Frizzled-1 is involved in the neuroprotective effect of Wnt3a against Aβ oligomers

Marcelo A. Chacón, Lorena Varela-Nallar, Nibaldo C. Inestrosa

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)215-227
Number of pages13
JournalJournal of Cellular Physiology
Volume217
Issue number1
DOIs
Publication statusPublished - Oct 2008

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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