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This bias is closely linked to declining estradiol levels during menopause. Our study demonstrated that estradiol can inhibit the accelerated progression of AD caused by ovariectomy (OVX) in female APP\/PS1 mice. Transcriptome analysis revealed that estradiol prevented the decline in sortilin-related receptor 1 (\n                    <jats:italic>Sorl1<\/jats:italic>\n                    ), which encodes the sorting receptor SORLA, in the hippocampus of female APP\/PS1-OVX mice. Neuronal\n                    <jats:italic>Sorl1<\/jats:italic>\n                    knockdown blocked estradiol\u2019s ability to alleviate AD symptoms. Mechanistically, estradiol enhanced SORLA-mediated redirection of amyloid precursor protein (APP) trafficking from early endosomes toward the Golgi apparatus and lysosomes, which were involved in non-amyloidogenic processing and reducing A\u03b2 levels. Additionally, estradiol promoted estrogen receptor \u03b1 (ER\u03b1) binding to the\n                    <jats:italic>Sorl1<\/jats:italic>\n                    promoter, thereby activating SORLA expression. Notably, estradiol ameliorated AD progression in female APP\/PS1-OVX mice through ER\u03b1, and this effect depended on SORLA. Overall, estradiol mitigated AD pathology by activating\n                    <jats:italic>Sorl1<\/jats:italic>\n                    transcription via ER\u03b1, which in turn directed APP endosomal trafficking through SORLA. This pathway provides valuable mechanistic insights into sex differences in AD and highlights potential therapeutic targets.\n                  <\/jats:p>","DOI":"10.1186\/s13195-026-02027-2","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:32:51Z","timestamp":1774420371000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Estradiol ameliorates AD pathology and cognitive deficits by SORLA-mediated APP endosomal trafficking"],"prefix":"10.1186","volume":"18","author":[{"given":"Fengting","family":"Cao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchun","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xulian","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixian","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhou","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"2027_CR1","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/s41582-025-01071-0","volume":"21","author":"L Castro-Aldrete","year":"2025","unstructured":"Castro-Aldrete L, et al. 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