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.

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…The heightened level of ER stress and downstream responses in AD‐affected regions has been confirmed by both in vivo and in vitro evidence (Remondelli & Renna, 2017). Conditional deletion of Ire1 , a key component of the UPR, directly results in reduced cognitive impairment in rodent neurodegenerative models, which further confirms the promotive role by ER stress toward AD progression (Duran‐Aniotz, Cornejo, Espinoza, Ardiles, & Medinas, 2017) (Table 2). At present, while the initiation of ER stress in susceptible neurons remains unclear, genetic alterations, age‐related functional insufficiency, oxidative stress, or secondary to proteotoxic damage are assumed to be possible causes, which eventually lead to the impaired chaperone, calcium imbalance, and ER stress (Cai, Arikkath, Yang, Guo, & Periyasamy, 2016).…”

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

“…Remarkably, genome wide screening to identify XBP1s-target genes uncovered a cluster of genes related to AD [47] and an etiological genetic association between XBP1 promoter polymorphism and AD increased risk development was revealed in the Chinese population [48]. Consistent with this we recently reported that XBP1 expression directly impacts APP metabolism [43]. A recent study indicated that delivering the active form of XBP1 into the hippocampus of AD mice restored synaptic function [50].…”

“…Consistent with this, brain samples from AD patients presented augmented XBP1 [41]. XBP1 mRNA splicing is also observed after amyloid β treatment in neuronal cell lines [45] and in the temporal cortex of AD patients [43,46]. Remarkably, genome wide screening to identify XBP1s-target genes uncovered a cluster of genes related to AD [47] and an etiological genetic association between XBP1 promoter polymorphism and AD increased risk development was revealed in the Chinese population [48].…”

“…We recently demonstrated that in human post-mortem tissue IRE1 activation progresses as the disease evolves. Using genetic manipulation of IRE1 in the nervous system, we determined the functional significance of IRE1 to AD, demonstrating that ablation of its expression reduces amylod plaque load and improves synaptic and cognitive function [43]. XBP1 is one of the main downstream components of IRE1 mediating proteostasis adjustment, promoting cell survival.…”

Meeting Report – proteostasis in Ericeira

“…Specifically, his group demonstrated that a brain-conditional knockdown of Xbp1 can also improve pathology in murine models of age-related diseases such as amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). He also showed that IRE1 deficiency protects against Alzheimer's disease (Duran-Aniotz et al, 2017), and discussed the development of gene therapy strategies to attenuate ER stress in disease.…”