Brito-Moreira_2017_J.Biol.Chem_292_7327

Brain accumulation of the amyloid-beta protein (Abeta) and synapse loss are neuropathological hallmarks of Alzheimer disease (AD). Abeta oligomers (AbetaOs) are synaptotoxins that build up in the brains of patients and are thought to contribute to memory impairment in AD. Thus, identification of novel synaptic components that are targeted by AbetaOs may contribute to the elucidation of disease-relevant mechanisms. Trans-synaptic interactions between neurexins (Nrxs) and neuroligins (NLs) are essential for synapse structure, stability, and function, and reduced NL levels have been associated recently with AD. Here we investigated whether the interaction of AbetaOs with Nrxs or NLs mediates synapse damage and cognitive impairment in AD models. We found that AbetaOs interact with different isoforms of Nrx and NL, including Nrx2alpha and NL1. Anti-Nrx2alpha and anti-NL1 antibodies reduced AbetaO binding to hippocampal neurons and prevented AbetaO-induced neuronal oxidative stress and synapse loss. Anti-Nrx2alpha and anti-NL1 antibodies further blocked memory impairment induced by AbetaOs in mice. The results indicate that Nrx2alpha and NL1 are targets of AbetaOs and that prevention of this interaction reduces the deleterious impact of AbetaOs on synapses and cognition. Identification of Nrx2alpha and NL1 as synaptic components that interact with AbetaOs may pave the way for development of novel approaches aimed at halting synapse failure and cognitive loss in AD.