Oxidative Stress Up-Regulates Presenilin 1 in Lipid Rafts in Neuronal Cells
Oxidative Stress Up-Regulates Presenilin 1 in Lipid Rafts in Neuronal Cells
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DOI：
10.1002/jnr.22271
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发表时间：
2010-04-01
影响因子：
4.2
通讯作者：
Araki, Wataru
中科院分区：
文献类型：
--
作者：
Oda, Akiko;Tamaoka, Akira;Araki, Wataru
氧化应激与阿尔茨海默病患者大脑中的β -淀粉样肽（A β）积累有关。β是由两种膜结合蛋白酶，p-分泌酶（BACE1）和γ -分泌酶复合物（包括早老素1 （PS1）、nicastrin、APH-1和PEN-2）对跨膜淀粉样前体蛋白（APP）的顺序蛋白水解裂解产生的。最近的证据表明，大量的BACE1和γ -分泌酶成分位于脂筏膜的富含胆固醇的区域，在那里A β的产生优先发生。在这项研究中，我们利用暴露于乙酸（一种诱导细胞谷胱甘肽耗竭的化合物）的人神经母细胞瘤SH-SY5Y细胞，研究了氧化应激对脂质囊中BACE1和γ -分泌酶成分的影响。细胞暴露于EA后，血红素氧化酶-1（一种氧化应激标记蛋白）被强烈诱导。此外，EA治疗导致PS1蛋白水平显著升高，而nicastrin、APH-1、PEN-2或BACE1在细胞裂解物和脂质筏分数中均未升高。与抗氧化剂n -乙酰半胱氨酸（NAC）共处理可阻止PS1蛋白表达的增加。EA还诱导PS1 mRNA表达显著增加，NAC抑制了这一表达。最后，我们发现EA处理可以促进表达瑞典突变体APP的细胞分泌A β。在我们的细胞培养模型中，氧化应激通过上调PS1转录来提高脂筏中PS1蛋白水平，这可能是氧化应激相关促进A β产生的机制。(C) 2009 Wiley-Liss, Inc。
Oxidative stress is associated with beta-amyloid peptide (A beta) accumulation in the brains of Alzheimer's disease patients. A beta is generated upon the sequential proteolytic cleavage of transmembrane amyloid precursor protein (APP) by two membrane-bound proteases, p-secretase (BACE1) and the gamma-secretase complex comprising presenilin 1 (PS1), nicastrin, APH-1 and PEN-2. Recent evidence suggests that significant amounts of BACE1 and gamma-secretase components localize in the cholesterol-rich region of membranes known as lipid rafts, where A beta production occurs preferentially. In this study, we investigated the effects of oxidative stress on the BACE1 and gamma-secretase components in lipid rafts using human neuroblastoma SH-SY5Y cells exposed to ethacrynic acid (EA), a compound that induces cellular glutathione depletion. Following exposure of cells to EA, heme oxygenase-1, a marker protein of oxidative stress, was strongly induced. Moreover, treatment with EA resulted in a significant increase in PS1 protein levels, but not those of nicastrin, APH-1, PEN-2 or BACE1, in both cell lysates and the lipid raft fraction. This increase in PS1 protein expression was prevented by co-treatment with an antioxidant, N-acetylcysteine (NAC). EA additionally induced a significant increase in PS1 mRNA expression, which was inhibited by NAC. Finally, EA treatment was found to promote A beta secretion from cells expressing Swedish mutant APP. It appears that in our cell culture model, oxidative stress enhances PS1 protein levels in lipid rafts via up-regulation of PS1 transcription, which may constitute the mechanism underlying the oxidative stress-associated promotion of A beta production. (C) 2009 Wiley-Liss, Inc.