Protective Effects Of Metformin On Impairment Of Learning And Memory And It’s Mechanism

Objective:To explore the protective effect of metformin and it’s mechanism on learning and memory deficit of AD animal model induced by STZ.Method:Streptozotocin (STZ) was used to establish AD model, metformin was administered through a gastric tube every day, whereas the control and STZ groups were given the same volume water. Morris water maze test was employed to assess the learning and memory ability of mice. The O-Glycosylation and phosphorylation of Tau and neurofilaments (NFs) proteins, the phosphorylated protein associated with insulin signaling pathway was analyzed by western blot and immunohistochemistiy. The microtubule binding assay was applied to detect the assembly function of Tau binding to microtubule, while the degenerative nerve cells were labeled with Fluoro-Jade B (FJB). The APP/PS1/Tau triple transgenic mice were identified by PCR and Western blot assays.Results:Compared with the control group, the AD mouse model, characterized a series of Alzheimer disease-like changes, displayed a significant increased of escape latency and path length as well as less number of crossing hidden platform in the Morris water maze (MWM) trail; A elevation of hyperphosphorylated Tau and NFs proteins. Impaired brain insulin signaling, a increase in expression of FJB-positive cells, a reduction of O-GlcNAcylation protein and ability of the Tau binding to microtubule was also observed in the STZ group; While after treatment with metformin, there is a significant amelioration in learning and memory, up-regulation of O-GlcNAcylation protein and the ability of Tau binding to microtubule, normalized the destructed neuronal insulin signaling, a suppression in hyperphosphorylated tau and neurofilaments (NFs) proteins levels,followed by FJB-positive cells.Conclusions:Metformin could protect learning and memory impairment of AD mice, which may be related to the suppression of the increased hyperphosphorylation of Tau and NFs proteins, down-regulation of O-GlcNAcylation protein, improving brain insulin signaling pathway.