Urokinase-type Plasminogen Activator Protects Cerebral Cortical Neurons From Soluble Aβ-induced Synaptic Damage.

Soluble amyloid beta (A beta)-induced synaptic dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that precedes the deposition of insoluble A beta 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: tissuetype (tPA) and urokinase-type (uPA). A dysfunctional tPA-plasmin system causes defective proteolytic degradation of A beta plaques in advanced stages of AD. In contrast, it is unknown whether 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 A beta decreases its expression in cerebral cortical neurons. Here we show that neuronal uPA protects the synapse from the harmful effects of soluble A beta. However, A beta-induced inactivation of the eukaryotic initiation factor 2 alpha halts the transcription of uPA mRNA, leaving unopposed the deleterious effects of A beta 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 A beta. 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 A beta oligomers. These data indicate that A beta-induced decrease in the synaptic abundance of uPA contributes to the development of synaptic damage in the early stages of AD.