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dc.creatorJiménez, Sebastiánes
dc.creatorTorres, Manueles
dc.creatorVizuete Chacón, María Luisaes
dc.creatorSánchez Varo, Raquel Maríaes
dc.creatorSánchez Mejías, Elisabethes
dc.creatorTrujillo Estrada, Laura Isabeles
dc.creatorCarmona Cuenca, Irenees
dc.creatorCaballero, Cristina M.es
dc.creatorRuano Caballero, Diegoes
dc.creatorGutiérrez, Antoniaes
dc.date.accessioned2016-12-16T10:39:56Z
dc.date.available2016-12-16T10:39:56Z
dc.date.issued2011
dc.identifier.citationJiménez, S., Torres, M., Vizuete Chacón, M.L., Sánchez Varo, R.M., Sánchez Mejías, E., Trujillo Estrada, L.I.,...,Gutiérrez, A. (2011). Age-dependent accumulation of soluble amyloid β (Aβ) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-α (sAPPα) by modulating phosphatidylinositol 3-kinase (PI3K)/Akt-GSK- 3β pathway in Alzheimer mouse model. Journal of Biological Chemistry, 286 (21), 18414-18425.
dc.identifier.issn0021-9258es
dc.identifier.urihttp://hdl.handle.net/11441/50560
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 PS1xAPP 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 PS1xAPP hippocampus, whereas in aged PS1xAPP 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 PS1xAPP 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 PS1xAPP 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 diseasees
dc.formatapplication/pdfes
dc.language.isoenges
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc.es
dc.relation.ispartofJournal of Biological Chemistry, 286 (21), 18414-18425.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.titleAge-dependent accumulation of soluble amyloid β (Aβ) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-α (sAPPα) by modulating phosphatidylinositol 3-kinase (PI3K)/Akt-GSK- 3β pathway in Alzheimer mouse modeles
dc.typeinfo:eu-repo/semantics/articlees
dc.type.versioninfo:eu-repo/semantics/publishedVersiones
dc.rights.accessrightsinfo:eu-repo/semantics/openAccesses
dc.contributor.affiliationUniversidad de Sevilla. Departamento de Bioquímica y Biología Moleculares
dc.relation.publisherversionhttp://www.jbc.org/content/286/21/18414es
idus.format.extent18 p.es
dc.journaltitleJournal of Biological Chemistryes
dc.publication.volumen286es
dc.publication.issue21es
dc.publication.initialPage18414es
dc.publication.endPage18425es

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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
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