High-fat diet-induced activation of SGK1 promotes Alzheimer's disease-associated tau pathology.
Alzheimer Disease
/ genetics
Animals
Diabetes Mellitus, Type 2
/ genetics
Diet, High-Fat
/ adverse effects
Enzyme Activation
/ genetics
Glycogen Synthase Kinase 3 beta
/ genetics
Humans
Immediate-Early Proteins
/ genetics
Mice
Mice, Transgenic
Multiprotein Complexes
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Signal Transduction
tau Proteins
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
28 08 2021
28 08 2021
Historique:
received:
27
01
2021
revised:
31
03
2021
accepted:
18
04
2021
pubmed:
24
4
2021
medline:
31
3
2022
entrez:
23
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33890983
pii: 6246109
doi: 10.1093/hmg/ddab115
pmc: PMC8411983
doi:
Substances chimiques
Immediate-Early Proteins
0
Mapt protein, mouse
0
Multiprotein Complexes
0
tau Proteins
0
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Gsk3b protein, mouse
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
serum-glucocorticoid regulated kinase
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1693-1710Informations de copyright
© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.