IRE1 signaling exacerbates Alzheimer's disease pathogenesis.
Altered 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 β 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.
Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.|Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.|Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (Sector B, second floor), University of Chile, Independencia 1027, P.O.BOX 70086, Santiago, Chile.
Claudia
C
Duran-Aniotz
Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.|Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.|Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (Sector B, second floor), University of Chile, Independencia 1027, P.O.BOX 70086, Santiago, Chile.
Victor Hugo
VH
Cornejo
Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.|Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.|Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (Sector B, second floor), University of Chile, Independencia 1027, P.O.BOX 70086, Santiago, Chile.
Sandra
S
Espinoza
Centro Interdisciplinario de Neurociencia de Valparaiso, Universidad de Valparaiso, Valparaiso, Chile.
Álvaro O
ÁO
Ardiles
Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.|Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.|Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (Sector B, second floor), University of Chile, Independencia 1027, P.O.BOX 70086, Santiago, Chile.
Danilo B
DB
Medinas
Centro Interdisciplinario de Neurociencia de Valparaiso, Universidad de Valparaiso, Valparaiso, Chile.
Claudia
C
Salazar
Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.|Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (Sector B, second floor), University of Chile, Independencia 1027, P.O.BOX 70086, Santiago, Chile.
Andrew
A
Foley
Centro Interdisciplinario de Neurociencia de Valparaiso, Universidad de Valparaiso, Valparaiso, Chile.
Ivana
I
Gajardo
Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston, MA, USA.
Peter
P
Thielen
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan.
Takao
T
Iwawaki
Department of Clinical Genetics and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands.|Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
Wiep
W
Scheper
Department of Neurology, Mitchell Center for Alzheimer's disease and Related Brain Disorders, The University of Texas Houston Medical School at Houston, Houston, TX, 77030, USA.
Claudio
C
Soto
Centro Interdisciplinario de Neurociencia de Valparaiso, Universidad de Valparaiso, Valparaiso, Chile.
Adrian G
AG
Palacios
Department of Pathology, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
Jeroen J M
JJM
Hoozemans
Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile. chetz@med.uchile.cl.|Center for Geroscience, Brain Health and Metabolism, Santiago, Chile. chetz@med.uchile.cl.|Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (Sector B, second floor), University of Chile, Independencia 1027, P.O.BOX 70086, Santiago, Chile. chetz@med.uchile.cl.|Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston, MA, USA. chetz@med.uchile.cl.|Buck Institute for Research on Aging, Novato, CA, 94945, USA. chetz@med.uchile.cl.
Claudio
C
Hetz
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D065852:Spatial Memory / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases
Alzheimer’s disease; Amyloid β; Endoplasmic reticulum stress; Proteostasis impairment; UPR; Unfolded protein response