RESUMEN
Estrogen was shown to promote neuronal survival against several neurotoxic insults including ß-amyloid (Aß). The proposed mechanism includes the activation of the mitogen activated protein kinase/extracellular signal-regulated kinase (Mapk/Erk), phosphatidylinositol 3-kinase/Akt pathways and the upregulation of antiapoptotic proteins. On the other hand, Aß neurotoxicity depends on the activation of apoptosis signal-regulating kinase 1 (Ask1), and both Ask1 activity and Aß toxicity are inhibited by thioredoxin-1 (Trx1). Here, we explored the possibility that estrogen could protect cells against Aß(1-42) toxicity by inhibiting the Ask1 cascade or by modulating Trx1. Cytosolic translocation of death-associated protein Daxx was used as indicator of Ask1 activity. Using human SH-SY5Y neuroblastoma cells, 17ß-estradiol (E2) and specific agonists for estrogen receptor (ER) α or ß we demonstrated that nM concentrations of E2 protected against Aß(1-42) by a mechanism depending upon ERα stimulation, Akt activation and Ask1 inhibition. Moreover, this protection would occur independently of ERß and the induction of Trx1 expression. Our results emphasize the importance of Ask1 cascade in Aß toxicity, and of ERα and Ask1 as targets for developing new neuroprotective drugs.