Abstract
The activation of the canonical Wnt signaling pathway protects hippocampal neurons against the toxicity of Alzheimer's amyloid‐β‐peptide (Aβ), however, the role played by the Wnt receptors Frizzleds, has not been studied. We report here that Frizzled‐1 mediates the activation of the canonical Wnt/β‐catenin pathway by Wnt3a in PC12 cells. In addition, the protective effect of Wnt3a against the toxicity of Aβ oligomers was modulated by Frizzled‐1 expression levels in both PC12 cells and hippocampal neurons. Over‐expression of Frizzled‐1 significantly increased cell survival induced by Wnt3a and diminished caspase‐3 activation, while knocking‐down Frizzled‐1 expression by antisense oligonucleotides decreased the Wnt3a protection. Over‐expression of wild‐type β‐catenin, but not a transcriptionally inactive mutated version, prevented the toxicity of Aβ suggesting that the transcription of Wnt target genes may be involved in these events. This was confirmed by co‐transfecting both Frizzled‐1 and the inactive form of β‐catenin, which does not elicited protection levels similar to those showed with endogenous β‐catenin. Our results indicate that Wnt3a protects from Aβ‐oligomers toxicity by activating the canonical Wnt signaling pathway through the Frizzled‐1 receptor, suggesting a therapeutic potential for this signaling pathway in the treatment of Alzheimer's disease. J. Cell. Physiol. 217: 215–227, 2008. © 2008 Wiley‐Liss, Inc.