IRE1 signaling exacerbates Alzheimer’s disease pathogenesis

Abstract

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.

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Acknowledgements

We thank Javiera Ponce for technical support in animal care supervision. We also thank Dr. Alejandra Alvarez from The Pontifical Catholic University of Chile for the use of behavioral facilities and Dr. Patricia Burgos from University Austral of Chile for providing APP-GFP constructs. Additionally, we would like to thank Dr. Rodrigo Morales, Dr. Ines Moreno-Gonzalez, and Dr. Mohammad Shahnawaz of University of Texas Houston Medical School at Houston and Dr. Rene Vidal and Dr. Gabriela Martinez Bravo of University of Chile, for providing helpful support. We also thank the Netherlands Brain Bank for supplying the human brain tissue, Wouter Gerritsen, Tjado Morrema, Kimberley Ummenthum, and Fabian Bangel for technical assistance in human studies. This work was directly funded by FONDAP program 15150012, CONICYT-Brazil cooperation Grant 441921/2016-7, Office of Naval Research Global (ONR-G) N62909-16-1-2003, Millennium Institute P09-015-F, FONDEF ID16I10223 (CH) and FONDECYT no 11160760 (CDA). We also thank the support Muscular Dystrophy Association 382453, FONDECYT No. 1140549, and ALSRP Therapeutic Idea Award AL150111, U.S. Air Force Office of Scientific Research FA9550-16-1-0384, European Commission R&D, MSCA-RISE #734749 (CH), FONDECYT Grant No. 3160725 (VHC), FONDECYT Grant No. 11150776 (AOA), and FONDECYT Grant No. 11150579 (DBM) and Rotary International Global Grant for Disease Treatment and Prevention (AF) and Millennium Institute ICM-P09-022-F (AP).

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Correspondence to Claudio Hetz.

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C. Duran-Aniotz and V. H. Cornejo contributed equally to this work

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Duran-Aniotz, C., Cornejo, V.H., Espinoza, S. et al. IRE1 signaling exacerbates Alzheimer’s disease pathogenesis. Acta Neuropathol 134, 489–506 (2017). https://doi.org/10.1007/s00401-017-1694-x

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Keywords

  • Alzheimer’s disease
  • Amyloid β
  • Endoplasmic reticulum stress
  • Unfolded protein response
  • UPR
  • Proteostasis impairment