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.
Wu
Gui-Mei
GM
Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huaihai Road, Jiangsu 221002, China.
Hou
Xiao-Yu
XY
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004789:Enzyme Activation / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity*; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology
D016229:Amyloid beta-Peptides; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine; D019061:src-Family Kinases; C501449:Dlg4 protein, rat; C074636:amyloid beta-protein (25-35)