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GSK-3β and ERK1/2 incongruously act in tau hyperphosphorylation in SPS-induced PTSD rats.

ABSTRACT: Post-traumatic stress disorder (PTSD) manifests in neurocognitive deficits in association with increased tau deposition, which mainly consist of phosphorylated tau in Alzheimer disease (AD) brain. However, the exact mechanism of PTSD inducing tau hyperphosphorylation remains unclear and therefore no effective treatment options are currently available. We here show that employing single prolonged stress (SPS), as a consensus PTSD model, induced a typical anxiety and abnormal hyperphosphorylation of tau at Ser202/Thr205 (AT8) and Ser404 but not at Ser199 and Ser396 in the hippocampus compared to the control rats. Furthermore, there was a decrease in the level of inactivated phosphorylated GSK-3β at Ser9, an increase in the level of activated phosphorylated GSK-3β at Thr216 and an obvious decrease in the level of activated phosphorylated ERK1/2, but no alterations in CaMKII and PP2A in hippocampus of SPS rats. On the other hand, the levels of both phosphorylated AKT and total SGK1, stress- and GSK-3β/ERK1/2-related proteins, were down-regulated. Interestingly, Overexpression of SGK1 increased the level of phosphorylated ERK1/2 and led to tau hyperphosphorylation at Ser199 and Ser396. These findings suggest that SPS exposure results in differential tau phosphorylation at different sites probably due to incongruous action between AKT-related GSK-3β activation and SGK1-related ERK1/2 inactivation, suggesting a link between SPS-induced PTSD and AD-associated tau pathogenic mechanisms.

SUBMITTER: Wei Z

PROVIDER: S-EPMC6782009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Testosterone induces cardiac hypertrophy through a mechanism that involves a concerted crosstalk between cytosolic and nuclear signaling pathways. Nuclear factor of activated T-cells (NFAT) is associated with the promotion of cardiac hypertrophy, glycogen synthase kinase-3β (GSK-3β) is considered to function as a negative regulator, mainly by modulating NFAT activity. However, the role played by calcineurin-NFAT and GSK-3β signaling in testosterone-induced cardiac hypertrophy has remained unknown. Here, we determined that testosterone stimulates cardiac myocyte hypertrophy through NFAT activation and GSK-3β inhibition. Testosterone increased the activity of NFAT-luciferase (NFAT-Luc) in a time- and dose-dependent manner, with the activity peaking after 24 h of stimulation with 100 nM testosterone. NFAT-Luc activity induced by testosterone was blocked by the calcineurin inhibitors FK506 and cyclosporine A and by 11R-VIVIT, a specific peptide inhibitor of NFAT. Conversely, testosterone inhibited GSK-3β activity as determined by increased GSK-3β phosphorylation at Ser9 and β-catenin protein accumulation, and also by reduction in β-catenin phosphorylation at residues Ser33, Ser37, and Thr41. GSK-3β inhibition with 1-azakenpaullone or a GSK-3β-targeting siRNA increased NFAT-Luc activity, whereas overexpression of a constitutively active GSK-3β mutant (GSK-3βS9A) inhibited NFAT-Luc activation mediated by testosterone. Testosterone-induced cardiac myocyte hypertrophy was established by increased cardiac myocyte size and [3H]-leucine incorporation (as a measurement of cellular protein synthesis). Calcineurin-NFAT inhibition abolished and GSK-3β inhibition promoted the hypertrophy stimulated by testosterone. GSK-3β activation by GSK-3βS9A blocked the increase of hypertrophic markers induced by testosterone. Moreover, inhibition of intracellular androgen receptor prevented testosterone-induced NFAT-Luc activation. Collectively, these results suggest that cardiac myocyte hypertrophy induced by testosterone involves a cooperative mechanism that links androgen signaling with the recruitment of NFAT through calcineurin activation and GSK-3β inhibition.

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GSK-3β and ERK1/2 incongruously act in tau hyperphosphorylation in SPS-induced PTSD rats.

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