Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of α-, β- and γ-secretase expression
Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of α-, β- and γ-secretase expression
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DOI：
10.1016/j.neuint.2009.06.012
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发表时间：
2009-12-01
影响因子：
4.2
通讯作者：
Arias, Clorinda
中科院分区：
文献类型：
--
作者：
Quiroz-Baez, Ricardo;Rojas, Emilio;Arias, Clorinda
阿尔茨海默病（Alzheimer disease，AD）的发病机制复杂，涉及多种病因，但基于遗传、生化和神经毒理学证据，淀粉样β蛋白（amyloid beta-protein，A β）在AD的发病机制中起着重要作用。与AP过度产生中基因突变的充分记录的影响相反，对占95%以上病例的散发性AD（SAD）中涉及的机制知之甚少。来自患者和体内动物模型的大量数据表明，氧化应激是与这种神经退行性疾病最常相关的主要因素之一。本研究的目的是探索氧化应激对人类神经母细胞瘤细胞中正常表达的野生型淀粉样前体蛋白（APP）的影响，这代表了神经元A β产生的更生理模型。由于H2 O2是大脑中高活性羟基自由基的主要来源，而FeCl 2可以刺激氧化应激，包括H2 O2形成羟基自由基，因此在本工作中，我们研究了这两种促氧化剂分子对人APP水平和α-，β-和γ-分泌酶加工的影响，以及应激激活激酶c-jun N-末端激酶（JNK）的作用。我们提供的证据表明，在分化的人神经母细胞瘤细胞中，淀粉样前体蛋白代谢的双重调节与α-分泌酶的下调和γ-分泌酶的上调有关，特别是β-分泌酶和依赖JNK的A β生成。(C)2009爱思唯尔有限公司保留所有权利。
The pathogenesis of Alzheimer disease (AD) is complex and is certain to involve diverse etiological factors, but a central role has been strongly suggested for amyloid beta-protein (A beta), based on genetic, biochemical and neurotoxicological evidence. In contrast with the well-documented effect of genetic mutations in AP overproduction, not much is known about the mechanisms involved in sporadic AD (SAD) which account for more than 95% of cases. Extensive data from patients and in vivo animal models indicate that oxidative stress is one of the cardinal factors most frequently associated with this neurodegenerative disease. The aim of the present study was to explore the effect of oxidative stress on the normally expressed wild-type amyloid precursor protein (APP) in human neuroblastoma cells, which represents a more physiological model of neuronal A beta generation. Since H2O2 is the main source of the highly reactive hydroxyl radical in the brain, and FeCl2 can stimulate oxidative stress, including the formation of the hydroxyl radical from H2O2, in the present work we studied the effect of these two pro-oxidant molecules on the levels and processing of human APP by alpha-, beta- and gamma-secretase, and the role of the stress-activated kinase c-jun N-terminal kinase (JNK). We provide evidence for a dual modulation of amyloid precursor protein metabolism in differentiated human neuroblastoma cells related with a down-regulation of alpha-secretase and up-regulation of gamma-secretase, and particularly of beta-secretase and also a JNK depending A beta generation. (C) 2009 Elsevier Ltd. All rights reserved.