IRE1 signaling exacerbates Alzheimer's disease pathogenesis
IRE1 signaling exacerbates Alzheimer's disease pathogenesis
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DOI：
10.1007/s00401-017-1694-x
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发表时间：
2017-09-01
影响因子：
12.7
通讯作者：
Hetz, Claudio
中科院分区：
文献类型：
--
作者：
Duran-Aniotz, Claudia;Cornejo, Victor Hugo;Hetz, Claudio
蛋白质稳态改变是阿尔茨海默病（AD）的显著特征，突出了内质网（ER）应激和异常蛋白质聚集的发生。内质网应激触发未折叠蛋白反应（UPR）的激活，这是一种信号通路，可执行适应性程序以维持蛋白质稳态或消除终末受损细胞。IRE1是一种位于内质网的激酶和核糖核酸内切酶，作为一个主要的压力传感器，介导的适应性和促凋亡程序下的内质网应激。IRE1信号传导控制转录因子XBP1的表达，此外还降解几种RNA。重要的是，XBP1启动子的多态性被认为是发展AD的危险因素。在这里，我们证明了AD组织病理学的进展与人脑组织中IRE1的激活之间的正相关性。为了确定UPR对AD的意义，我们在AD的转基因小鼠模型中靶向IRE1表达。尽管最初预期IRE1信号传导可以预防AD，但神经系统中IRE1的RNase结构域的遗传消融显著减少了淀粉样蛋白沉积、淀粉样蛋白β寡聚体的含量和星形胶质细胞活化。IRE1缺陷完全恢复了AD小鼠的学习和记忆能力，与改善的突触功能和改善的长时程增强（LTP）有关。在分子水平上，IRE1缺失降低了AD小鼠皮质和海马区淀粉样前体蛋白（APP）的表达。体外实验表明，抑制IRE1下游信号传导降低APP稳态水平，这与其在ER的保留以及随后的蛋白酶体介导的降解有关。我们的研究结果揭示了IRE1在AD发病机制中的意想不到的作用，为疾病干预提供了一个新的靶点。
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.