Soluble amyloid β (Aβ)-induced synaptic dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that precedes the deposition of insoluble Aβ and correlates with the development of cognitive deficits better than the number of plaques. The mammalian plasminogen activation (PA) system catalyzes the generation of plasmin via two activators: tissue-type (tPA) and urokinase-type (uPA). A dysfunctional tPA-plasmin system causes defective proteolytic degradation of Aβ plaques in advanced stages of AD. In contrast, it is unknown if uPA and its receptor (uPAR) contribute to the pathogenesis of this disease. Neuronal cadherin (NCAD) plays a pivotal role in the formation of synapses and dendritic branches, and Aβ decreases its expression in cerebral cortical neurons. Here we show that neuronal uPA protects the synapse from the harmful effects of soluble Aβ. However, Aβ-induced inactivation of the eukaryotic initiation factor 2α (eIF2α) halts the transcription of uPA mRNA, leaving unopposed the deleterious effects of Aβ on the synapse. In line with these observations, the synaptic abundance of uPA but not uPAR is decreased in the frontal cortex of AD patients and 5xFAD mice, and in cerebral cortical neurons incubated with soluble Aβ. We found that uPA-treatment increases the synaptic expression of NCAD by a uPAR-mediated plasmin-independent mechanism, and that uPA-induced formation of NCAD dimers protects the synapse from the harmful effects of soluble Aβ oligomers. These data indicate that Aβ-induced decrease in the synaptic abundance of uPA contributes to the development of synaptic damage in the early stages of AD. [ABSTRACT FROM AUTHOR]