PT - JOURNAL ARTICLE AU - Montasir Elahi AU - Yumiko Motoi AU - Shotaro Shimonaka AU - Yoko Ishida AU - Hiroyuki Hioki AU - Masashi Takanashi AU - Koichi Ishiguro AU - Yuzuru Imai AU - Nobutaka Hattori TI - High-fat diet-induced activation of SGK1 promotes Alzheimer’s disease-associated tau pathology AID - 10.1101/2020.05.14.095471 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.05.14.095471 4099 - http://biorxiv.org/content/early/2020/11/12/2020.05.14.095471.short 4100 - http://biorxiv.org/content/early/2020/11/12/2020.05.14.095471.full AB - Type2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimer’s disease (AD). However, the molecular links between T2DM and AD remain obscure. Here, we reported that serum/glucocorticoid-regulated kinase1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3ß, forming SGK1-GSK-3ß-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid-mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3ß-tau complex were also observed in the hippocampi of AD cases. Our results suggest that SGK1 is a key modifier of tau pathology in AD, linking AD to corticosteroid effects and T2DM.Competing Interest StatementThe authors have declared no competing interest.