Tau Phosphorylation And Mu-Calpain Activation Mediate The Dexamethasone-Induced Inhibition On The Insulin-Stimulated Akt Phosphorylation

Evidence has suggested that insulin resistance (IR) or high levels of glucocorticoids (GCs) may be linked with the pathogenesis andor progression of Alzheimer's disease (AD). Although studies have shown that a high level of GCs results in IR, little is known about the molecular details that link GCs and IR in the context of AD. Abnormal phosphorylation of tau and activation of mu-calpain are two key events in the pathology of AD. Importantly, these two events are also related with GCs and IR. We therefore speculate that tau phosphorylation and mu-calpain activation may mediate the GCs-induced IR. Akt phosphorylation at Ser-473 (pAkt) is commonly used as a marker for assessing IR. We employed two cell lines, wild-type HEK293 cells and HEK293 cells stably expressing the longest human tau isoform (tau-441; HEK293tau441 cells). We examined whether DEX, a synthetic GCs, induces tau phosphorylation and mu-calpain activation. If so, we examined whether the DEX-induced tau phosphorylation and mu-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. The results showed that DEX increased tau phosphorylation and induced tau-mediated mu-calpain activation. Furthermore, pre-treatment with LiCl prevented the effects of DEX on tau phosphorylation and mu-calpain activation. Finally, both LiCl pre-treatment and calpain inhibition prevented the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. In conclusion, our study suggests that the tau phosphorylation and mu-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation.