{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:18:24Z","timestamp":1783297104192,"version":"3.54.6"},"reference-count":33,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82104424"],"award-info":[{"award-number":["82104424"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81560594"],"award-info":[{"award-number":["81560594"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Open Project of Department of Education of Guizhou Province","award":["KY[2019]049"],"award-info":[{"award-number":["KY[2019]049"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      One of the hallmark pathological characteristics of Alzheimer's disease (AD) is amyloid-\u03b2 (A\u03b2) accumulated in brain, which is mainly derived from the proteolytic processing of amyloid-\u03b2 protein precursor (A\u03b2PP). The ubiquitin-proteasome system is able to reduce A\u03b2 generation by ubiquitination and degradation of A\u03b2PP. Icariin (ICA), a flavonoid isolated from\n                      <jats:italic>Epimedium brevicornum<\/jats:italic>\n                      Maxim., has been reported that it could regulate the metabolism of A\u03b2PP and reduce the A\u03b2 level in AD\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate whether the effect of ICA on A\u03b2PP and A\u03b2 is related to A\u03b2PP ubiquitination.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      models to observe the effect of ICA on A\u03b2PP ubiquitination as well as to investigate the effect of HMG-CoA reductase degradation protein 1 (HRD1), an E3 ubiquitin-protein ligase, on the processing of A\u03b2PP ubiquitination.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      This study showed that ICA improved the cognitive abilities of APP\/PS1 AD mice in Morris Water Maze and Y-maze tests, upregulated HRD1 expression, subsequently elevated the total ubiquitination and K48-linked polyubiquitination of A\u03b2PP level, as well as increased A\u03b2PP degradation. Moreover, silenced\n                      <jats:italic>HRD1<\/jats:italic>\n                      gene abolished the aforementioned effects of ICA. Furthermore, ICA decreased the location of A\u03b2PP in the early endosome, where A\u03b2PP is cleaved into A\u03b2, evidenced by reducing the co-localization of A\u03b2PP and early endosome antigen 1 (EEA1).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrated that ICA increased A\u03b2PP degradation by upregulating HRD1 mediated ubiquitination.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877241303949","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T20:53:39Z","timestamp":1736974419000},"page":"616-626","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Icariin improves learning and memory function by enhancing HRD1-mediated ubiquitination of amyloid precursor protein in APP\/PS1 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