The unfolded protein response transcription factor XBP1s ameliorates Alzheimer’s disease by improving synaptic function and proteostasisdoi:10.34691/FK2/VUWSYPRepositorio de datos de investigación de la Universidad de Chile2021-12-302Hetz, Claudio; Duran-Aniotz, Claudia; Rivera-Krstulovic, Catalina; Poblete, Natalia; Ardiles, Alvaro O.; Sabusap, Carleen; Gerakis, Yannis; Cabral Miranda, Felipe; Diaz, Javier; Fuentealba, Matias; Muño, Ernesto; Espinosa, Sandra; Martinez, Gabriela; Quiroz, Gabriel; Tamburini, Giovanni; Medinas, Danilo B.; Contreras, Darwin; Piña, Ricardo; Lourenci, Mychael; Figueiredo, Claudia; Ferreira, Sergio; Rozas, Carlos; Morales, Bernardo; Plate, Lars; Gonzalez-Billault, Christian; Palacios, Adrian, 2021, "The unfolded protein response transcription factor XBP1s ameliorates Alzheimer’s disease by improving synaptic function and proteostasis", https://doi.org/10.34691/FK2/VUWSYP, Repositorio de datos de investigación de la Universidad de Chile, V2, UNF:6:SCI3Lz4cZaT9RodbHbGDFg== [fileUNF]The unfolded protein response transcription factor XBP1s ameliorates Alzheimer’s disease by improving synaptic function and proteostasisdoi:10.34691/FK2/VUWSYPHetz, ClaudioDuran-Aniotz, ClaudiaRivera-Krstulovic, CatalinaPoblete, NataliaArdiles, Alvaro O.Sabusap, CarleenGerakis, YannisCabral Miranda, FelipeDiaz, JavierFuentealba, MatiasMuño, ErnestoEspinosa, SandraMartinez, GabrielaQuiroz, GabrielTamburini, GiovanniMedinas, Danilo B.Contreras, DarwinPiña, RicardoLourenci, MychaelFigueiredo, ClaudiaFerreira, SergioRozas, CarlosMorales, BernardoPlate, LarsGonzalez-Billault, ChristianPalacios, AdrianChile2018-AARG-591107ID20I1015211615241118018615150012P09-015-FID16I10223441921/2016-7734749Repositorio de datos de investigación de la Universidad de ChileHetz, ClaudioHetz, Claudio2021-12-30Medicine, Health and Life SciencesProteostasisUPRAlzheimerAlteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer´s disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main signaling pathway emerging from the ER to cope with protein folding stress. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter was suggested as a risk factor to develop AD. To artificially enforce the adaptive capacity of the UPR, here we developed strategies to express the active form of XBP1 in neurons on a preclinical model of AD. The overexpression of XBP1s in the nervous system using transgenic mice significantly reduced the load of amyloid deposition in cerebral cortex and hippocampus, in addition to preserve synaptic and cognitive function. Moreover, the local delivery of XBP1s in the hippocampus of AD mice using viral vectors improved long-term potentiation, memory performance and the density of dendritic spines. Quantitative proteomics of hippocampus indicated that XBP1 expression restores the levels of many synaptic protein and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of XBP1s-deppedent responses as a strategy to ameliorate AD features and sustain synaptic function.AbO prep 512 SEC Paper-2.tab355217text/tab-separated-valuesUNF:6:jy4TLL1SsU0EVRg3bFxghg==BM behavior 6 Months Paper 2021.tab25429text/tab-separated-valuesUNF:6:OopLmA5uH/swWc8z1MQUMw==BM behavior 8 month Paper 2021-2.tab5126text/tab-separated-valuesUNF:6:+fV+OW8hlMNE0MWLymXcBw==Cuantificación y análisis Figura 5C y D.tab358text/tab-separated-valuesUNF:6:0+EGonEe6xZ1dOB9GNn30g==MWM behavior 6 Months Paper 2021.tab10539text/tab-separated-valuesUNF:6:rHnOWlm21TG1Q/q8xbVlGA==MWM behavior 9 Months Paper 2021.tab11039text/tab-separated-valuesUNF:6:s4HVRv9AIjW15PzemhDvig==Y Maze behavior Paper 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