Amyloid-β_1-42 Induces Reactive Oxygen Species-Mediated Autophagic Cell Death in U87 and SH-SY5Y Cells

Article type: Research Article

Authors: Wang, Hongmei^{a; b;} | Ma, Jianfang^a; | Tan, Yuyan^{a; b} | Wang, Zhiquan^b | Sheng, Chengyu^b | Chen, Shengdi^{a; b; *} | Ding, Jianqing^{a; b; *}

Affiliations: [a] Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China | [b] Lab of Neurodegenerative Diseases, & Key Laboratory of Stem Cell Biology, Institute of Health Science, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China

Correspondence: [*] Correspondence to: Shengdi Chen and Jianqing Ding, Department of Neurology &} Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China. Tel./Fax: +86 21 64457249; E-mail: jqding18@yahoo.com (Jian-qing Ding), chen_sd@medmail.com.cn (Sheng-di Chen).

Note: [1] Authors contributed equally to this work.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder initiated by the aggregation of amyloid-β peptide (Aβ). Macroautophagy, which is essential for cell survival as well as the promotion of cell death, has been observed extensively in AD brains or transgenic mice overexpressing Aβ protein precursor. However, the role of macroautophagy in the pathogenesis of AD is unclear. In this study, we showed that Aβ1-42 triggered autophagic cell death in both human glioma cell line (U87 cell) and human neuroblastoma cell line (SH-SY5Y cell). Aβ1-42-induced cytotoxicity and autophagic cell death were blocked by the autophagy inhibitor 3-methyladenine (3-MA) or by small interfering RNA against the autophagy gene Beclin-1. Reactive oxygen species (ROS) accumulation was also detected in both Aβ1-42 treated cell lines and this accumulation was not affected by 3-MA. Moreover, pretreatment with the ROS scavenger N-acetylcysteine inhibited ROS accumulation and autophagic cell death induced by Aβ1-42, suggesting that Aβ1-42-induced ROS accumulation might trigger the onset of autophagy and subsequent autophagic cell death. These findings provide further insights into the mechanisms underlying Aβ-induced cytotoxicity.

Keywords: Apoptosis, autophagic cell death, Beclin-1, N-acetylcysteine, reactive oxygen species

DOI: 10.3233/JAD-2010-091207

Journal: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 597-610, 2010