Effect of chronic treatment with lithium on protein cyclin-dependent kinase 5 (CDK5) and tau protein in a primary culture of cortical neurons

Abstract

In the last few years a special attention has been given to the possible neuroprotective effects of lithium, especially after the discovery of his regulatory effects on pro and antiapoptotic proteins. Low lithium concentration has a significant positive effect in synaptic plasticity and reduces Tau phosphorylation in neuronal cell culture studies for distinct mechanisms. Lithium negatively regulates the expression and activity of two enzymes, cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3 β). In primary cultures of rat neurons, lithium reduces the amount of intracellular calcium, calpain activity, activation of CDK5 and consequently reduces cell death. Among the substrates of CDK5 there are several proteins involved in axonal transport, such as Tau protein. GSK3 β reduces tau phosphorylation and significantly decreases the overall rate of axonal transport of tau in rat cortical neurons. Primary cultures of cortical and neurons were treated after 4 days in culture (DIC), and were incubated (37°C, 5% CO 2) with different concentrations of lithium chloride until to 10 days in culture. Working concentrations of lithium were 0.02mM, 0.2mM and 2mM. The effects of lithiumon Tau and CDK5 protein was determined by Western-blot, using a panel of primary antibodies. The expression of Tau protein reduced in the three treatments, comparing to the control, to 18%, 23% and 20%, respectively. And CDK5 showed an increase of 35% in 0.02mM and 33% 0.2mM and a reduction of 10% in 2mM. Subterapeutics doses of lithium were able to reduce the phosphorylation of Tau protein. The CDK5 has increased at doses subterapeucs, and its increase this related corticogenesis, which needs the protein tau for this.