Insulin transiently increases tau phosphorylation:: Involvement of glycogen synthase kinase-3β and Fyn tyrosine kinase

The modulation of tau phosphorylation in response to insulin was examined in human neuroblastoma SH-SY5Y cells. Insulin treatment resulted in a transient increase in tau phosphorylation followed by a decrease in tau phosphorylation that correlated directly with a sequential activation and deactivation of glycogen synthase kinase-3 beta (GSK-3 beta). The insulin-induced increase in tau phosphorylation and concurrent activation of GSK-3 beta was rapid (<2 min) and transient, and was associated with increased tyrosine phosphorylation of GSK-3 beta. The increase in GSK-3 beta tyrosine phosphorylation corresponded directly to an increase in the association of Fyn tyrosine kinase with GSK-3 beta, and Fyn immunoprecipitated from cells treated with insulin for 1 min phosphorylated GSK-3 beta to a significantly greater extent than Fyn immunoprecipitated from control cells. Subsequent to the increase in GSK-3 beta activation and tau phosphorylation, treatment of cells with insulin for 60 min resulted in a dephosphorylation of tau and a decrease in GSK-3 beta activity. Thus, insulin rapidly and transiently activated GSK-3 beta and modulated tau phosphorylation, alterations that may contribute to neuronal plasticity.