Figure 1

The Wnt signaling pathway and its inhibition by Aβ aggregates. First when the Wnt ligand is available, the Fz receptor together with LRP5/6 translates its signal through Dvl, which in turn inactivates GSK-3β in the cytoplasmic destruction complex. This allows β-catenin to accumulate in the cytoplasm, and subsequently to move to the nucleus, where it binds to TCF/LEF transcription factors activating Wnt target gene transcription (Left Panel). On the other hand, when the Aβ aggregates become available, the signaling through the Wnt pathway might be affected: GSK-3β activates, β-catenin destroyed, and the Wnt mediated gene transcription is stopped (Right Panel). Several potential mechanisms of how Aβ aggregates affect Wnt signaling might be possible: (a) Aβ may bind to the Wnt ligand (scavenger effect), (b) Aβ may directly interact with the Fz receptor, (c) Dkk-1 may become available and block the transduction at the receptor level, or (d) Aβ may affect calcium flux by direct activation of the α7-nicotinic ACh and/or NMDA receptors. As a consequence, GSK-3β is activated and β-catenin function attenuated.