Journal of Biological Chemistry
Volume 280, Issue 12, 25 March 2005, Pages 11615-11625
Journal home page for Journal of Biological Chemistry

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

https://doi.org/10.1074/jbc.M411936200Get rights and content
Under a Creative Commons license
open access

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

Cited by (0)

*

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.