The cell survival kinase SGK1 and its targets FOXO3a and NDRG1 in aged human brain.
OBJECTIVE
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 < 0.001). In immunoblots no difference in SGK1 abundance was detected between AC and AD tissues. Phosphorylation of NDRG1 (an SGK1-specific target) was greater in AD, relative to AC cases (approximately twofold, P = 0.023).


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 localization.
Stroke & Dementia Research Centre, Division of Clinical Sciences, St Georges University of London, London, UK.
P
P
Sahin
C
C
McCaig
J
J
Jeevahan
J T
JT
Murray
A H
AH
Hainsworth
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C499517:FOXO3 protein, human
Akt; Alzheimer's disease; FOXO3a; SGK1; apoptosis; cell survival