Reduction And The Intracellular Translocation Of EphB2 Receptor In Tg2576 Mice And The Effects On Tau Phosporylation

Background EphB2 is a member of receptor tyrosine kinases (RTKs) family that is essential for the cell adhesion, neural crest migration, axon guidance and synaptogenesis in the nervous system. The level of EphB2 decreased in the hippocampus of Alzheimer's disease (AD) patients and in AD transgenitic mouse models, while increasing EphB2 expression in the dentate gyrus of APP transgenic mice could reverse the deficits in N-methyl-d-aspartic acid (NMDA) receptor-dependent long-term potentiation (LTP) and memory impairment. However, the age-dependent alteration of EphB2 in different brain regions and its intracellular distribution in tg2576 mice has not been reported. Additionally, it is well known thatβ-Amyloid (Aβ) oligomers could induce intracellular tau hyperphosphorylation, however, it is not known whether EphB2 meadiates the role of Aβin tau hyperphosphorylation, and whether upregulation of EphB2 could attenuate AD-like pathologies.Objective It was to explore the effect of AB on EphB2 and the potential role of EphB2 in the progress of AD.Methods Immunohistochemistry, Western blot, primary hippocampal culture, immunofluorescent staining, cell culture, and plasmid transfection have been used in this study.Results In tg2576 mice, the level of EphB2 decresed age- and brain area- dependently, the decrease was first shown in the olfactory bulb (OB), then hippocampus and neocortex. The delption of EphB2 expression was prior to MAP2 in the same brain area in vivo and in primary neuron in vitro. An age-dependent translocation of EphB2 from the neuronal processess to the cell bodies was also detected in the neocortex. In AB oligomers-treated SK-N-SH, HEK293-tau (HEK293 with stable expression of human tau441) and primary hippocampal neurons, tau hyperphosphorylation was prior to the decrease of EphB2. Activatin of EphB2 attenuates tau phosphorylation with an increased phosphorylation (activation) of its own tyrosine residues and activation of Akt, and as well as inhibition of glycogen synthase kinase-3β(GSK-3β). Deletion of the kinase domain(VM) of EphB2 eliminated the upregulation of Eph B2-induced tau dephosphorylation, whereas deletion of the PDZ-binding dormain of the receptor did not affect the role of EphB2 in dephosphorylating tau.Conclusions The foremost decrement of EphB2 in the olfactory bulb may represent an early sign of AD. Overexpression of exougenous EphB2 or activating endogenous EphB2 with ephrinBl/Fc could attenuate tau hyperphosphorylation with mechanisms involving the VM-mediated activation of Akt and inhibition of GSK-3β.