Oligomeric Aβ25-35 induces the tyrosine phosphorylation of PSD-95 by SrcPTKs in rat hippocampal CA1 subfield

Purpose: Although amyloid-beta (A beta) is one of the neuropathological hallmarks of Alzheimer's Disease (AD), the mechanisms of A beta neurotoxicity remain to be clarified. This study was aimed to evaluate the effect of AB on postsynaptic density-95 (PSD-95) tyrosine phosphorylation. Elucidating the regulatory mechanisms underlying it may be a promising therapy in AD. Methods: A beta 25-35 oligomers (20 mu g/rat) were administered intracerebroventricularly in adult male Sprague-Dawley rats. PSD-95 tyrosine phosphorylation was assessed using immunoprecipitation followed by immunoblot analysis. Immunoblot was applied for measuring the protein levels of PSD-95 and beta-actin. Results: Following 3, 7, 14, 21 days after oligomeric A beta 25-35 treatment, the tyrosine phosphorylation of PSD-95 increased significantly, and peaked at 3 days after oligomeric A beta 25-35 treatment in hippocampal CA1 subfield. Src family protein tyrosine kinases (SrcPTKs) specific inhibitor PP2 attenuated the tyrosine phosphorylation of PSD-95 induced by A beta 25-35. Amantadine [N-methyl-D-aspartate (NMDA) receptor noncompetitive antagonist], NVP-AAM077 (GluN2A-containing NMDA receptor selective inhibitor) and Ro25-6981 (GluN2B-containing NMDA receptor selective inhibitor) also suppressed the A beta 25-35-induced PSD-95 tyrosine phosphorylation. Conclusion: These results suggest that A beta oligomers induce the tyrosine phosphorylation of PSD-95 by SrcPTKs, which is mediated by the activation of GluN2A- and GluN2B-containing NMDA receptors.