The aim of this study was to investigate the effect of liraglutide on Alzheimer-like learning and memory impairment in mice, which were intracerebroventricularly (i.c.v.) injected with streptozotocin (STZ). Twenty-four mice were randomly divided into three groups: control (CON), AD model (STZ), and liraglutide-treated (LIR). The results show that both hyperphosphorylated tau and neurofilament proteins had deceased protein glycosylation and the tau bound to microtubules was lower in the STZ group compared to the CON group. The expression of JNK phosphorylation was higher and the number of Fluoro-Jade-B-positive degenerative neurons was increased in the STZ group as compared to both the CON and liraglutide groups. Escape latency in the STZ group was longer than that in both the CON and LIR groups, while the number of hidden platform crossings in path length was less than that in the other two groups. Liraglutide decreased the hyperphosphorylation levels of tau and neurofilament proteins, increased protein O-glycosylation, increased tau bound to microtubules, and also significantly improved the learning and memory ability of the mice. These results suggest that the effects of liraglutide on decreasing the hyperphosphorylation of tau and neurofilament proteins by enhancing O-glycosylation of neuronal cytoskeleton protein, improving the JNK and ERK signaling pathway, and reducing neural degeneration may be related to its protective effects on AD-like learning and memory impairment induced by i.c.v. injection of STZ. Our results indicate that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.