Modulation of miR-19 in Aluminum-Induced Neural Cell Apoptosis

Article type: Research Article

Authors: Zhu, Mingming^a | Huang, Cong^a | Ma, Xiao^a | Wu, Rui^a | Zhu, Weiwei^a | Li, Xiaoting^{a; b} | Liang, Zhaofeng^a | Deng, Feifei^a | Zhu, Jianyun^a | Xie, Wei^a | Yang, Xue^a | Jiang, Ye^a | Wang, Shijia^a | Wu, Jieshu^{a; b} | Geng, Shanshan^{a; b} | Xie, Chunfeng^{a; b} | Zhong, Caiyun^{a; b; *}

Affiliations: [a] Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China | [b] The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China

Correspondence: [*] Correspondence to: Caiyun Zhong, PhD, DABT, Department of Nutrition and Food Safety, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Tel.: +86 25 86868450; Fax: +86 25 86868499; E-mail: cyzhong@njmu.edu.cn.

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.

Keywords: Aluminum, apoptosis, miR-19, modulation, neurodegenerative diseases

DOI: 10.3233/JAD-150763

Journal: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1149-1162, 2016