{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:13:54Z","timestamp":1792714434034,"version":"4.5.0"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"52","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,12,27]]},"abstract":"<jats:p>Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age- and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examined the onset and severity of AD pathology associated with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased \u03b2 amyloid peptide (A\u03b2) deposition. These mice also exhibited increased A\u03b2 production, and microglia cultures prepared from the brains of these mice were impaired in A\u03b2 clearance\/degradation. In contrast, ovariectomized APP23 mice exhibited plaque pathology similar to that observed in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.<\/jats:p>","DOI":"10.1073\/pnas.0505203102","type":"journal-article","created":{"date-parts":[[2005,12,19]],"date-time":"2005-12-19T20:43:55Z","timestamp":1135025035000},"page":"19198-19203","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":358,"title":["Brain estrogen deficiency accelerates A\u03b2 plaque formation in an Alzheimer's disease animal model"],"prefix":"10.1073","volume":"102","author":[{"given":"Xu","family":"Yue","sequence":"first","affiliation":[{"name":"L. J. Roberts Center for Alzheimer's Research and Haldeman Laboratory for Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351; School of Medicine, Fujita Health University, Kutsukake-cho Toyoake, Aichi 470-1192, Japan; and Nervous System Research, Novartis Pharma Ltd., CH-4002 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Lu","sequence":"additional","affiliation":[{"name":"L. J. Roberts Center for Alzheimer's Research and Haldeman Laboratory for Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351; School of Medicine, Fujita Health University, Kutsukake-cho Toyoake, Aichi 470-1192, Japan; and Nervous System Research, Novartis Pharma Ltd., CH-4002 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Techie","family":"Lancaster","sequence":"additional","affiliation":[{"name":"L. J. 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