Trolox and 17β-estradiol protect against amyloid β-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway

被引:110
作者
Quintanilla, RA
Muñoz, FJ
Metcalfe, MJ
Hitschfeld, M
Olivares, G
Godoy, JA
Inestrosa, NC
机构
[1] Pontificia Univ Catolica Chile, Ctr Regulac Celular & Patol Joaquin V Luco, Fondo Areas Prioritarias Ctr,Fac Ciencias Biol, Millennium Inst Fundamental & Appl Biol, Santiago, Chile
[2] Univ Pompeu Fabra, Unitat Senyalitzacio Cellular, Dept Ciencies Expt & Salut, Barcelona 08003, Spain
关键词
D O I
10.1074/jbc.M411936200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Oxidative stress is a key mechanism in amyloid beta-peptide (A beta)-mediated neurotoxicity; therefore, the protective roles of 17 beta-estradiol (E-2) and antioxidants ( Trolox and vitamin C) were assayed on hippocampal neurons. Our results show the following: 1) E-2 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 E-2 and Trolox. 4) Two key Wnt signaling components were affected by E-2 and Trolox; in fact, the enzyme glycogen synthase kinase 3 beta was inhibited by both E-2 and Trolox, and both compounds were able to stabilize cytoplasmic beta-catenin. 5) E-2 activated the expression of the Wnt-5a and Wnt-7a ligands, and at the same time, E-2, 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.
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页码:11615 / 11625
页数:11
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