Research on the protective effect and mechanism of rosiglitazone on learning and memory impairment of AD-like mice induced by streptozotocin (STZ) intracerebroventricular (i.c.v.) injection. STZ i.c.v. injection was used to establish AD mice model and the treatment mice were administered orally with rosiglitazone for 30 days. Morris water maze was applied to detect the learning and memory ability of mice and Western blot and immunofluorescence to analyze the phosphorylation levels of Tau，the expression levels of phosphorylation and glycosylation of neurofilaments (NFs) protein, the expression levels of JNK and ERK. The microtubule binding assay was used to detect the assembly function of Tau binding with microtubule. The degenerative neurons were labeled by Fluoro -Jade B (FJB). Compared with the control group, the escape latency and path length were increased of the model group with less number of crossing hidden platform, and the Tau and NFs proteins were hyperphosphorylated and the glycosylation of NFs protein were lower. But compared with the model group, the rosiglitazone significantly improved the learning and memory ability of mice and decreased the hyperphosphorylated levels of Tau and NFs proteins, increased the glycosylation of NFs protein, and increased the microtubule-binding of Tau in treated-mice. The phosphorylated expression levels of JNK of model group were higher than the other two groups, while ERK1 were lower, but there was no significant difference of ERK2 in three groups. And the numbers of FJB-degenerative neurons of model group were much more than the other two groups. Rosiglitazone could protect learning and memory impairment of AD-like mice induced by STZ i.c.v. injection, which may be related to ameliorate the insulin signal pathway, decrease the hyperphosphorylation of Tau and NFs proteins, and protect from the neural degeneration.