Oligomerized Abeta25-35 induces increased tyrosine phosphorylation of NMDA receptor subunit 2A in rat hippocampal CA1 subfield.

Amyloid-beta peptide (Abeta) plays a causal role in the pathogenesis of Alzheimer's disease (AD). To elucidate the mechanisms underlying the over-activation of NMDA receptors in AD, we investigated the alteration of NR2A tyrosine phosphorylation after intracerebroventricular infusion of Abeta25-35 oligomers. Abeta25-35 treatment resulted in the elevated tyrosine phosphorylation of NR2A in rat hippocampal CA1 subfield and facilitated the interactions of NR2A or PSD-95 with Src kinases. PP2, a specific inhibitor of Src family protein tyrosine kinases (SrcPTKs), not only attenuated the Abeta25-35-induced increases in the tyrosine phosphorylation of NR2A and in the associations among Src, NR2A, and PSD-95, but also protected against neuronal loss in the CA1 region. Preapplication of a noncompetitive NMDA receptor antagonist amantadine, an NR2A-selective NMDA receptor antagonist NVP-AAM077, or an NR2B-selective NMDA receptor antagonist Ro25-6981 inhibited the increased tyrosine phosphorylation of NR2A and prevented the associations among Src, NR2A, and PSD-95, but Ro25-6981 had less contribution. These results suggest that the activation of NMDA receptors after Abeta treatment promotes the formation of NR2A-PSD-95-Src complex and thus increases the tyrosine phosphorylation of NR2A by Src kinases, which up-regulates the function of NMDA receptors. Such positive feedback mediates the Abeta-induced over-activation of NMDA receptors and is involved in neuronal impairment.