title: Estrogen protects against amyloid-β toxicity by estrogen receptor α-mediated inhibition of Daxx translocation.
abstract: Estrogen was shown to promote neuronal survival against several neurotoxic insults including β-amyloid (Aβ). 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, Aβ neurotoxicity depends on the activation of apoptosis signal-regulating kinase 1 (Ask1), and both Ask1 activity and Aβ toxicity are inhibited by thioredoxin-1 (Trx1). Here, we explored the possibility that estrogen could protect cells against Aβ(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, 17β-estradiol (E2) and specific agonists for estrogen receptor (ER) α or β we demonstrated that nM concentrations of E2 protected against Aβ(1-42) by a mechanism depending upon ERα stimulation, Akt activation and Ask1 inhibition. Moreover, this protection would occur independently of ERβ and the induction of Trx1 expression. Our results emphasize the importance of Ask1 cascade in Aβ toxicity, and of ERα and Ask1 as targets for developing new neuroprotective drugs.
authors: Karolinska Institutet, NVS, KI-Alzheimer Disease Research Center, NOVUM, 5th floor, SE-14186 Stockholm, Sweden.
authors: Laura
authors: L
authors: Mateos
authors: Torbjörn
authors: T
authors: Persson
authors: Shirin
authors: S
authors: Katoozi
authors: Shirin
authors: S
authors: Kathozi
authors: Francisco Javier
authors: FJ
authors: Gil-Bea
authors: Angel
authors: A
authors: Cedazo-Minguez
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D018832:Molecular Chaperones; D018696:Neuroprotective Agents / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D004958:Estradiol; D048848:MAP Kinase Kinase Kinase 5