Wang Jun Ming, Irwin Ronald W, Brinton Roberta Diaz
Department of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16983-8. doi: 10.1073/pnas.0608128103. Epub 2006 Oct 31.
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), ERalpha and ERbeta. In this study, we determined the relationship between ER subtype and estrogen regulation of ApoE expression in HT-22 cells ectopically transfected with ERalpha or ERbeta, 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 ERalpha either by 17beta-estradiol or a specific-agonist, propylpyrazole triol, up-regulated ApoE mRNA and protein expression. In contrast, the ERbeta-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.
先前的证据表明，在载脂蛋白E4（ApoE4）携带者中，雌激素疗法会增加晚发性阿尔茨海默病（AD）的风险，而在携带ApoE2/3的个体中，雌激素疗法可降低AD风险[考利JA，兹穆达JM，亚夫K，库勒LH，费雷尔RE，维斯涅夫斯基SR，卡明斯SR（1999年）《骨矿物质研究杂志》14：1175 - 1181；亚夫K，哈恩M，拜尔斯A，坦根C，库勒L（2000年）《神经病学》54：1949 - 1954]。雌激素的作用机制由两种雌激素受体（ERs）介导，即雌激素受体α（ERα）和雌激素受体β（ERβ）。在本研究中，我们通过分子生物学和药理学分析，确定了在体外异位转染ERα或ERβ的HT - 22细胞、原代培养的大鼠海马神经元以及体内大鼠海马中，ER亚型与雌激素对ApoE表达调控之间的关系。这些分析结果表明，17β - 雌二醇或特异性激动剂丙基吡唑三醇激活ERα会上调ApoE mRNA和蛋白表达。相反，ERβ选择性激动剂二芳基丙腈会下调ApoE mRNA和蛋白表达。这些结果表明，在体外和体内，ApoE表达可根据ER亚型的激活而受到不同调控。这些数据表明使用ER选择性配体可能通过增加ApoE2/3等位基因携带者的ApoE表达以及降低ApoE4等位基因携带者的ApoE表达来提供治疗益处，以降低AD风险。
