Frizzled-1 is involved in the neuroprotective effect of Wnt3a against Abeta oligomers.
The activation of the canonical Wnt signaling pathway protects hippocampal neurons against the toxicity of Alzheimer's amyloid-beta-peptide (Abeta), 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/beta-catenin pathway by Wnt3a in PC12 cells. In addition, the protective effect of Wnt3a against the toxicity of Abeta 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 beta-catenin, but not a transcriptionally inactive mutated version, prevented the toxicity of Abeta 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 beta-catenin, which does not elicited protection levels similar to those showed with endogenous beta-catenin. Our results indicate that Wnt3a protects from Abeta-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.
Chacón
Marcelo A
MA
Centro de Regulación Celular y Patología Joaquín V. Luco (CRCP), Instituto Milenio (MIFAB), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Varela-Nallar
Lorena
L
Inestrosa
Nibaldo C
NC
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D051157:Frizzled Receptors / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D051157:Frizzled Receptors; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; D053148:Caspase 3