| First Author | Diaz A | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 21 | Pages | 4251-4263 |
| PubMed ID | 32332118 | Mgi Jnum | J:289441 |
| Mgi Id | MGI:6430843 | Doi | 10.1523/JNEUROSCI.2804-19.2020 |
| Citation | Diaz A, et al. (2020) Urokinase-Type Plasminogen Activator Protects Cerebral Cortical Neurons from Soluble Abeta-Induced Synaptic Damage. J Neurosci 40(21):4251-4263 |
| abstractText | Soluble amyloid beta (Abeta)-induced synaptic dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that precedes the deposition of insoluble Abeta 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 Abeta 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 Abeta decreases its expression in cerebral cortical neurons. Here we show that neuronal uPA protects the synapse from the harmful effects of soluble Abeta. However, Abeta-induced inactivation of the eukaryotic initiation factor 2alpha halts the transcription of uPA mRNA, leaving unopposed the deleterious effects of Abeta 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 Abeta. 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 Abeta oligomers. These data indicate that Abeta-induced decrease in the synaptic abundance of uPA contributes to the development of synaptic damage in the early stages of AD.SIGNIFICANCE STATEMENT Soluble amyloid beta (Abeta)-induced synaptic dysfunction is an early event in the pathogenesis of cognitive deficits in Alzheimer's disease (AD). We found that neuronal urokinase-type (uPA) protects the synapse from the deleterious effects of soluble Abeta. However, Abeta-induced inactivation of the eukaryotic initiation factor 2alpha decreases the synaptic abundance of uPA, leaving unopposed the harmful effects of Abeta on the synapse. In line with these observations, the synaptic expression of uPA is decreased in the frontal cortex of AD brains and 5xFAD mice, and uPA treatment abrogates the deleterious effects of Abeta on the synapse. These results unveil a novel mechanism of Abeta-induced synaptic dysfunction in AD patients, and indicate that recombinant uPA is a potential therapeutic strategy to protect the synapse before the development of irreversible brain damage. |
