Amyloid-beta oligomers (A beta o) play a major role in the synaptic dysfunction of Alzheimer's disease (AD). Neuroligins are postsynaptic cell-adhesion molecules, that share an extracellular domain with high degree of similarity to acetylcholinesterase (AChE), one of the first putative A beta o receptors. We recently found that A beta o interact with the soluble N-terminal fragment of neuroligin-1 (NL-1). We report here that AN associate with NL-1 at excitatory hippocampal synapses, whereas almost no association was observed with neuroligin-2, an isoform present at inhibitory synapses. Studies using purified hippocampal postsynaptic densities indicate that NL-1 interacts with A beta o in a complex with GluN2B-containing NMDA receptors. Additionally, the soluble fragment of NL-1 was used as a scavenger for A beta o. Field excitatory postsynaptic potentials indicate that fragments of NL-1 protect hippocampal neurons from the impairment induced by A beta o. To our knowledge, this is the first report of the interaction between this extracellular fragment of NL-1 and A beta o, strongly suggest that NL-1 facilitates the targeting of A beta o to the postsynaptic regions of excitatory synapses. (C) 2015 Elsevier Inc. All rights reserved.