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IRE1 signaling exacerbates Alzheimer’s disease pathogenesis
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2017-03-24 , DOI: 10.1007/s00401-017-1694-x
Claudia Duran-Aniotz , Victor Hugo Cornejo , Sandra Espinoza , Álvaro O. Ardiles , Danilo B. Medinas , Claudia Salazar , Andrew Foley , Ivana Gajardo , Peter Thielen , Takao Iwawaki , Wiep Scheper , Claudio Soto , Adrian G. Palacios , Jeroen J. M. Hoozemans , Claudio Hetz

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.



中文翻译:

IRE1信号加剧阿尔茨海默氏病的发病机理

改变的蛋白质稳态是阿尔茨海默氏病(AD)的显着特征,突出了内质网(ER)应激的发生和异常的蛋白质聚集。内质网应激会触发未折叠蛋白应答(UPR)的激活,这是一种信号通路,可以执行适应性程序来维持蛋白稳态或消除最终受损的细胞。IRE1是一种位于内质网的激酶和核糖核酸内切酶,可作为主要的应激转导子,在内质网应激下介导适应性程序和凋亡程序。IRE1信号传导除了降解多个RNA外,还控制转录因子XBP1的表达。重要的是,XBP1启动子的多态性被认为是发展AD的危险因素。这里,我们证明了AD组织病理学的进展与人脑组织中IRE1的激活之间呈正相关。为了定义UPR对AD的重要性,我们将IRE1表达定位于AD的转基因小鼠模型中。尽管最初预期IRE1信号转导可以预防AD,但神经系统中IRE1的RNase结构域的遗传切除显着减少了淀粉样蛋白沉积,淀粉样β寡聚体的含量以及星形胶质细胞的活化。IRE1缺乏症完全恢复了AD小鼠的学习和记忆能力,与突触功能的改善和长期增强(LTP)的改善相关。在分子水平上,IRE1缺失降低了AD小鼠皮质和海马区淀粉样蛋白前体蛋白(APP)的表达。体外实验表明,IRE1下游信号的抑制降低了APP稳态水平,与其在ER处的保留以及蛋白酶体介导的降解有关。我们的发现揭示了IRE1在AD发病机理中的意外作用,为疾病干预提供了新的靶点。

更新日期:2017-03-24
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