Journal
HUMAN MOLECULAR GENETICS
Volume 30, Issue 18, Pages 1693-1710Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab115
Keywords
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Funding
- JSPS in Japan [20H03453]
- Otsuka Pharmaceutical
- AbbVie GK
- Research Center for Old Age grant, Juntendo University
- Sportology Center grant, Juntendo University
- Project-Kenkyu grant, Juntendo University
- Grants-in-Aid for Scientific Research [20H03453] Funding Source: KAKEN
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SGK1 is activated by chronic high-fat diet, increasing the risk of T2DM and promoting Tau pathology in AD by phosphorylating tau and activating GSK-3 beta. This activation leads to neurodegeneration and impairments in learning and memory, linking AD to corticosteroid effects and T2DM.
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-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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