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Authordc.contributor.authorDurán Aniotz, Claudia 
Authordc.contributor.authorCornejo, Victor Hugo 
Authordc.contributor.authorEspinoza, Sandra 
Authordc.contributor.authorArdiles, Alvaro O. 
Authordc.contributor.authorMedinas Bilches, Danilo 
Authordc.contributor.authorSalazar, Claudia 
Authordc.contributor.authorFoley, Andrew 
Authordc.contributor.authorGajardo, Ivana 
Authordc.contributor.authorThielen, Peter 
Authordc.contributor.authorIwawaki, Takao 
Authordc.contributor.authorScheper, Wiep 
Authordc.contributor.authorSoto, Claudio 
Authordc.contributor.authorPalacios, Adrian G. 
Authordc.contributor.authorHoozemans, Jeroen J. M. 
Authordc.contributor.authorHetz Flores, Claudio 
Admission datedc.date.accessioned2018-07-06T14:42:44Z
Available datedc.date.available2018-07-06T14:42:44Z
Publication datedc.date.issued2017
Cita de ítemdc.identifier.citationActa Neuropathol (2017) 134:489–506es_ES
Identifierdc.identifier.other10.1007/s00401-017-1694-x
Identifierdc.identifier.urihttps://repositorio.uchile.cl/handle/2250/149590
Abstractdc.description.abstractAltered proteostasis is a salient feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress and abnormal protein aggregation. ER stress triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis or eliminate terminally damaged cells. IRE1 is an ER-located kinase and endoribonuclease that operates as a major stress transducer, mediating both adaptive and proapoptotic programs under ER stress. IRE1 signaling controls the expression of the transcription factor XBP1, in addition to degrade several RNAs. Importantly, a polymorphism in the XBP1 promoter was suggested as a risk factor to develop AD. Here, we demonstrate a positive correlation between the progression of AD histopathology and the activation of IRE1 in human brain tissue. To define the significance of the UPR to AD, we targeted IRE1 expression in a transgenic mouse model of AD. Despite initial expectations that IRE1 signaling may protect against AD, genetic ablation of the RNase domain of IRE1 in the nervous system significantly reduced amyloid deposition, the content of amyloid beta oligomers, and astrocyte activation. IRE1 deficiency fully restored the learning and memory capacity of AD mice, associated with improved synaptic function and improved long-term potentiation (LTP). At the molecular level, IRE1 deletion reduced the expression of amyloid precursor protein (APP) in cortical and hippocampal areas of AD mice. In vitro experiments demonstrated that inhibition of IRE1 downstream signaling reduces APP steady-state levels, associated with its retention at the ER followed by proteasome-mediated degradation. Our findings uncovered an unanticipated role of IRE1 in the pathogenesis of AD, offering a novel target for disease intervention.es_ES
Patrocinadordc.description.sponsorshipFONDAP 15150012 CONICYT-Brazil cooperation Grant 441921/2016-7 Office of Naval Research Global (ONR-G) N62909-16-1-2003 Millennium Institute P09-015-F ICM-P09-022-F FONDEF ID16I10223 FONDECYT 11160760 1140549 3160725 11150776 11150579 Muscular Dystrophy Association 382453 ALSRP Therapeutic Idea Award AL150111 U.S. Air Force Office of Scientific Research FA9550-16-1-0384 European Commission RD MSCA-RISE 734749 Rotary International Global Grant for Disease Treatment and Preventiones_ES
Lenguagedc.language.isoenes_ES
Publisherdc.publisherSpringeres_ES
Type of licensedc.rightsAttribution-NonCommercial-NoDerivs 3.0 Chile*
Link to Licensedc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
Sourcedc.sourceActa Neuropathologicaes_ES
Keywordsdc.subjectAlzheimer's diseasees_ES
Keywordsdc.subjectAmyloid betaes_ES
Keywordsdc.subjectEndoplasmic reticulum stresses_ES
Keywordsdc.subjectUnfolded protein responsees_ES
Keywordsdc.subjectUPRes_ES
Keywordsdc.subjectProteostasis impairmentes_ES
Títulodc.titleIRE1 signaling exacerbates Alzheimer's disease pathogenesises_ES
Document typedc.typeArtículo de revistaes_ES
dcterms.accessRightsdcterms.accessRightsAcceso abierto
Catalogueruchile.catalogadortjnes_ES
Indexationuchile.indexArtículo de publicación ISIes_ES
Indexationuchile.indexArtículo de publicación SCOPUS


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Attribution-NonCommercial-NoDerivs 3.0 Chile
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Chile