Involvement of glutaredoxin-1 and thioredoxin-1 in -amyloid toxicity and Alzheimer's disease

25 páginas, 10 figuras.Strong evidence indicates oxidative stress in the pathogenesis of Alzheimer's disease (AD). Amyloid (A) 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 A neurotoxicity. We show an increase in GRX1 and a decrease in neuronal TRX1 in AD brains. Using SH-SY5Y cells, we demonstrate that A causes an oxidation of both GRX1 and TRX1, and nuclear export of Daxx, a protein downstream of ASK1. Atoxicity was inhibited by insulin-like growth factor-I (IGF-I) and by overexpressing GRX1 or TRX1. Thus, A 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.This research was supported by grants from the following Swedish foundations: Hjärnfonden (Swedish Brain Foundation), Gun och Bertil Stohnes Stiftelse, Karolinska Institutets Foundation for geriatric research, Loo and Hans Ostermans Foundation, Åke Wiberg Foundation, Svenska Lundbeck-stiftelsen, Demensförbundet, Alzheimer Foundation; Sweden, Lars Hiertas minnesstiftelse, Gamla Tjänarinnor foundation, Insamlingsstiftelsen för Alzheimer och demenforskning (SADF) and Swedish Brain Power project. AM-V was supported by Swedish Medical Research Council (Projects 03P-14096, 03X-14041, and 13X-10370). AJ was supported by a postdoctoral fellowship EX2003-0390 from the Spanish Ministerio de Educacion, Cultura y Deporte.Peer reviewe