Oligomerized Aβ25–35 induces increased tyrosine phosphorylation of NMDA receptor subunit 2A in rat hippocampal CA1 subfield

Amyloid-β peptide (Aβ) 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 Aβ25–35 oligomers. Aβ25–35 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 Aβ25–35-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 Aβ 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 Aβ-induced over-activation of NMDA receptors and is involved in neuronal impairment.