Leptin is a centrally acting hormone controlling metabolic pathways. Recently, it was shown that leptin can reduce amyloid beta levels both in vitro and in vivo. Herein, phosphorylation of tau was investigated following treatment of neuronal cells with leptin and insulin. Specifically, phosphorylation of tau at amino acid residues Ser(202), Ser(396) and Ser(404) was monitored in retinoic acid induced, human cell lines: SH-SY5Y and NTera-2. Both hormones induced a concentration- and time-dependent reduction of tau phosphorylation, and were synergistic at suboptimum concentrations. Importantly, leptin was 300-fold more potent than insulin (IC(50)L=46.9 nM vs. IC(50)I=13.8 microM). A central role for AMP-dependent kinase as a mediator of leptin's action is demonstrated by the ability of 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) to decrease tau phosphorylation, and by blocking leptin in the presence of Compound C. Thus, leptin, which ameliorates both amyloid beta and tau-related pathological pathways, holds promise as a novel therapeutic for Alzheimer's disease.