title: Modulation of miR-19 in Aluminum-Induced Neural Cell Apoptosis.
abstract: Neuronal cell death is an important feature of neurodegeneration. Aluminum is associated with neurodegenerative disorders, particularly Alzheimer's disease. However, the underlying mechanisms by which aluminum induces neuronal apoptosis remain to be elucidated. miR-19 is a key miRNA implicated in regulating cell survival process, while the role of miR-19 in Alzheimer's disease has not been investigated. In the present study, we showed that Aluminum maltolate (Al-malt), a lipophilic Al complex which is a common component of human diet with the ability to facilitate the entry of Al into the brain, induced apoptosis in human neuroblastoma SH-SY5Y cells, along with downregulation of miR-19a/miR-19b, upregulation of miR-19-targeted PTEN, and alterations of its downstream apoptosis related proteins including AKT, p53, Bax, and Bcl-2. miR-19 overexpression attenuated Al-malt-induced apoptosis as well as changes in the expression of apoptosis related proteins in SH-SY5Y cells. We further revealed that exposure of rats to Al-malt for 12 weeks at doses relevant to human exposure significantly elevated Al concentrations in serum and brain tissues. Al-malt dose-dependently induced apoptosis in rat brain, as evidenced by increased caspase activation and increased TUNEL staining. Consistent with in vitro results, Al-malt reduced miR-19 expression and altered the expression of apoptotic related proteins in rat brain. Taken together, our data suggest for the first time that miR-19 modulation is critically involved in Al-induced neural cell apoptosis. Findings from this study could provide new insight into the molecular mechanisms of Al-associated neurodegenerative pathogenesis.
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Zhaofeng
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Deng
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Jianyun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Shijia
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Jieshu
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Geng
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.|The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Caiyun
authors.initials: C
authors.lastname: Zhong
mesh_terms: D000535:Aluminum / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C549214:MIRN19A microRNA, human; C586754:MIRN19 microRNA, rat; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D000535:Aluminum; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487216:Pten protein, rat
keywords: Aluminum; apoptosis; miR-19; modulation; neurodegenerative diseases