RT Journal Article
SR Electronic
T1 High-fat diet-induced activation of SGK1 contributes to Alzheimer’s disease pathogenesis by promoting tau pathology
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.14.095471
DO 10.1101/2020.05.14.095471
A1 Montasir Elahi
A1 Yumiko Motoi
A1 Shotaro Shimonaka
A1 Koichi Ishiguro
A1 Yuzuru Imai
A1 Nobutaka Hattori
YR 2020
UL http://biorxiv.org/content/early/2020/05/15/2020.05.14.095471.abstract
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. 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.ADAlzheimer’s diseaseCDControl chow dietDXMDexamethasoneGSK-3ßGlycogen synthetase kinase subunit ßGAPDHGlyceraldehyde phosphate dehydrogenaseHFDHigh-Fat DietIPGTTIntra-peritoneal glucose tolerance testITTInsulin tolerance testSGK1Serum/Glucocorticoid Regulated Kinase 1T2DMType2 diabetes mellitus