IRE1 signaling exacerbates Alzheimer's disease pathogenesis
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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 beta 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.
FONDAP 15150012 CONICYT-Brazil cooperation Grant 441921/2016-7 Office of Naval Research Global (ONR-G) N62909-16-1-2003 Millennium Institute P09-015-F ICM-P09-022-F FONDEF ID16I10223 FONDECYT 11160760 1140549 3160725 11150776 11150579 Muscular Dystrophy Association 382453 ALSRP Therapeutic Idea Award AL150111 U.S. Air Force Office of Scientific Research FA9550-16-1-0384 European Commission RD MSCA-RISE 734749 Rotary International Global Grant for Disease Treatment and Prevention
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Quote ItemActa Neuropathol (2017) 134:489–506
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