beta-Amyloid induces oxidative DNA damage and cell death through activation of c-Jun N terminal kinase.
Oxidative stress induced by reactive oxygen species has been implicated in the pathophysiology of many neurodegenerative disorders including Alzheimer's disease (AD). In this study, we have investigated the molecular mechanisms underlying oxidative cell death induced by beta-amyloid, a neurotoxic peptide associated with senile plaques found in the brains of patients with AD. PC12 cells treated with beta-amyloid underwent apoptotic cell death as determined by characteristic morphological features, cleavage of poly(ADP-ribose)polymerase, and positive in situ terminal-end labeling (TUNEL). Furthermore, beta-amyloid treatment led to activation of c-Jun N terminal kinase (JNK) and intracellular accumulation of ROS. In another experiment, beta-amyloid caused strand scission in phiX174 DNA in the presence of ferrous iron. These findings suggest that production of ROS and subsequent activation of JNK play an important role in beta-amyloid-induced apoptotic cell death.
Jang
Jung-Hee
JH
College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, Korea.
Surh
Young-Joon
YJ
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology*; D010673:Pheochromocytoma; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C074636:amyloid beta-protein (25-35); D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases