{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:51:53Z","timestamp":1788389513757,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271472"],"award-info":[{"award-number":["82271472"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing Municipality","doi-asserted-by":"publisher","award":["CSTB2022NSCQ\u2010LZX0033"],"award-info":[{"award-number":["CSTB2022NSCQ\u2010LZX0033"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012459","name":"Chongqing Graduate Student Research Innovation Project","doi-asserted-by":"publisher","award":["CYS23377"],"award-info":[{"award-number":["CYS23377"]}],"id":[{"id":"10.13039\/501100012459","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2021J01016"],"award-info":[{"award-number":["2021J01016"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD), the most common form of dementia, lacks effective disease\u2010modifying treatments. Rapamycin, an mTOR inhibitor with immunomodulatory properties, may mitigate AD pathology by restoring microglial functions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Rapamycin was orally administered to 2\u2010month\u2010old 5xFAD and hAPP\n                      <jats:sup>NL<\/jats:sup>\n                      \u2010G\u2010F mice (amyloid plaque\u2010dominant AD models). At 5 months of age, these mice were subjected to behavioral, histopathological, and molecular analyses. To assess microglial function, primary microglia were treated with rapamycin and evaluated for their ability to phagocytose and degrade fluorescently labeled amyloid\u2010\u03b2 (A\u03b2) via the IncuCyte real\u2010time imaging system. Furthermore, the effects of rapamycin and autophagy inhibitors on lipid droplet content were analyzed in oleic acid\u2010treated BV2 microglial cells using flow cytometry and confocal microscopy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Rapamycin treatment reduced the cerebral A\u03b2 plaque burden, alleviated dystrophic neurites, suppressed glial hyperactivation, and increased plaque\u2010associated microglial density in both mouse models, with more pronounced effects in female mice. These pathological improvements were associated with attenuated deficits in hippocampal\u2010dependent memory tasks (spontaneous alternation in the Y\u2010maze and contextual fear conditioning tasks). Mechanistically, rapamycin enhances microglial lysosomal degradation, promotes lipid droplet clearance in BV2 cells, and increases A\u03b2 phagocytic clearance in primary microglial cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that rapamycin reduces amyloid pathology and associated behavioral deficits in AD mice, an effect associated with enhanced microglial lysosomal activity and A\u03b2 clearance, highlighting its therapeutic potential in AD treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70807","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:56:32Z","timestamp":1772970992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rapamycin Reduces Amyloid\u2010\u03b2 Plaques and Improves Behavioral Performance in a Sex\u2010Dependent Manner in Mouse Models of Amyloidosis"],"prefix":"10.1002","volume":"32","author":[{"given":"Shihui","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences Chongqing Medical University  Chongqing China"},{"name":"Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) The First Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weishan","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, School of Basic Medical Sciences Chongqing Medical University  Chongqing China"},{"name":"Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) The First Affiliated Hospital of Chongqing Medical University  Chongqing 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