LITHIUM REDUCES TAU-PHOSPHORYLATION BY INHIBITION OF GLYCOGEN-SYNTHASE KINASE-3

Lithium is one of the most widely used drugs for treating bipolar (man ic-depressive) disorder. Despite its efficacy, the molecular mechanism underlying its action has not been elucidated, One recent study has p roposed that lithium inhibits glycogen synthase kinase-3 and thereby a ffects multiple cellular functions, Because glycogen synthase kinase-3 regulates the phosphorylation of tau (microtubule binding protein tha t forms paired helical filaments in neurons of the Alzheimer's disease brain), we hypothesized that lithium could affect tau phosphorylation by inhibiting glycogen synthase kinase-3. Using cultured human NT2N n eurons, we demonstrate that lithium reduces the phosphorylation of tau , enhances the binding of tau to microtubules, and promotes microtubul e assembly through direct and reversible inhibition of glycogen syntha se kinase-3. These results provide new insights into how Lithium media tes its effects in the central nervous system, and these findings coul d be exploited to develop a novel intervention for Alzheimer's disease .