@article{199e653dabb34b9bb70b24d59480af69,
title = "The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis",
abstract = "Alteration 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 adaptive pathway to cope with protein folding stress at the ER. Inositol-requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an 5xFAD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the AD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.",
keywords = "Alzheimer's disease, ER stress, UPR, XBP1, amyloid β",
author = "Claudia Duran-Aniotz and Natalia Poblete and Catalina Rivera-Krstulovic and Ardiles, {{\'A}lvaro O.} and D{\'i}az-Hung, {Mei Li} and Giovanni Tamburini and Sabusap, {Carleen Mae P.} and Yannis Gerakis and Felipe Cabral-Miranda and Javier Diaz and Matias Fuentealba and Diego Arriagada and Ernesto Mu{\~n}oz and Sandra Espinoza and Gabriela Martinez and Gabriel Quiroz and Pablo Sardi and Medinas, {Danilo B.} and Darwin Contreras and Ricardo Pi{\~n}a and Lourenco, {Mychael V.} and Ribeiro, {Felipe C.} and Ferreira, {Sergio T.} and Carlos Rozas and Bernardo Morales and Lars Plate and Christian Gonzalez-Billault and Palacios, {Adrian G.} and Claudio Hetz",
note = "Funding Information: We thank Francisco Aburto, Maria Jose Altamirano, and Javiera Ponce for technical support in animal care supervision. We thank Claudia Sepulveda and Susana Marriquez for lab management and administrative accounting. We also thank Dr. Hery Urra (BNI) for performing phaloidine staining. This work was directly funded by Alzheimer's Association research grant 2018-AARG-591107 (C.D.-A.), US Air Force Office of Scientific Research FA9550-21-1-0096 (C.H.), FONDAP program 15150012, Millennium Institute P09-015-F, and Department of Defense grant W81XWH2110960 (C.H.), ANID/FONDEF IDID22I10120 (CH) and Swiss Consolidation Grant-The Leading House for the Latin American Region (CH). We also acknowledge support from ANID/FONDEF ID16I10223 and ANID/FONDECYT 1220573 (C.H.), ANID/FONDECYT 1200880 (A.G.P.), ANID/FONDECYT 1161524 (B.M.), ANID/FONDECYT 3190897 (D.C.), and ANID/FONDECYT 1191538 (D.B.M.), ICM-P09-022-F (A.O.A. and A.G.P.), a binational collaborative grant from CONICYT(Chile)-CNPq(Brazil) 441921/2016-7 (C.H. S.T.F.), Alzheimer's Association AARG-D-615714 (M.V.L.) and Serrapilheira Institute R-2012-37967 (M.V.L.), ANID/FONDECYT 11140430 and DICYT 021843RS (C.R.), DICYT-Usach 021843MM (D.C.), 021943MM, 5392202MM{\~N}-ACDicyt (B.M.), POSTDOC_DICYT 021223MM{\~N}_postdoc (BM), ANID/FONDECYT 3190596 (ML), ANID/NAM22I0057(ML), ANID/FONDECYT 1201342 (A.O.A.). C.D.-A. M.L.D. and C.H. wrote the paper; C.D.-A. N.P. C.R.-K. {\'A}.O.A. C.M.P.S. Y.G. F.C.M. J.D. D.A. E.M. S.E. G.M. G.Q. D.B.M. D.C. R.P. F.C.R. and C.R. performed experiments; C.D.-A. N.P. {\'A}.O.A. M.L.D. D.A. M.V.L. S.T.F. C.R. B.M. L.P. C.G.-B. and A.G.P. analyzed data; M.F. performed bioinformatic analysis; C.H. wrote the paper, discussed data, obtained funding, and administered the project. The authors declare that no conflicts of interest exist. Publisher Copyright: {\textcopyright} 2023",
year = "2023",
month = jul,
day = "5",
doi = "10.1016/j.ymthe.2023.03.028",
language = "English",
volume = "31",
pages = "2240--2256",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Cell Press",
number = "7",
}