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Urokinase-Type Plasminogen Activator Protects Cerebral Cortical Neurons from Soluble Aß-Induced Synaptic Damage.
Diaz, Ariel; Merino, Paola; Guo, Ji-Dong; Yepes, Manuel A; McCann, Patrick; Katta, Tapasya; Tong, Elise M; Torre, Enrique; Rangaraju, Srikant; Yepes, Manuel.
Afiliação
  • Diaz A; Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, Georgia 30329.
  • Merino P; Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, Georgia 30329.
  • Guo JD; Silvio O. Conte Center for Oxytocin and Social Cognition & Center for Translational Social Neuroscience, Yerkes National Primate Research Center, Atlanta, Georgia 30329.
  • Yepes MA; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30329.
  • McCann P; Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, Georgia 30329.
  • Katta T; Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, Georgia 30329.
  • Tong EM; Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, Georgia 30329.
  • Torre E; Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, Georgia 30329.
  • Rangaraju S; Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Atlanta, Georgia 30329.
  • Yepes M; Department of Neurology, Emory University, Atlanta, Georgia 30329.
J Neurosci ; 40(21): 4251-4263, 2020 05 20.
Article em En | MEDLINE | ID: mdl-32332118
Soluble amyloid ß (Aß)-induced synaptic dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that precedes the deposition of insoluble Aß 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 Aß 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 Aß decreases its expression in cerebral cortical neurons. Here we show that neuronal uPA protects the synapse from the harmful effects of soluble Aß. However, Aß-induced inactivation of the eukaryotic initiation factor 2α halts the transcription of uPA mRNA, leaving unopposed the deleterious effects of Aß 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 Aß. 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 Aß oligomers. These data indicate that Aß-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 ß (Aß)-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 Aß. However, Aß-induced inactivation of the eukaryotic initiation factor 2α decreases the synaptic abundance of uPA, leaving unopposed the harmful effects of Aß 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 Aß on the synapse. These results unveil a novel mechanism of Aß-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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinapses / Ativador de Plasminogênio Tipo Uroquinase / Córtex Cerebral / Peptídeos beta-Amiloides / Neurônios Limite: Animals Idioma: En Revista: J Neurosci Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinapses / Ativador de Plasminogênio Tipo Uroquinase / Córtex Cerebral / Peptídeos beta-Amiloides / Neurônios Limite: Animals Idioma: En Revista: J Neurosci Ano de publicação: 2020 Tipo de documento: Article