Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells.
Several lines of evidence suggest that enhanced oxidative stress is involved in the pathogenesis and/or progression of Alzheimer's disease (AD). Amyloid beta-protein (Abeta) that composes senile plaques, a major neuropathological hallmark of AD, is considered to have a causal role in AD. Thus, we have studied the effect of oxidative stress on Abeta metabolism within the cell. Here, we report that oxidative stress induced by H(2)O(2) (100-250 microM) caused an increase in the levels of intracellular Abeta in human neuroblastoma SH-SY5Y cells. Treatment with 200 microM H(2)O(2) caused significant decreases in the protein levels of full-length beta-amyloid precursor protein (APP) and its COOH-terminal fragment that is generated by beta-cleavage, while the gene expression of APP was not altered under these conditions. A pulse-chase experiment further showed a decrease in the half-life of this amyloidogenic COOH-terminal fragment but not in that of nonamyloidogenic counterpart in the H(2)O(2)-treated cells. These results suggest that oxidative stress promotes intracellular accumulation of Abeta through enhancing the amyloidogenic pathway.
Misonou
H
H
Department of Neuropathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Morishima-Kawashima
M
M
Ihara
Y
Y
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D006224:Cricetinae; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009447:Neuroblastoma; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D002839:Chromans; D010446:Peptide Fragments; D010718:Phosphatidylserines; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D006861:Hydrogen Peroxide; C022616:thiazolyl blue; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D004121:Dimethyl Sulfoxide