Reduction Of Tau Phosphorylation By Activating EphB2Receptor In HTau Mice And Type1Diabetic Mice And Its Mechanisms

Background EphB2receptor is a important member of tyrosine kinases (RTKs) family, expressed in hippocampus abundantly, which is essential for the development of synapse. The level of EphB2decreased in the hippcampus of Alzheimer’s disease(AD) patients and in AD transgenic mouse model. Recently it was reported that increasing EphB2expression in a transgenic mouse model of Alzheimer’s disease(AD) could rescue the cognitive deficit, suggesting a crucial role of EphB2in AD. In previous study, we have reported that activation of EphB2receptor reduced the level of tau phosphorylation (10-20mmol/L) in vitro. However, whether activation of EphB2can reduce the level of tau phosphorylation in vivo have not been reported yet. In addition, it has been confirmed that diabetes related with AD and he level of tau phosphorylation significantly increased in hippocampus of diabetic mice. While the role of the EphB2in the process of diabetes to AD has not been reported.Objective It was to explore how change of tau phosphorylation under the effect of activation of EphB2receptor in hTau mice and in HEK293/tau cells which treated by high glucose.Methods EphrinBl/Fc was administrated in CA3area in hippocampus of hTau mice by stereotaxic injection and the control group was injected with Fc.The expression of EphB2was detected by immunohistochemisty and western-blot, the activity was detected by Eph2activity Kit. Immuno-fluorescent staining and western-blot was used to detect the level of Ser396and Thr231.The change of GSK3β，Akt, PI3K was detect by western-blot.We made the type I diabetes mice model by tail vein injection of alloxan. According to the blood glucose concentration, we divided into mild hyperglycemia group (7-10mmol/L), medium high blood glucose group (10-20mmol/L), high blood glucose group (20-30mmol/L). The expression of EphB2, Ser396and Thr231in the hippocampus were detected by western-blot in different groups. The expression of Ser396, Thr231in HEK293cells induced by high glucose detected by Western-blot,and then we overexpressed and activated of EphB2in HEK293/tau cells which cultured by high glucose medium and detected the level of Ser396and Thr231by western-blot.Results Compare with the control group, the level of EphB2expression and activity decreased in AD transgenic (hTau) modol mice had no obviously change. Activation of EphB2in hippocampus of hTau mice attenuates tau phosphorylation and activation of PI3K and Akt, as well as inhibition of GSK3β. Compare with the control group, the expression of EphB2decreased in hippocampus of Type I diabetes and the level of tau phosphorylation increased obviously. In HEK293/tau cells, we also observed that the level of tau phosphorylation increased obviously by high glucose. Overexpression and activation of EphB2reversed tau phosphorylation caused by high glucose level.Conclusions Activation of EphB2attenuates tau phosphorylation in hTau mice with involving activation of PI3K and Akt and inhibition of GSK-3β.Overexpression and activation of EphB2reversed tau phosphorylation caused by high glucose.