Review

The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease

Nibaldo C Inestrosa^1,2* and Enrique M Toledo¹

• * Corresponding author: Nibaldo C Inestrosa ninestrosa@bio.puc.cl

Author Affiliations

¹ Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología "Joaquín V. Luco" (CRCP), MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile

² CARE & CRCP Biomedical Center, Faculty of Biological Sciences, P. Catholic University of Chile, P.O. Box 114-D, Santiago, Chile

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Molecular Neurodegeneration 2008, 3:9 doi:10.1186/1750-1326-3-9

Published: 24 July 2008

Abstract

Recent evidence supports a neuroprotective role for Wnt signaling in neurodegenerative disorders such as Alzheimer's Disease (AD). In fact, a relationship between amyloid-β-peptide (Aβ)-induced neurotoxicity and a decrease in the cytoplasmic levels of β-catenin has been observed. Apparently Aβ binds to the extracellular cysteine-rich domain of the Frizzled receptor (Fz) inhibiting Wnt/β-catenin signaling. Cross-talk with other signaling cascades that regulate Wnt/β-catenin signaling, including the activation of M₁ muscarinic receptor and PKC, the use of Ibuprofen-ChE bi-functional compounds, PPAR α, γ agonists, nicotine and some antioxidants, results in neuroprotection against Aβ. These studies indicate that a sustained loss of Wnt signaling function may be involved in the Aβ-dependent neurodegeneration observed in Alzheimer's brain. In conclusion the activation of the Wnt signaling pathway could be proposed as a therapeutic target for the treatment of AD.