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dc.contributor.authorJiménez, Sebastián
dc.contributor.authorTorres, Manuel
dc.contributor.authorVizuete, Marisa
dc.contributor.authorSánchez-Varo, Raquel María 
dc.contributor.authorSánchez-Mejías, Elisabeth 
dc.contributor.authorTrujillo-Estrada, Laura Isabel 
dc.contributor.authorCarmona-Cuenca, Irene
dc.contributor.authorCaballero, Cristina
dc.contributor.authorRuano, Diego
dc.contributor.authorGutiérrez-Pérez, Antonia 
dc.contributor.authorVitorica Ferrández, Javier
dc.date.accessioned2024-07-04T10:00:32Z
dc.date.available2024-07-04T10:00:32Z
dc.date.issued2011-05
dc.identifier.citationJimenez S, Torres M, Vizuete M, Sanchez-Varo R, Sanchez-Mejias E, Trujillo-Estrada L, Carmona-Cuenca I, Caballero C, Ruano D, Gutierrez A, Vitorica J. Age-dependent accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sAPP(alpha)) by modulating phosphatidylinositol 3-kinase (PI3K)/Akt-GSK-3beta pathway in Alzheimer mouse model. J Biol Chem. 2011 May 27;286(21):18414-25. doi: 10.1074/jbc.M110.209718. Epub 2011 Apr 1. PMID: 21460223; PMCID: PMC3099658.es_ES
dc.identifier.urihttps://hdl.handle.net/10630/31886
dc.description.abstractNeurotrophins, activating the PI3K/Akt signaling pathway, control neuronal survival and plasticity. Alterations in NGF, BDNF, IGF-1, or insulin signaling are implicated in the pathogenesis of Alzheimer disease. We have previously characterized a bigenic PS1×APP transgenic mouse displaying early hippocampal Aβ deposition (3 to 4 months) but late (17 to 18 months) neurodegeneration of pyramidal cells, paralleled to the accumulation of soluble Aβ oligomers. We hypothesized that PI3K/Akt/GSK-3β signaling pathway could be involved in this apparent age-dependent neuroprotective/neurodegenerative status. In fact, our data demonstrated that, as compared with age-matched nontransgenic controls, the Ser-9 phosphorylation of GSK-3β was increased in the 6-month PS1×APP hippocampus, whereas in aged PS1×APP animals (18 months), GSK-3β phosphorylation levels displayed a marked decrease. Using N2a and primary neuronal cell cultures, we demonstrated that soluble amyloid precursor protein-α (sAPPα), the predominant APP-derived fragment in young PS1×APP mice, acting through IGF-1 and/or insulin receptors, activated the PI3K/Akt pathway, phosphorylated the GSK-3β activity, and in consequence, exerted a neuroprotective action. On the contrary, several oligomeric Aβ forms, present in the soluble fractions of aged PS1×APP mice, inhibited the induced phosphorylation of Akt/GSK-3β and decreased the neuronal survival. Furthermore, synthetic Aβ oligomers blocked the effect mediated by different neurotrophins (NGF, BDNF, insulin, and IGF-1) and sAPPα, displaying high selectivity for NGF. In conclusion, the age-dependent appearance of APP-derived soluble factors modulated the PI3K/Akt/GSK-3β signaling pathway through the major neurotrophin receptors. sAPPα stimulated and Aβ oligomers blocked the prosurvival signaling. Our data might provide insights into the selective vulnerability of specific neuronal groups in Alzheimer disease.es_ES
dc.description.sponsorshipFondo de Investigación Sanitaria (Proyecto FIS) del Instituto de Salud Carlos III de España, ref. PS09/00151 (JV), ref. PS09/00099 (A.G.), y ref. PS09/00848 (DR). Junta de Andalucía ref. CTS-4795 (J V.) y SAS PI-0496/2009 (AG). SJ, MT y RSV contratados CIBERNED. ESM y LTE becas predoctorales del programa FPU (Formación del Profesorado Universitario).es_ES
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectAlzheimer, Enfermedad de - Modelos animaleses_ES
dc.subjectAlzheimer, Enfermedad de - Investigaciónes_ES
dc.subject.otherAlzheimer’s diseasees_ES
dc.subject.otherAmyloid betaes_ES
dc.subject.otherNeuroprotectiones_ES
dc.subject.otherTransgenic micees_ES
dc.subject.otherAmyloid precursor proteines_ES
dc.titleAge-dependent accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sAPP(alpha)) by modulating phosphatidylinositol 3-kinase (PI3K)/Akt-GSK-3beta pathway in Alzheimer mouse model.es_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.centroFacultad de Cienciases_ES
dc.identifier.doi10.1074/jbc.M110.209718
dc.rights.ccAtribución 4.0 Internacional*
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersiones_ES


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