Neurexins (NRXNs) are synaptic cell adhesion molecules having essential roles in the assembly and maturation of synapses into fully functional units. Immunocytochemical and electrophysiological studies have shown that specific binding, across the synaptic cleft, of the ectodomains of presynaptic NRXNs and postsynaptic Neuroligins (NLGNs) have the potential to bidirectionally coordinate and trigger synapse formation. Moreover, in vivo studies as well as genome-wide association studies pointed out implication of NRXNs in the pathogenesis of cognitive disorders including autism spectrum disorders (ASDs) and different types of addictions including opioid and alcohol dependences, suggesting an important role in synaptic function. Despite extensive investigations, the mechanisms by which NRXNs modulate the properties of synapses remain largely unknown. We report here that α- and γ-secretases can sequentially process neurexin-3β(NRXN3β), leading to the formation of two final products: a ~80 kDa N-terminal extracellular domain of Neurexin-3β (sNRXN3β) and ~12 kDa C-terminal intracellular NRXN3β domain (NRXN3β-ICD), with both of them being potentially implicated in the regulation of NRXNs and NLGNs functions at the synapses, or in yet unidentified signal transduction pathways. We further report that this processing is altered by several PS1 mutations in the catalytic subunit of the γ-secretase that causes early-onset familial Alzheimer's disease.