{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:33:03Z","timestamp":1789173183136,"version":"build-2803163510"},"reference-count":63,"publisher":"National Academy of Sciences","issue":"45","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,11,7]]},"abstract":"<jats:p>\n                    Previous evidence indicates that, in carriers of apolipoprotein E4 (\n                    <jats:italic>ApoE4<\/jats:italic>\n                    ), estrogen therapy increased the risk of late-onset Alzheimer's disease (AD), whereas in individuals carrying\n                    <jats:italic>ApoE2\/3<\/jats:italic>\n                    , estrogen therapy reduced the risk of AD [Cauley JA, Zmuda JM, Yaffe K, Kuller LH, Ferrell RE, Wisniewski SR, Cummings SR (1999)\n                    <jats:italic>J Bone Miner Res<\/jats:italic>\n                    14:1175\u20131181; Yaffe K, Haan M, Byers A, Tangen C, Kuller L (2000)\n                    <jats:italic>Neurology<\/jats:italic>\n                    54:1949\u20131954]. Estrogen mechanisms of action are mediated by two estrogen receptors (ERs), ER\u03b1 and ER\u03b2. In this study, we determined the relationship between ER subtype and estrogen regulation of ApoE expression in HT-22 cells ectopically transfected with ER\u03b1 or ER\u03b2, in primary cultured rat hippocampal neurons\n                    <jats:italic>in vitro<\/jats:italic>\n                    and in rat hippocampus\n                    <jats:italic>in vivo<\/jats:italic>\n                    by both molecular biological and pharmacological analyses. Results of these analyses demonstrated that activation of ER\u03b1 either by 17\u03b2-estradiol or a specific-agonist, propylpyrazole triol, up-regulated ApoE mRNA and protein expression. In contrast, the ER\u03b2-selective agonist, diarylpropionitrile, down-regulated ApoE mRNA and protein expression. These results demonstrate that,\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , 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\n                    <jats:italic>ApoE2\/3<\/jats:italic>\n                    allele carriers and decreasing ApoE expression in\n                    <jats:italic>ApoE4<\/jats:italic>\n                    allele carriers.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0608128103","type":"journal-article","created":{"date-parts":[[2006,11,2]],"date-time":"2006-11-02T08:25:30Z","timestamp":1162455930000},"page":"16983-16988","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":91,"title":["Activation of estrogen receptor \u03b1 increases and estrogen receptor \u03b2 decreases apolipoprotein E expression in hippocampus\n                    <i>in vitro<\/i>\n                    and\n                    <i>in vivo<\/i>"],"prefix":"10.1073","volume":"103","author":[{"given":"Jun 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