AbstractAmyloid-β oligomers (AβOs), toxic peptide aggregates found in Alzheimer’s disease (AD), cause synapse pathology. AβOs interact with Neurexins (NRXs), key synaptic organizers, and this interaction dampens normal trafficking and function of NRXs. Axonal trafficking of NRX is in part regulated by its interaction with SorCS1, a protein sorting receptor, but the impact of SorCS1 regulation of NRXs in Aβ pathology was previously unstudied. Here, we show competitive interaction of SorCS1 and AβOs with β-NRXs and rescue effects of SorCS1 on AβO-induced synaptic pathology. Like AβOs, SorCS1 binds to NRX1β through the histidine-rich-domain (HRD) of NRX1β, and SorCS1 and AβOs compete for NRX1β binding. In cultured hippocampal neurons, SorCS1 colocalizes with NRX1β on the axon surface, and axonal expression of SorCS1 rescues AβO-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling as well as AβO-induced structural defects in excitatory synapses. Thus, we reveal a role of SorCS1 in the rescue of AβO-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for AD.