Asymmetric dimethylarginine exacerbates Aβ-induced toxicity and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease
Asymmetric dimethylarginine exacerbates Aβ-induced toxicity and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease
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不对称二甲基精氨酸会加剧阿尔茨海默病的人类细胞和秀丽隐杆线虫模型中 Abeta 诱导的毒性和氧化应激。
DOI：
10.1016/j.freeradbiomed.2014.12.002
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发表时间：
2015-02-01
影响因子：
7.4
通讯作者：
Lu, Zhongbing
中科院分区：
文献类型：
--
作者：
Luo, Yunfeng;Yue, Wenhui;Lu, Zhongbing
越来越多的证据表明，心血管危险因素与阿尔茨海默病(AD)的发病率之间存在很强的相关性。内源性一氧化氮合酶抑制物不对称二甲基精氨酸(ADMA)已被认为是一种独立的心血管危险因素，AD患者血浆中ADMA水平也升高。然而，ADMA是否参与AD的发病机制尚不清楚。在这项研究中，我们发现，在转基因秀丽线虫β-淀粉样蛋白(Aβ)过表达模型CL2006株中，ADMA含量增加，并且在过度表达瑞典突变形式的人Aβ前体蛋白(APPsw)的人SH-SY5Y细胞中，ADMA含量增加。此外，ADMA治疗加剧了Aβ诱导的CL2006蠕虫的瘫痪和氧化应激，并进一步增加了APPsw细胞的氧化应激和Aβ的分泌。敲除1型蛋白精氨酸N-甲基转移酶以减少ADMA的产生并未显示出对Aβ毒性的保护作用，而是导致CL2006蠕虫更多的瘫痪，以及APPsw细胞中氧化应激和Aβ分泌的增加。然而，过表达二甲基精氨酸二甲氨基水解酶1(DDAH1)以促进ADMA降解显著减弱APPsw细胞的氧化应激和Aβ分泌。总体而言，我们的数据支持ADMA升高与AD发病机制有关的假设。我们的发现表明，增加神经细胞中DDAH1活性的策略可能是减缓AD发展的一种新方法。(C)2014 Elsevier Inc.保留所有权利。
Growing evidence suggests a strong association between cardiovascular risk factors and incidence of Alzheimer disease (AD). Asymmetric dimethylarginine (ADMA), the endogenous nitric oxide synthase inhibitor, has been identified as an independent cardiovascular risk factor and is also increased in plasma of patients with AD. However, whether ADMA is involved in the pathogenesis of AD is unknown. In this study, we found that ADMA content was increased in a transgenic Caenorhabditis elegans beta-amyloid (A beta) overexpression model, strain CL2006, and in human SH-SY5Y cells overexpressing the Swedish mutant form of human A beta precursor protein (APPsw). Moreover, ADMA treatment exacerbated A beta-induced paralysis and oxidative stress in CL2006 worms and further elevated oxidative stress and A beta secretion in APPsw cells. Knockdown of type 1 protein arginine N-methyltransferase to reduce ADMA production failed to show a protective effect against A beta toxicity, but resulted in more paralysis in CL2006 worms as well as increased oxidative stress and A beta secretion in APPsw cells. However, overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) to promote ADMA degradation significantly attenuated oxidative stress and A beta secretion in APPsw cells. Collectively, our data support the hypothesis that elevated ADMA contributes to the pathogenesis of AD. Our findings suggest that strategies to increase DDAH1 activity in neuronal cells may be a novel approach to attenuating AD development. (C) 2014 Elsevier Inc. All rights reserved.