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-beta-peptide (Abeta)-induced neurotoxicity and a decrease in the cytoplasmatic levels of beta-catenin has been proposed. Also, the inhibition of glycogen synthase kinase (GSK-3beta), a central modulator of the pathway, protects rat hippocampal neurons from Abeta-induced damage. Interestingly, during the progression of AD, it has been described that active GSK-3beta is found in neuronal cell bodies and neurites, co-localizing with pre-neurofibrillary tangles observed in disease brains. Since Abeta 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 Abeta 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 Abeta-dependent neurodegeneration observed in AD brains and that the activation of this signaling pathway could be of therapeutic interest in AD.
Inestrosa
Nibaldo C
NC
Centro de Regulación Celular y Patología "Joaquín V. Luco" (CRCP), MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. ninestr@bio.puc.cl
Varela-Nallar
Lorena
L
Grabowski
Catalina P
CP
Colombres
Marcela
M
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D051153:Wnt Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3