Decreased thioredoxin and increased thioredoxin reductase levels in Alzheimer's disease brain

Increasing evidence supports the role of reactive oxygen species (ROS) in t he pathogenesis of Alzheimer's disease (AD). Both in vivo and in vitro stud ies demonstrate that thioredoxin (Trx) and thioredoxin reductase (TR), the enzyme responsible for reduction of oxidized Trx, have protective roles aga inst cytotoxicity mediated by the generation of ROS. The present study meas ured levels of Tn; protein and activities of TR in the brain in AD compared with control subjects, and evaluated the possible protective role of TR an d Trx against amyloid beta-peptide (A beta) toxicity in neuronal cultures. Analysis of Trx; protein levels in 10 AD and 10 control subjects demonstrat ed a general decrease in all AD brain regions studied, with statistically s ignificant decreases in the amygdala (p < .05), hippocampus/parahippocampal gyrus (p < .05), and marginally significant (p < .10) depletions in the su perior and middle temporal gryi. Thioredoxin reductase activity levels were increased in all AD brain regions studied with statistically significant i ncreases occurring in AD amygdala (p = .01) and cerebellum (p = .007). To i nvestigate the protective effects of Trx and TR against A beta-induced toxi city, primary hippocampal cultures were treated with Trx or TR in combinati on with toxic doses of A beta. Treatment of cultures with Tn led to a stati stically significant concentration-dependent enhancement in cell survival a gainst A beta-mediated toxicity as did treatment with TR. Together, these d ata suggest that, although TR is protective against A beta-mediated toxicit y, the increase observed in AD brain offers no protection due to the signif icant decrease in Trx levels. This decrease in the antioxidant Trx-TR syste m may contribute to the increased oxidative stress and subsequent neurodege neration observed in the brain in AD. (C) 2000 Elsevier Science Inc.