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dc.contributor.authorDíaz-Moreno, María
dc.contributor.authorArmenteros, Tomás
dc.contributor.authorGradari, Simona
dc.contributor.authorHortigüela, Rafael 
dc.contributor.authorGarcía-Corzo, Laura
dc.contributor.authorFontán-Lozano, Ángela
dc.contributor.authorTrejo, José Luis
dc.contributor.authorMira, Helena
dc.identifier.citationProc Natl Acad Sci U S A. 2018 Nov 6;115(45):11625-11630.es_ES
dc.description.abstractIncreasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer's disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored. We here investigated the effect of age on NSCs and neurogenesis by analyzing the senescence accelerated mouse prone 8 (SAMP8) strain, a nontransgenic short-lived strain that spontaneously develops a pathological profile similar to that of AD and that has been employed as a model system to study the transition from healthy aging to neurodegeneration. We show that SAMP8 mice display an accelerated loss of the NSC pool that coincides with an aberrant rise in BMP6 protein, enhanced canonical BMP signaling, and increased astroglial differentiation. In vitro assays demonstrate that BMP6 severely impairs NSC expansion and promotes NSC differentiation into postmitotic astrocytes. Blocking the dysregulation of the BMP pathway and its progliogenic effect in vivo by intracranial delivery of the antagonist Noggin restores hippocampal NSC numbers, neurogenesis, and behavior in SAMP8 mice. Thus, manipulating the local microenvironment of the NSC pool counteracts hippocampal dysfunction in pathological aging. Our results shed light on interventions that may allow taking advantage of the brain's natural plastic capacity to enhance cognitive function in late adulthood and in chronic neurodegenerative diseases such as AD.es_ES
dc.description.sponsorshipThis work was supported by a predoctoral fellowship from the Spanish Ministerio de Educación (to M.D.-M.), Spanish Ministerio de Economía y Competitividad Grant BFU2013-48907-R (to J.L.T.), and Grants PI12/101 and SAF2015-70433-R (to H.M.). We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).es_ES
dc.publisherNational Academy of Scienceses_ES
dc.relation.isversionofPublisher's versiones_ES
dc.subjectAlzheimer’s diseasees_ES
dc.subjectBMP signalinges_ES
dc.subjectadult neurogenesises_ES
dc.subjectneural stem cellses_ES
dc.subject.meshAdult Stem Cells es_ES
dc.subject.meshAging es_ES
dc.subject.meshAlzheimer Disease es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshAstrocytes es_ES
dc.subject.meshBone Morphogenetic Protein 6 es_ES
dc.subject.meshCarrier Proteins es_ES
dc.subject.meshCell Differentiation es_ES
dc.subject.meshDisease Models, Animales_ES
dc.subject.meshHippocampus es_ES
dc.subject.meshHumans es_ES
dc.subject.meshInjections, Intraventricular es_ES
dc.subject.meshMale es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Transgenic es_ES
dc.subject.meshNeural Stem Cells es_ES
dc.subject.meshNeurogenesis es_ES
dc.subject.meshNeurons es_ES
dc.subject.meshNeuroprotective Agents es_ES
dc.subject.meshSignal Transduction es_ES
dc.titleNoggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathologyes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.contributor.funderMinisterio de Educación (España)es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaes_ES
dc.repisalud.centroISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)es_ES

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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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