Abstract: Objective To study the association of leptin with the occurrence and development of Alzheimer's disease. Methods A model of tau hyperphosphorylation was induced by all-trans retinoic acid (ATRA) in SH-SY5Y cells and treated with exogenous leptin. Expression of phosphorylated tau protein in SH-SY5Y cells was detected. Results PCR showed that the expression level of leptin long receptor ObRb was higher after the model of hyperphosphorylated tau protein was established (P< 0.01) whereas western blot showed that the expression level of phosphorylated tau protein was lower and the morphology of SH-SY5Y cells was changed after leptin was given (P< 0.01). Conclusion Leptin can reduce Alzheimer's disease-related tau protein hyperphosphorylation in vitro.