Asymmetric dimethylarginine exacerbates A beta-induced toxicity and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease

分类： 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间： 2016-05-11

Luo, Yunfeng Yue, Wenhui Quan, Xin Wang, Yue Lu, Zhongbing Zhao, Baolu

摘要： 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.

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