ABSTRACT
Wnt signaling is essential in cell adhesion and regulation of cell fate determination during development.1,2 Recently, it has been implicated in oncogenic processes and in neurodegenerative disorders such as autism, schizophrenia and Alzheimer’s disease (AD). The activation of the canonical Wnt pathway results in the inhibition of glycogen synthase kinase-3β (GSK-3β), a key modulator of this signaling pathway.3 According to the classical view of Wnt signal transduction,4 in the presence of an extracellular Wnt ligand, membrane-anchored receptors of the Frizzled protein family transduce its signal to the intracellular space and activate Dishevelled, which in turn inactivates GSK-3β activity. As a result of GSK-3β inactivation, intracellular levels of β-catenin increase, allowing it to pass to the nucleus, where it binds to components of the high-mobility family of transcription factors (Tcell factor/lymphoid enhancer-binding factor (Tcf/LEF)) and activates the expression of Wnt target genes. Alternatively, in the absence of a Wnt ligand, the activity of GSK-3β is switched on and thus it phosphorylates β-catenin for ubiquitin-proteosome-mediated degradation.5,6
As a net result, β-catenin levels are diminished within the cytosol and therefore the expression
of Wnt-target genes such as cyclin D1 and engrailed is switched off (Figure 45.1). Our recent findings indicate that Wnt/β-catenin signaling may play a role in AD pathology.
