High-fat diet-induced activation of SGK1 promotes Alzheimer's disease-associated tau pathology

Hum Mol Genet. 2021 Aug 28;30(18):1693-1710. doi: 10.1093/hmg/ddab115.


Type 2 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 kinase 1 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diet, High-Fat / adverse effects*
  • Enzyme Activation / genetics
  • Glycogen Synthase Kinase 3 beta / genetics
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • Immediate-Early Proteins
  • Mapt protein, mouse
  • Multiprotein Complexes
  • tau Proteins
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase