High-fat diet-induced activation of SGK1 promotes Alzheimer’s disease-associated tau pathology
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Abstract
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.
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Pathological states differ significantly across neurological diseases, and alterations in SGK1 vary, leading to distinct impacts of SGK1 on different diseases; even within the same disease, SGK1's influence on progression can vary.
“However, the pathological states differ significantly across various neurological diseases, and the alterations in SGK1 also vary, leading to distinct impacts of SGK1 on different diseases. Even within the same disease, the influence of SGK1 on its progression can vary”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Elahi et al., 2021
The Results (page unavailable) show that SGK1 overexpression worsened tau pathology and memory in Tg601 mice. The References list a study reporting improved memory and amyloid pathology with SGK1 overexpression in a different Alzheimer’s mouse model, offering some support for variation within one disease. This paper does not establish that differing pathological states and SGK1 alterations cause distinct effects across neurological diseases. (LLM, conf=0.78)
Experimental — accuracy not yet measuredInteraction of SGK1, GSK-3β, and Tau leads to formation of an SGK1-GSK-3β-Tau complex, contributing to abnormal Tau tangles and disintegrating microtubules in neurons.
“Interaction of these proteins lead to the formation of an SGK1-GSK-3β-Tau complex, contributing to abnormal Tau tangles and ultimately resulting in disintegrating microtubules in neurons”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Elahi et al., 2021
The Results section ('SGK1-mediated tau phosphorylation at Ser214 and GSK-3ß activation'; page unavailable) describes a scaffold-like SGK1–GSK-3β–tau complex and increased tau aggregation and fibril formation. It reports reduced tubulin polymerization activity, but does not show that the complex causes neurofibrillary tangles or disintegrating microtubules in neurons. The Discussion says SGK1 might disassemble microtubules, rather than establishing that outcome. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEMD638683 inhibits SGK1 by blocking ATP binding, suppressing its phosphorylation activity.
“It inhibits SGK1 by blocking ATP binding, suppressing its phosphorylation activity”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Elahi et al., 2021
The Results section (Figure 6 and the accompanying text; page unavailable) reports that EMD638683 inhibits SGK1 activity and reduces SGK1-mediated tau phosphorylation. Neither those passages nor the Discussion establish that it works by blocking ATP binding, so the claimed mechanism is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn a Tau transgenic mouse model, prolonged high-fat diet activates SGK1, which promotes Tau pathology through phosphorylation of Tau at Ser214 and activation of GSK-3β.
“In the Tau transgenic mouse model, a prolonged high-fat diet activates SGK1, which promotes Tau pathology through the phosphorylation of Tau at the Ser214 site and the activation of an essential Tau kinase, GSK-3β”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Elahi et al., 2021
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Publications from Juntendo University Graduate School of Medicine, 2021 [3/6]
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Publications from Juntendo University Graduate School of Medicine, 2021 [6/6]
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- Authors
- Elahi, M., Motoi, Y., Shimonaka, S., Ishida, Y., Hioki, H., Takanashi, M., Ishiguro, K., Imai, Y., & Hattori, N.
- Affiliations
- Juntendo University (JP)
- Corresponding author
- Imai, Yuzuru
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-04-22
- Volume
- 30
- Issue
- 18
- Pages
- 1693-1710
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC8411983
- OpenAlex
- W3154257672
- Cited by
- 57
- References
- 78
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 12 · 2023: 10 · 2022: 9 · 2021: 4
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Sportology Center
- Project-Kenkyu
- Research Center for Old Age
- AbbVie GK
- Otsuka Pharmaceutical
- Grant-in-Aid for Scientific Research (20H03453)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Keywords
- SGK1, Alzheimer's disease, tau pathology, high-fat diet, type 2 diabetes, GSK3β, tau phosphorylation, glucocorticoids, hyperglycemia, hippocampus, neurodegeneration, learning and memory impairment, insulin resistance
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Serum-Glucocorticoid Regulated Kinases, Alzheimer Disease, Animals, Diabetes Mellitus, Type 2, Enzyme Activation, Humans, Mice, Transgenic, Signal Transduction, tau Proteins, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Multiprotein Complexes, Mice, Diet, High-Fat
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