title: Trolox and 17beta-estradiol protect against amyloid beta-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway.
abstract: Oxidative stress is a key mechanism in amyloid beta-peptide (A beta)-mediated neurotoxicity; therefore, the protective roles of 17beta-estradiol (E2) and antioxidants (Trolox and vitamin C) were assayed on hippocampal neurons. Our results show the following: 1) E2 and Trolox attenuated the neurotoxicity mediated by A beta and H2O2 as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assays, quantification of apoptotic cells, and morphological studies of the integrity of the neurite network. 2) Vitamin C failed to protect neurons from A beta toxicity. 3) A beta-mediated endoperoxide production, reported to induce cell damage, was decreased in the presence of E2 and Trolox. 4) Two key Wnt signaling components were affected by E2 and Trolox; in fact, the enzyme glycogen synthase kinase 3beta was inhibited by both E2 and Trolox, and both compounds were able to stabilize cytoplasmic beta-catenin. 5) E2 activated the expression of the Wnt-5a and Wnt-7a ligands, and at the same time, E2, through the alpha-estrogen receptor, was able to prevent the excitotoxic A beta-induced rise in bulk-free Ca2+ as an alternative pathway to increase cell viability. 6) Finally, the Wnt-7a ligand protected against cytoplasmic calcium disturbances induced by A beta treatment. Our results suggest that control of oxidative stress, regulation of cytoplasmic calcium, and activation of Wnt signaling may prevent A beta neurotoxicity.
authors.affiliation: Centro de Regulación Celular y Patología Joaquín V. Luco, Millennium Institute of Fundamental and Applied Biology, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Quintanilla
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Muñoz
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Metcalfe
authors.forename: Maureen
authors.initials: M
authors.lastname: Hitschfeld
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Olivares
authors.forename: Juan A
authors.initials: JA
authors.lastname: Godoy
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D018696:Neuroprotective Agents / Q000633:toxicity*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins; D051176:beta Catenin
chemical_list: D016229:Amyloid beta-Peptides; D002839:Chromans; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D004958:Estradiol; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D002118:Calcium