A novel defense mechanism that is activated on amyloid-β insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling

Abstract

Amyloid-b (Ab) is known to induce apoptotic cell death and its underlying mechanism has been studied extensively, but the endogenous protection mechanism that results from Ab insult is less known. In this study, we have found that Ab 1À42 produced a dose-dependent decrease in cell viability and dose-dependent increase in apoptotic cell death in PC12 cells. Meanwhile, Ab 1À42 (0.1 lM) increased the phosphorylation of serum-and glucocorticoid-inducible kinase1 (SGK1) at Ser-78 specifically. A parallel increase in ERK1/2, STAT1 and STAT2 phosphorylation and the anti-apoptotic gene Mcl-1 expression was also observed. Transfection of rat siRNAs against ERK1/2, SGK1, STAT1 and STAT2 abolished these effects of Ab. Transfection of sgkS78D, the constitutively active SGK1, dose-dependently protected against Ab-induced apoptosis and dose-dependently increased the expression of Mcl-1. SGK1 activation further phosphorylates STAT1 at Tyr-701 and Ser-727 directly, and activates STAT2 at The presence of senile plaque is a major pathological hallmark of Alzheimer's disease (AD) and amyloid-b peptides (Ab 1À40 , Ab 1À42 ) are the major components of senile plaque. Ab is generated from sequential and proteolytic cleavage of the amyloid precursor protein (APP) by b-and g-secretases. 1 Ab is known to cause lipid peroxidation, free radical production, caspase-3 activation, protein cleavage and DNA fragmentation that finally lead to apoptosis. [2][3][4] Ab also promotes the expression of some pro-inflammatory genes, such as cyclooxygenase-2 and interleukin-1b, and activation of these signalings would also result in apoptosis. 5 Further, Ab was shown to activate the p53 promoter and result in p53-dependent apoptosis. 6 On the other hand, when Ab produces its toxicity, cells would also develop defense mechanisms to cope with Ab toxicity. For example, a nonamyloidogenic neurotrophic peptide sAPPa is generated by a-secretase cleavage of APP and sAPPa is shown to activate neuroprotectin D1 to promote cell survival. 5 However, with the role and mechanism of Ab-induced toxicity been studied extensively, the endogenous rescue mechanism caused by Ab is less known.Serum-and glucocorticoid-inducible kinase 1 (SGK1) is a member of the serine/threonine protein kinase family that is induced transcriptionally by glucocorticoid and serum 7 and it governs a variety of cellular functions. 8 SGK1 is a downstream target of phosphatidylinositol 3-kinase (PI3-K) signaling. 9 SGK1 is directly phosphorylated by 3-phosphoinositidedependent protein kinase 1 (PDK1) at Thr-256 on SGK1 phosphorylation by PDK2 at Ser-422. 10 In addition, SGK1 is phosphorylated by p38 mitogen-activated protein kinase (p38 MAPK) at Ser-78 and p38 MAPK phosphorylation of SGK1 mediates cell survival in response to interleukin-6 stimulation. 11 In another study, SGK1 was shown to promote cell survival through phosphorylation and inactivation of the proapoptotic forkhead transcription factor FKHRL1. 12 Further, induction of SGK1 protects epithelial tumor cells from serum starvation-indu...

Hes-1 SUMOylation by protein inhibitor of activated STAT1 enhances the suppressing effect of Hes-1 on GADD45α expression to increase cell survival

“…This explanation is supported by the observation that transfection of the Hes-1 sumo-mutant (Hes-1 3KR) prevented the anti-apoptotic effect of PIAS1. On the other hand, because PIAS1 inhibits STAT1 activity, the present results are congruent with the reports showing that STAT1 regulates cell death [62,63] and STAT1 mediates the neurotoxicity of amyloid-beta [64], although the apoptotic role of STAT1 may depend on the cell type and the specific STAT1 dimers formed [65,66]. …”

STAT1 Negatively Regulates Spatial Memory Formation and Mediates the Memory-Impairing Effect of Aβ

“…Animals were divided into three groups to receive 1% NH 4 OH, rA β , or A β (both at 21 μg) injections to the CA1 area and were subject to water maze learning 10 days later. Both NH 4 OH and rA β -injected animals served as control groups because rA β was previously shown not to produce toxicity to the hippocampal neurons (Hsu et al , 2009). Results revealed that A β , but not rA β , markedly impaired acquisition performance in rats (F 2,20 =20.41; q =8.28, P <0.001) (Figure 4a).…”

Laminin-β1 Impairs Spatial Learning through Inhibition of ERK/MAPK and SGK1 Signaling

“…Laminin also activates the transcription factor, signal transducer and activation of transcription (STAT1) during macrophage maturation (Coccia et al, 1999), and we have demonstrated recently that STAT1 phosphorylation impairs spatial learning in rats (Tai et al, 2011). Furthermore, STAT1/STAT2 could be activated by serum-and glucocorticoid-inducible kinase-1 (SGK1) to mediate amyloid-b-induced defense mechanism (Hsu et al, 2009), and we have shown previously that the protein kinase SGK1 facilitates spatial learning and hippocampal LTP in rats (Tsai et al, 2002;Ma et al, 2006). Much evidence supports the notion that the mechanism associated with neuronal plasticity is also implicated in the therapeutic action of antidepressants.…”