Amyloid β peptide oligomers directly activate NMDA receptors

Amyloid beta (A beta) oligomers accumulate in the brain tissue of Alzheimer disease patients and are related to disease pathogenesis. The precise mechanisms by which A beta oligomers cause neurotoxicity remain unknown. We recently reported that A beta oligomers cause intracellular Ca2+ overload and neuronal death that can be prevented by NMDA receptor antagonists. This study investigated whether A beta oligomers directly activated NMDA receptors (NMDARs) using NR1/NR2A and NR1/NR2B receptors that were heterologously expressed in Xenopus laevis oocytes. Indeed. A beta 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 A beta 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 Ca2+ induced by A beta 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 A beta 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 A beta damage to neurons in Alzheimeris disease. (c) 2011 Elsevier Ltd. All rights reserved.