FIGURE 2.

Wnt signaling deregulation in the aging brain and in AD. (A) Wnt signaling components are deregulated in both the aging and AD brain. Notably, the Wnt antagonist Dkk1 is upregulated, whereas Wnt ligands, Dvl, ß-catenin, and TCF are downregulated, leading to decreased canonical Wnt signaling. (B) As Dkk1 mainly affects the canonical Wnt signaling pathway, we propose a model by which elevation of Dkk1 results in an imbalance between the Wnt/ß-catenin and PCP pathways, resulting in synaptic defects and synapse loss. (C) In the brain of AD subjects and AD mouse models, the Wnt antagonist Dkk1 is elevated, leading to increased activity of both Gsk3ß and ROCK, thus resulting in reduced Wnt/ß-catenin signaling and increased PCP signaling. The activation of these two kinases leads to synapse vulnerability but the precise mechanisms downstream remain to be defined. A possible mechanism is that tau phosphorylation and actin remodeling contribute to synaptic changes (gray arrows and diffuse red boxes in the scheme) and subsequent cognitive deficits. These results suggest that pharmacologically targeting Wnt signaling could be a promising therapeutic strategy for synapse protection in AD.