Figure 3. Interactions between Aβ, WNT pathway and energy metabolism in AD. In AD, Aβ protein activates DKK-1, an inhibitor of WNT pathway. In absence of WNT ligands, cytosolic β-catenin is phosphorylated by GSK-3β. APC and Axin combine with GSK-3β and β-catenin to enhance the destruction process in the proteasome. β-catenin does not translocate to the nucleus et does not bind TCF/LEF co-transcription factor. WNT taget genes, such as cMyc, are not activated. Aβ protein accumulation decreases level of PI3K/Akt pathway and results in inactivation of HIF-1alpha. Downregulation of beta-catenin reduces the expression of PI3K/Akt signaling. HIF-1alpha inactivated does not stimulate Glut, HK, PKM2, LDH-A and PDK1. Inactivation of HIF-1alpha involves PKM2 non-translocation to the nucleus. PKM2 inhibits PEP cascade and the formation of pyruvate. PKM2 does not bind beta-catenin and does not induce cMyc-mediated expression of glycolytic enzymes (Glut, LDH-A, PDK1). Inhibition of Glut and HK involves glucose hypo-metabolism with decreased in glucose transport and phosphorylation rates. PDK1 does not inhibit PDH, which stimulates pyruvate entrance into mitochondria. Aβ toxicity is associated with mitochondrial-derived ROS (reactive oxygen species). GSK-3β phosphorylation activates hyperphosphorylation of Tau, which induces neurofibrillary tangles and neuroinflammation.