Activation of estrogen receptor α increases and estrogen receptor β decreases apolipoprotein E expression in hippocampus in vitro and in vivo

Jun Ming Wang, Ronald W. Irwin, Roberta Diaz Brinton

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

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 ERβ. In this study, we determined the relationship between ER subtype and estrogen regulation of ApoE expression in HT-22 cells ectopically transfected with ERα or ERβ, 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-estradiot or a specific-agonist, propylpyrazole triol, up-regulated ApoE mRNA and protein expression. In contrast, the ERβ-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.

Original languageEnglish (US)
Pages (from-to)16983-16988
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number45
DOIs
StatePublished - Nov 7 2006
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Alzheimer's disease prevention
  • Estrogen therapy
  • Risk factor regulation

ASJC Scopus subject areas

  • General

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