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Aß and NMDAR activation cause mitochondrial dysfunction involving ER calcium release.
Ferreira, Ildete Luísa; Ferreiro, Elisabete; Schmidt, Jeannette; Cardoso, João M; Pereira, Cláudia M F; Carvalho, Ana Luísa; Oliveira, Catarina R; Rego, A Cristina.
Afiliación
  • Ferreira IL; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal.
  • Ferreiro E; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal.
  • Schmidt J; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal; PhD Programme in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, Univers
  • Cardoso JM; Instrumentation Center, Physics Department, University of Coimbra, Coimbra, Portugal.
  • Pereira CM; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
  • Carvalho AL; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
  • Oliveira CR; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
  • Rego AC; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: a.cristina.rego@gmail.com.
Neurobiol Aging ; 36(2): 680-92, 2015 Feb.
Article en En | MEDLINE | ID: mdl-25442114
Early cognitive deficits in Alzheimer's disease (AD) seem to be correlated to dysregulation of glutamate receptors evoked by amyloid-beta (Aß) peptide. Aß interference with the activity of N-methyl-d-aspartate receptors (NMDARs) may be a relevant factor for Aß-induced mitochondrial toxicity and neuronal dysfunction. To evaluate the role of mitochondria in NMDARs activation mediated by Aß, we followed in situ single-cell simultaneous measurement of cytosolic free Ca(2+)(Cai(2+)) and mitochondrial membrane potential in primary cortical neurons. Our results show that direct exposure to Aß + NMDA largely increased Cai(2+) and induced immediate mitochondrial depolarization, compared with Aß or NMDA alone. Mitochondrial depolarization induced by rotenone strongly inhibited the rise in Cai(2+) evoked by Aß or NMDA, suggesting that mitochondria control Ca(2+) entry through NMDARs. However, incubation with rotenone did not preclude mitochondrial Ca(2+) (mitCa(2+)) retention in cells treated with Aß. Aß-induced Cai(2+) and mitCa(2+) rise were inhibited by ifenprodil, an antagonist of GluN2B-containing NMDARs. Exposure to Aß + NMDA further evoked a higher mitCa(2+) retention, which was ameliorated in GluN2B(-/-) cortical neurons, largely implicating the involvement of this NMDAR subunit. Moreover, pharmacologic inhibition of endoplasmic reticulum (ER) inositol-1,4,5-triphosphate receptor (IP3R) and mitCa(2+) uniporter (MCU) evidenced that Aß + NMDA-induced mitCa(2+) rise involves ER Ca(2+) release through IP3R and mitochondrial entry by the MCU. Altogether, data highlight mitCa(2+) dyshomeostasis and subsequent dysfunction as mechanisms relevant for early neuronal dysfunction in AD linked to Aß-mediated GluN2B-composed NMDARs activation.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Calcio / Péptidos beta-Amiloides / Receptores de N-Metil-D-Aspartato / Retículo Endoplásmico / Mitocondrias Tipo de estudio: Etiology_studies Idioma: En Revista: Neurobiol Aging Año: 2015 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Calcio / Péptidos beta-Amiloides / Receptores de N-Metil-D-Aspartato / Retículo Endoplásmico / Mitocondrias Tipo de estudio: Etiology_studies Idioma: En Revista: Neurobiol Aging Año: 2015 Tipo del documento: Article