and in rat hippocampus in vivo by both molecular biological and pharmacological analyses. Results of these analyses demonstrated that activation of ERα either by 17β-estradiol or a specific-agonist, propylpyrazole triol, up-regulated ApoE mRNA and protein expression. In contrast, the ERP3-selective agonist, diarylpropionitrile, down-regulated ApoE mRNA and protein expression. These results demonstrate that, in vitro and in vivo, ApoE expression can be differentially regulated depending on activation of ER subtypes. These data suggest that use of ER-selective ligands could provide therapeutic benefit to reduce the risk of AD by increasing ApoE expression in ApoE2/3 allele carriers and decreasing ApoE expression in ApoE4 allele carriers.