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

Abstract

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 H 2O2 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. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.