Synaptotoxicity in Alzheimer's disease: The Wnt signaling pathway as a molecular target

Recent evidence supports a role of the Wnt pathway in neurodegenerative disorders such as Alzheimer's disease (AD). A relationship between amyloid-β-peptide (Aβ)-induced neurotoxicity and a decrease in the cytoplasmatic levels of β-catenin has been proposed. Also, the inhibition of glycogen synthase kinase (GSK-3β), a central modulator of the pathway, protects rat hippocampal neurons from Aβ-induced damage. Interestingly, during the progression of AD, it has been described that active GSK-3β is found in neuronal cell bodies and neurites, co-localizing with pre-neurofibrillary tangles observed in disease brains. Since Aβ oligomers are associated with the post-synaptic region and we have found that the non-canonical Wnt signaling modulates PSD-95 and glutamate receptors, we propose that the synaptic target for Aβ oligomers in AD is the postsynaptic region and at the molecular level is the non-canonical Wnt signaling pathway. Altogether, our evidence suggests that a sustained loss of Wnt signaling function may be involved in the Aβ-dependent neurodegeneration observed in AD brains and that the activation of this signaling pathway could be of therapeutic interest in AD.