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dc.contributor.authorMartin-de-Saavedra, Maríaes_ES
dc.contributor.authorNavarro, Elisaes_ES
dc.contributor.authorMoreno-Ortega, Ana J.es_ES
dc.contributor.authorCunha, Mauricio P.es_ES
dc.contributor.authorBuendía Abaitua, Izaskunes_ES
dc.contributor.authorHernansanz-Agustín, Pabloes_ES
dc.contributor.authorLeón Martínez, Rafaeles_ES
dc.contributor.authorCano-Abad, María F.es_ES
dc.contributor.authorMartínez-Ruiz, Antonioes_ES
dc.contributor.authorMartínez-Murillo, Ricardoes_ES
dc.contributor.authorDuchen, Michael R.es_ES
dc.contributor.authorLópez, Manuela G.es_ES
dc.identifier.citationJournal of Neurochemistry 145(2): 170-182 (2018)es_ES
dc.description.abstractGrowing evidence suggests a close relationship between Alzheimer's Disease (AD) and cerebral hypoxia. Astrocytes play a key role in brain homeostasis and disease states, while some of the earliest changes in AD occur in astrocytes. We have therefore investigated whether mutations associated with AD increase astrocyte vulnerability to ischemia. Two astroglioma cell lines derived from APPSWE /PS1A246E (APP, amyloid precursor protein; PS1, presenilin 1) transgenic mice and controls from normal mice were subjected to oxygen and glucose deprivation (OGD), an in vitro model of ischemia. Cell death was increased in the APPSWE /PS1A246E line compared to the control. Increasing extracellular calcium concentration ([Ca2+ ]) exacerbated cell death in the mutant but not in the control cells. In order to explore cellular Ca2+ homeostasis, the cells were challenged with ATP or thapsigargin and [Ca2+ ] was measured by fluorescence microscopy. Changes in cytosolic Ca2+ concentration ([Ca2+ ]c ) were potentiated in the APPSWE /PS1A246E transgenic line. Mitochondrial function was also altered in the APPSWE /PS1A246E astroglioma cells; mitochondrial membrane potential and production of reactive oxygen species were increased, while mitochondrial basal respiratory rate and ATP production were decreased compared to control astroglioma cells. These results suggest that AD mutations in astrocytes make them more sensitive to ischemia; Ca2+ dysregulation and mitochondrial dysfunction may contribute to this increased vulnerability. Our results also highlight the role of astrocyte dyshomeostasis in the pathophysiology of neurodegenerative brain disorders.es_ES
dc.description.sponsorshipThis work was supported by the Spanish Government (partially funded by the European Union ERDF/FEDER) Ref. SAF2015-63935R to M.G.L.; Ref. SAF2015-65586 to R.M.M; Ref. PI15/ 00107 to A.M.R.; FPU/contract Ref. AP2009/0343 to A.J.M.O., the Spanish Ministry of Health (Instituto de Salud Carlos III) Ref. PI14/00372 to R.L and a grant from the Fundación Domingo Martínez (Spain) to A.M.R. and M.G.L. R.L. thanks the Instituto de Salud Carlos III and the European Regional Development’s funds (FEDER) for a research contract under the Miguel Servet II Program (CPII16/00014). We also thank the Fundación Teófilo Hernando for its continuous support.es_ES
dc.publisherInternational Society for Neurochemistryes_ES
dc.publisherJohn Wiley & Sonses_ES
dc.subjectAlzheimer's diseasees_ES
dc.subjectCalcium dyshomeostasises_ES
dc.subjectCell deathes_ES
dc.subjectMitochondrial dysfunctiones_ES
dc.titleThe APPswe/PS1A246E mutations in an astrocytic cell line leads to increased vulnerability to oxygen and glucose deprivation, Ca2+ dysregulation, and mitochondrial abnormalitieses_ES
dc.description.peerreviewedPeer reviewedes_ES
dc.contributor.funderInstituto de Salud Carlos IIIes_ES
dc.contributor.funderFundación Domingo Martínezes_ES
dc.contributor.funderInstituto Fundación Teófilo Hernandoes_ES
dc.contributor.funderEuropean Commissiones_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
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