Soluble amyloid-b peptide (Ab) oligomers, known to accumulate in Alzheimer´s disease brains, target excitatory post-synaptic terminals. This is thought to trigger synapse deterioration, a mechanism possibly underlying memory loss in early stage Alzheimer´s disease. A major unknown is the identity of the receptor(s) targeted by oligomers at synapses. Because oligomers have been shown to interfere with N-methyl-D-aspartate receptor (NMDAR) function and trafficking, we hypothesized that NMDARs might be required for oligomer binding to synapses. An amplicon vector was used to knock-down NMDARs in mature hippocampal neurons in culture, yielding 90% reduction in dendritic NMDAR expression and blocking neuronal oxidative stress induced by Ab oligomers, a pathological response that has been shown to be mediated by NMDARs. Remarkably, NMDAR knock-down abolished oligomer binding to dendrites, indicating that NMDARs are required for synaptic targeting of oligomers. Nevertheless, oligomers do not appearto bind directly to NMDARs as indicated by the fact that both oligomer-attacked and non-attacked neurons exhibit similar surface levels of NMDARs. Furthermore, pre-treatment of neurons with insulin down-regulates oligomer-binding sites in the absence of a parallel reduction in surface levels of NMDARs. Establishing that NMDARs are key components of the synaptic oligomer binding complex may illuminate the development of novel approaches to prevent synapse failure triggered by Ab oligomers.Fil: Decker, Helena. Universidade Federal do Rio de Janeiro; BrasilFil: Jürgensen, Sofia. Universidade Federal do Rio de Janeiro; BrasilFil: Adrover, Martín Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Brito Moreira, Jordano. Universidade Federal do Rio de Janeiro; BrasilFil: Bomfim, Theresa R.. Universidade Federal do Rio de Janeiro; BrasilFil: Klein, William L.. Northwestern University; Estados UnidosFil: Epstein, Alberto L.. Universite Claude Bernard Lyon 1. Institut de Physique Nucléaire de Lyon.; FranciaFil: De Felice, Fernanda G.. Universidade Federal do Rio de Janeiro; BrasilFil: Jerusalinsky, Diana Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Ferreira, Sergio Teixeira. Universidade Federal do Rio de Janeiro; Brasil