The cell survival kinase SGK 1 and its targets FOXO 3a and NDRG 1 in aged human brain
Abstract
Aims Serum- and glucocorticoid-inducible kinase 1 (SGK1) protects neuronal cells from injury stimuli in vitro, and exerts anti-apoptotic effects via downstream targets including the forkhead-like transcription factor FOXO3a. SGK1 is a homolog of Akt, a related survival kinase that is up-regulated in Alzheimer's disease (AD). Here we aimed to examine the expression pattern of SGK1 and FOXO3a in aged human cerebral cortex. Methods Cortical tissue from aged donors without brain disease (aged controls, AC, n = 19) and from severe AD patients (Braak stage V-VI; n = 14) were examined by immunohistochemistry and immunoblot analysis. Results SGK1 was present in all samples (detected by immunohistochemistry and immunoblotting). Large cortical neuronal cells were strongly positive for SGK1, with predominantly nuclear labelling. Some astrocytes and oligodendrocytes were also labelled. SGK1 was not seen in nerve tracts (axons or myelin) and rarely seen in CD68-positive cells (microglia, perivascular macrophages) or vascular cells (myocytes or endothelia). The fraction of large cortical neurones with nuclear FOXO3a was lower in AD cases relative to AC (54%, 70%, respectively, P Conclusions Neuronal expression of SGK1 in aged human brain and its nuclear compartmentalization suggest a possible neuroprotective role. FOXO3a and NDRG1 data suggest augmented SGK1 activity (as reported for Akt) in severe AD. Increased intracellular SGK1 may complement enhanced Akt, with a distinct subcellular lo…
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In human AD patients, SGK1 levels are not significantly different from age-matched controls, but there is a notable increase in phosphorylation of NDRG1, a specific target of SGK1.
“In human AD patients, the level of SGK1 is not significantly different from age-matched controls. Still, there is a notable increase in the phosphorylation of N-myc downstream-regulated gene family member 1 (NDRG1), a specific target of SGK1”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Sahin et al., 2013
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Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress
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(Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms
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Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology
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Significance of SGK1 in the regulation of neuronal function
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Cao, Q., Wang, W., Williams, J. B., Yang, F., Wang, Z.-J., & Yan, Z. (2020) · Science Advances · doi:10.1126/sciadv.abc8096 · Cited by 108 · see citing works
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“(2015) 134, 677--692 factor FOXO3a (or FKHRL1; Brunet et al. 2001; Sahin et al. 2013). mTORC2 can activate AKT to repress FOXO1 and FOXO3 in mammalian cells (Guertin et al. 2006).”
BackgroundHigh-fat diet-induced activation of SGK1 promotes Alzheimer’s disease-associated tau pathology
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Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
Howard, P. G., Zou, P., Zhang, Y., Huang, F., Tesic, V., Wu, C. Y.-C., & Lee, R. H.-C. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114973 · Cited by 13 · see citing works
- Authors
- Sahin, P., McCaig, C., Jeevahan, J., Murray, J. T., & Hainsworth, A. H.
- Affiliations
- St George's, University of London (GB)
- St George's Hospital (GB)
- Trinity College Dublin (IE)
- Corresponding author
- Hainsworth, A. H.
- Venue
- Neuropathology and Applied Neurobiology
- Publisher
- Wiley
- Published
- 2013-09-09
- Volume
- 39
- Issue
- 6
- Pages
- 623-633
- ISSN
- 0305-1846 (ISSN-L)
- 1365-2990
- OpenAlex
- W1813428079
- Cited by
- 57
- References
- 5
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 4 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 8 · 2014: 1 · 2013: 3
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropathology and Applied Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Versus Arthritis
- Medical Research Council (MR/L022656/1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- SGK1, FOXO3, NDRG1, Alzheimer's disease, brain aging, cerebral cortex, neuroprotection, Akt, subcellular localization, phosphorylation, astrocytes, oligodendrocytes, microglia
- MeSH terms
- Forkhead Box Protein O3, Serum-Glucocorticoid Regulated Kinases, N-myc Downstream-Regulated Gene 1 Protein, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Cell Survival, Cerebral Cortex, Female, Humans, Male, Neurons, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Cell Cycle Proteins, Intracellular Signaling Peptides and Proteins, Forkhead Transcription Factors
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