Oligomeric Aß25-35 induces the tyrosine phosphorylation of PSD-95 by SrcPTKs in rat hippocampal CA1 subfield.

ABSTRACT

PURPOSE: Although amyloid-ß (Aß) is one of the neuropathological hallmarks of Alzheimer's Disease (AD), the mechanisms of Aß neurotoxicity remain to be clarified. This study was aimed to evaluate the effect of Aß on postsynaptic density-95 (PSD-95) tyrosine phosphorylation. Elucidating the regulatory mechanisms underlying it may be a promising therapy in AD. METHODS: Aß25-35 oligomers (20 µg/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 ß-actin. RESULTS: Following 3, 7, 14, 21 days after oligomeric Aß25-35 treatment, the tyrosine phosphorylation of PSD-95 increased significantly, and peaked at 3 days after oligomeric Aß25-35 treatment in hippocampal CA1 subfield. Src family protein tyrosine kinases (SrcPTKs) specific inhibitor PP2 attenuated the tyrosine phosphorylation of PSD-95 induced by Aß25-35. 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 Aß25-35-induced PSD-95 tyrosine phosphorylation. CONCLUSION: These results suggest that Aß oligomers induce the tyrosine phosphorylation of PSD-95 by SrcPTKs, which is mediated by the activation of GluN2A- and GluN2B-containing NMDA receptors.