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Its main pathological feature is the formation of neurofibrillary tangles through abnormal \u03b2\u2010amyloid protein (A\u03b2) aggregation and excessive Tau protein phosphorylation. Ring finger and WD repeating domain 2 (RFWD2) is an E3 ubiquitin ligase that regulates neuronal dendrite complexity through the c\u2010Jun N\u2010terminal kinase (JNK) pathway. This study aimed to investigate the regulatory effect of RFWD2 on the downstream protein, serum\/glucocorticoid\u2010regulated kinase 1 (SGK1), through the JNK pathway and explore its influence on AD pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Cognitive\u2010level behavioral detection was performed in RFWD2\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      mice. Cultured PC12 cells and cortical neurons were also used to analyze the changes in signaling pathways caused by the decreased expression of RFWD2 in\u00a0vitro and correlations between the expression of related proteins and key signaling pathways of AD at the molecular level.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Decreased RFWD2 expression led to cognitive deficits in AD mice, resulting in mitochondrial swelling, fragmentation of hippocampal neurons, abnormally high reactive oxygen species levels, and an imbalance between antiapoptotic and proapoptotic proteins. This effect was significantly improved by inhibiting the JNK pathway and SGK1 protein expression. Furthermore, in\u00a0vitro experiments showed that in PC12 cells and cortical neurons downregulated by RFWD2, the expression levels of p\u2010JNK, SGK1, and p\u2010Tau increased, and those of LC3B\/Beclin\u20101 decreased; ROS levels increased, and apoptosis was induced; inhibiting JNK or SGK1 expression reversed these changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>RFWD2 regulates SGK1 expression through the JNK pathway, thereby regulating mitochondrial autophagy and apoptosis, altering the expression levels of p\u2010Tau and A\u03b2 proteins, inducing AD\u2010like symptoms in mice, and promoting AD development. The RFWD2\u2013JNK\u2013SGK1 axis provides a valuable basis for studying the mechanisms of AD occurrence and developing early intervention strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70860","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T14:06:07Z","timestamp":1775743567000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>RFWD2<\/scp>\n                    Mitigates\n                    <scp>AD<\/scp>\n                    \u2010Like Cognitive Impairments via the\n                    <scp>JNK<\/scp>\n                    \u2013\n                    <scp>SGK1<\/scp>\n                    Signaling Pathway in Mice"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0914-9193","authenticated-orcid":false,"given":"Mengjiao","family":"Ying","sequence":"first","affiliation":[{"name":"Anhui Provincial Center for Neural 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