Interaction of amyloid- (A) oligomers with neurexin 2 and neuroligin 1 mediates synapse damage and memory loss in mice

Brain accumulation of the amyloid- protein (A) and synapse loss are neuropathological hallmarks of Alzheimer disease (AD). A oligomers (AOs) 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 AOs 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 AOs with Nrxs or NLs mediates synapse damage and cognitive impairment in AD models. We found that AOs interact with different isoforms of Nrx and NL, including Nrx2 and NL1. Anti-Nrx2 and anti-NL1 antibodies reduced AO binding to hippocampal neurons and prevented AO-induced neuronal oxidative stress and synapse loss. Anti-Nrx2 and anti-NL1 antibodies further blocked memory impairment induced by AOs in mice. The results indicate that Nrx2 and NL1 are targets of AOs and that prevention of this interaction reduces the deleterious impact of AOs on synapses and cognition. Identification of Nrx2 and NL1 as synaptic components that interact with AOs may pave the way for development of novel approaches aimed at halting synapse failure and cognitive loss in AD.