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

Summary Recent evidence supports a role of the Wnt pathway in neurodegenerative disorders such as Alzheimer’s disease (AD). A relationship between amyloid-b-peptide (Ab)-induced neurotoxicity and a decrease in the cytoplasmatic levels of b-catenin has been proposed. Also, the inhibition of glycogen synthase kinase (GSK3b), a central modulator of the pathway, protects rat hippocampal neurons from Ab-induced damage. Interestingly, during the progression of AD, it has been described that active GSK-3b is found in neuronal cell bodies and neurites, co-localizing with preneurofibrillary tangles observed in disease brains. Since Ab 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 Ab 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 Ab-dependent neurodegeneration observed in AD brains and that the activation of this signaling pathway could be of therapeutic interest in AD. IUBMB Life, 59: 316–321, 2007