<scp>RFWD2</scp> Mitigates <scp>AD</scp> ‐Like Cognitive Impairments via the <scp>JNK</scp> – <scp>SGK1</scp> Signaling Pathway in Mice

BACKGROUND: Alzheimer disease (AD) is a degenerative disorder of the central nervous system. Its main pathological feature is the formation of neurofibrillary tangles through abnormal β-amyloid protein (Aβ) 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-Jun N-terminal kinase (JNK) pathway. This study aimed to investigate the regulatory effect of RFWD2 on the downstream protein, serum/glucocorticoid-regulated kinase 1 (SGK1), through the JNK pathway and explore its influence on AD pathogenesis. METHODS: 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 vitro and correlations between the expression of related proteins and key signaling pathways of AD at the molecular level. RESULTS: 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 vitro experiments showed that in PC12 cells and cortical neurons downregulated by RFWD2, the expression levels of p-JNK, SGK1, and p-Tau increased, and those of LC3B/Beclin-1 decreased; ROS levels increased, and apoptosis was induced; inhibiting JNK or SGK1 expression reversed these changes. CONCLUSION: RFWD2 regulates SGK1 expression through the JNK pathway, thereby regulating mitochondrial autophagy and apoptosis, altering the expression levels of p-Tau and Aβ proteins, inducing AD-like symptoms in mice, and promoting AD development. The RFWD2-JNK-SGK1 axis provides a valuable basis for studying the mechanisms of AD occurrence and developing early intervention strategies.