{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T22:15:59Z","timestamp":1772662559774,"version":"3.50.1"},"posted":{"date-parts":[[2024,7,23]]},"group-title":"Neuroscience","reference-count":43,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Menopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimer\u2019s disease (AD). Activation of estrogen receptor beta (ER\u03b2) can be clinically relevant since it avoids the negative systemic effects of ER\u03b1 activation. However, very few studies have explored ER\u03b2-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study we specifically explored the role of ER\u03b2 in mediating sex-specific protection against AD pathology in the clinically relevant\n                  <jats:italic>\n                    App\n                    <jats:sup>NL-G-F<\/jats:sup>\n                  <\/jats:italic>\n                  knock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model. We treated male and female\n                  <jats:italic>\n                    App\n                    <jats:sup>NL-G-F<\/jats:sup>\n                  <\/jats:italic>\n                  mice with the selective ER\u03b2 agonist LY500307 and subset of the females was ovariectomized prior to treatment. Memory performance was assessed and a battery of biochemical assays were used to evaluate amyloid pathology and neuroinflammation. Primary microglial cultures from male and female wild-type and ER\u03b2-knockout mice were used to assess ER\u03b2\u2019s effect on microglial activation and phagocytosis. We find that ER\u03b2 activation protects against amyloid pathology and cognitive decline in male and female\n                  <jats:italic>\n                    App\n                    <jats:sup>NL-G-F<\/jats:sup>\n                  <\/jats:italic>\n                  mice. Ovariectomy increased soluble amyloid beta (A\u03b2) in cortex and insoluble A\u03b2 in hippocampus, but had otherwise limited effects on pathology. We further identify that ER\u03b2 does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ER\u03b2 protects against AD pathology differently in males and females, warranting reassessment of ER\u03b2 in combating AD.\n                <\/jats:p>","DOI":"10.1101\/2024.07.22.604543","type":"posted-content","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T18:16:04Z","timestamp":1721758564000},"source":"Crossref","is-referenced-by-count":2,"title":["ER\u03b2 mediates sex-specific protection in the\n                  <i>App-NL-G-F<\/i>\n                  mouse model of Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Aphrodite","family":"Demetriou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birgitta","family":"Lindqvist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heba 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