title: Amyloid β peptide oligomers directly activate NMDA receptors.
abstract: Amyloid beta (Aβ) oligomers accumulate in the brain tissue of Alzheimer disease patients and are related to disease pathogenesis. The precise mechanisms by which Aβ oligomers cause neurotoxicity remain unknown. We recently reported that Aβ oligomers cause intracellular Ca(2+) overload and neuronal death that can be prevented by NMDA receptor antagonists. This study investigated whether Aβ oligomers directly activated NMDA receptors (NMDARs) using NR1/NR2A and NR1/NR2B receptors that were heterologously expressed in Xenopus laevis oocytes. Indeed, Aβ oligomers induced inward non-desensitizing currents that were blocked in the presence of the NMDA receptor antagonists memantine, APV, and MK-801. Intriguingly, the amplitude of the responses to Aβ oligomers was greater for NR1/NR2A heteromers than for NR1/NR2B heteromers expressed in oocytes. Consistent with these findings, we observed that the increase in the cytosolic concentration of Ca(2+) induced by Aβ oligomers in cortical neurons is prevented by AP5, a broad spectrum NMDA receptor antagonist, but slightly attenuated by ifenprodil which blocks receptors with the NR2B subunit. Together, these results indicate that Aβ oligomers directly activate NMDA receptors, particularly those with the NR2A subunit, and further suggest that drugs that attenuate the activity of such receptors may prevent Aβ damage to neurons in Alzheimeŕs disease.
authors.affiliation: Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Texidó
authors.forename: Mireia
authors.initials: M
authors.lastname: Martín-Satué
authors.forename: Elena
authors.initials: E
authors.lastname: Alberdi
authors.forename: Carles
authors.initials: C
authors.lastname: Solsona
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D055724:Electrophysiological Phenomena; D005260:Female; D006801:Humans; D008559:Memantine / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D014982:Xenopus laevis / Q000196:embryology
chemical_list: D016229:Amyloid beta-Peptides; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010446:Peptide Fragments; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); D016291:Dizocilpine Maleate; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine; C010739:ifenprodil; D002118:Calcium; D008559:Memantine