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bioRxiv · 10.1101/2020.05.14.095471

High-fat diet-induced activation of SGK1 contributes to Alzheimer's disease pathogenesis by promoting tau pathology

Elahi, M.·Motoi, Y.·Shimonaka, S.·Ishiguro, K.·Imai, Y.·Hattori, N.
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Abstract

Type2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimers 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-3{beta}, forming SGK1-GSK-3{beta}-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-3{beta}-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.

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Elahi, M., Motoi, Y., Shimonaka, S., Ishiguro, K., Imai, Y., Hattori, N.. 2020-05-15. High-fat diet-induced activation of SGK1 contributes to Alzheimer's disease pathogenesis by promoting tau pathology. https://doi.org/10.1101/2020.05.14.095471

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