title: Asymmetric dimethylarginine exacerbates Aβ-induced toxicity and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease.
abstract: 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 β-amyloid (Aβ) overexpression model, strain CL2006, and in human SH-SY5Y cells overexpressing the Swedish mutant form of human Aβ precursor protein (APPsw). Moreover, ADMA treatment exacerbated Aβ-induced paralysis and oxidative stress in CL2006 worms and further elevated oxidative stress and Aβ secretion in APPsw cells. Knockdown of type 1 protein arginine N-methyltransferase to reduce ADMA production failed to show a protective effect against Aβ toxicity, but resulted in more paralysis in CL2006 worms as well as increased oxidative stress and Aβ secretion in APPsw cells. However, overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) to promote ADMA degradation significantly attenuated oxidative stress and Aβ 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.
authors.affiliation: College of Life Sciences, University of the Chinese Academy of Science, Beijing 100049, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Luo
authors.affiliation: College of Life Sciences, University of the Chinese Academy of Science, Beijing 100049, China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Yue
authors.affiliation: College of Life Sciences, University of the Chinese Academy of Science, Beijing 100049, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Quan
authors.affiliation: College of Life Sciences, University of the Chinese Academy of Science, Beijing 100049, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Baolu
authors.initials: B
authors.lastname: Zhao
authors.affiliation: College of Life Sciences, University of the Chinese Academy of Science, Beijing 100049, China. Electronic address: luzhongbing@ucas.ac.cn.
authors.forename: Zhongbing
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000378:metabolism*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D018384:Oxidative Stress / Q000187:drug effects*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D012097:Repressor Proteins; C018524:N,N-dimethylarginine; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: ADMA; Alzheimer disease; DDAH1; Free radicals; Oxidative stress; PRMT1