Amyloid-beta1-42 induces reactive oxygen species-mediated autophagic cell death in U87 and SH-SY5Y cells.
Alzheimer's disease (AD) is a neurodegenerative disorder initiated by the aggregation of amyloid-beta peptide (Abeta). 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 Abeta protein precursor. However, the role of macroautophagy in the pathogenesis of AD is unclear. In this study, we showed that Abeta1-42 triggered autophagic cell death in both human glioma cell line (U87 cell) and human neuroblastoma cell line (SH-SY5Y cell). Abeta1-42-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 Abeta1-42 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 Abeta1-42, suggesting that Abeta1-42-induced ROS accumulation might trigger the onset of autophagy and subsequent autophagic cell death. These findings provide further insights into the mechanisms underlying Abeta-induced cytotoxicity.
Wang
Hongmei
H
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Ma
Jianfang
J
Tan
Yuyan
Y
Wang
Zhiquan
Z
Sheng
Chengyu
C
Chen
Shengdi
S
Ding
Jianqing
J
D000111:Acetylcysteine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004347:Drug Interactions; D005910:Glioma; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C047915:2-methyladenine; D000225:Adenine; D000111:Acetylcysteine