Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer's disease.
Strong evidence indicates oxidative stress in the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Abeta) has been implicated in both oxidative stress mechanisms and in neuronal apoptosis. Glutaredoxin-1 (GRX1) and thioredoxin-1 (TRX1) are antioxidants that can inhibit apoptosis signal-regulating kinase (ASK1). We examined levels of GRX1 and TRX1 in AD brain as well as their effects on Abeta neurotoxicity. We show an increase in GRX1 and a decrease in neuronal TRX1 in AD brains. Using SH-SY5Y cells, we demonstrate that Abeta causes an oxidation of both GRX1 and TRX1, and nuclear export of Daxx, a protein downstream of ASK1. Abeta toxicity was inhibited by insulin-like growth factor-I (IGF-I) and by overexpressing GRX1 or TRX1. Thus, Abeta neurotoxicity might be mediated by oxidation of GRX1 or TRX1 and subsequent activation of the ASK1 cascade. Deregulation of GRX1 and TRX1 antioxidant systems could be important events in AD pathogenesis.
Akterin
S
S
Section of Experimental Geriatrics, Neurotec Department, Karolinska Institutet, Kliniskt Forskningscentrum (KFC), Novum, Huddinge, Sweden.
Cowburn
R F
RF
Miranda-Vizuete
A
A
Jiménez
A
A
Bogdanovic
N
N
Winblad
B
B
Cedazo-Minguez
A
A
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D053492:Elafin / Q000378:metabolism; D054477:Glutaredoxins; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D021381:Protein Transport; D013879:Thioredoxins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D053492:Elafin; D054477:Glutaredoxins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C506806:PI3 protein, human; D010446:Peptide Fragments; C491203:TXN protein, human; C075222:amyloid beta-protein (1-42); D013879:Thioredoxins; D007334:Insulin-Like Growth Factor I; D010088:Oxidoreductases; D002374:Catalase; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D005978:Glutathione