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J. Biol. Chem., Vol. 280, Issue 12, 11615-11625, March 25, 2005

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Trolox and 17-Estradiol Protect against Amyloid -Peptide Neurotoxicity by a Mechanism That Involves Modulation of the Wnt Signaling Pathway^*

Rodrigo A. Quintanilla, Francisco J. Muñoz¶, Maria J. Metcalfe, Maureen Hitschfeld, Gonzalo Olivares, Juan A. Godoy, and Nibaldo C. Inestrosa||

From the 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 and ^¶Unitat de Senyalització Cellular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain

Oxidative stress is a key mechanism in amyloid -peptide (A)-mediated neurotoxicity; therefore, the protective roles of 17-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 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 toxicity. 3) A-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 3 was inhibited by both E₂ and Trolox, and both compounds were able to stabilize cytoplasmic -catenin. 5) E₂ activated the expression of the Wnt-5a and Wnt-7a ligands, and at the same time, E₂, through the -estrogen receptor, was able to prevent the excitotoxic A-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 treatment. Our results suggest that control of oxidative stress, regulation of cytoplasmic calcium, and activation of Wnt signaling may prevent A neurotoxicity.

Received for publication, October 20, 2004 , and in revised form, January 18, 2005.

^* This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico Grant 3980024 and Field-Initiated Studies Program Grant 01-1029 (to F. J. M.) and Fondo de Areas Prioritarias Biomedicine Grant 13980001 (to N. C. I.) and by the Millennium Institute of Fundamental and Applied Biology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Centro de Regulación Celular y Patología "Joaquín V. Luco"-Fondo de Areas Prioritarias Center, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile. Tel.: 56-2-6862724; Fax: 56-2-6862959; E-mail: ninestr{at}genes.bio.puc.cl.

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