Optimized adeno-associated vector to deliver the unfolded protein response transcription factor XBP1s into the hippocampus ameliorates Alzheimer’s disease features in mouse modelsdoi:10.34691/UCHILE/IAE3N6Repositorio de datos de investigación de la Universidad de Chile2024-06-172Hetz, Claudio; Mei Li Diaz; Diego Arriagada; Giovanni Tamburini; Natalia Poblete; Alvaro Ardiles; David Neira; Denisse Sepulveda; Gabriela Martinez; Els Henckaerts; Julie Tordo; Sergio T. Ferreira; Adrian G. Palacios; Marcia Weber, 2024, "Optimized adeno-associated vector to deliver the unfolded protein response transcription factor XBP1s into the hippocampus ameliorates Alzheimer’s disease features in mouse models", https://doi.org/10.34691/UCHILE/IAE3N6, Repositorio de datos de investigación de la Universidad de Chile, V2, UNF:6:x5ZPoCTpoVEyN5PY+SQZTQ== [fileUNF]Optimized adeno-associated vector to deliver the unfolded protein response transcription factor XBP1s into the hippocampus ameliorates Alzheimer’s disease features in mouse modelsdoi:10.34691/UCHILE/IAE3N6Hetz, ClaudioMei Li DiazDiego ArriagadaGiovanni TamburiniNatalia PobleteAlvaro ArdilesDavid NeiraDenisse SepulvedaGabriela MartinezEls HenckaertsJulie TordoSergio T. FerreiraAdrian G. PalaciosMarcia WeberRepositorio de datos de investigación de la Universidad de ChileHetz, ClaudioHetz, Claudio2024-06-14Medicine, Health and Life SciencesProteostasis impairment at the level of the endoplasmic reticulum (ER) is a salient feature of Alzheimer’s disease (AD). The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER, where the expression of the transcription factor X-Box binding protein 1 (XBP1) is central to establish repair programs. To artificially enforce the adaptive capacity of the UPR in the AD brain, we recently reported the protective effects of overexpressing active XBP1 in the nervous system through the local delivery into the hippocampus of an AD mice using adeno-associated vectors (AAVs). Here we have generated a next generation vector suitable for clinical trials by (i) expressing codon optimized human XBP1s without tags, (ii) the use the synapsin promoter to restrict expression to neurons, and (iii) a novel variant of AAV2 that has greater spreading capacity (AAV-TT) in the brain because of reduced affinity to heparin (termed AAV-TT-Syn-hXBP1s or Proteostaser-1). Treatment of 5xFAD mice with AAV-TT-Syn-hXBP1s improved long-term potentiation, memory performance, and reduced amyloid plaques deposition. In addition, we validated the protective effects of AAV-TT-Syn-hXBP1s on a model of sporadic AD based on the intracerebral injection of amyloid beta oligomers. 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