FIGURE 12.

Proposed schematic representation showing the mechanism of ETH and its effect on neurogenesis. On the basis of our experimental and in silico studies, we found that ETH may induce the PI3K/Akt/Wnt/β-catenin signaling. Binding of Wnt ligands with Frizzled receptor and phosphorylated co-receptor low density lipoprotein (LRP-5/6) leads to activation of cytoplasmic dishevelled (Dvl) protein. Activated dishevelled then binds with destruction complex Axin·APC·GSK-3β, inhibits GSK-3β by its phosphorylation, and activates the levels of β-catenin. Inhibition of GSK-3β leads to accumulation of cytoplasmic β-catenin and its translocation into the nucleus. In the nucleus, β-catenin interacts with the Tcf·Lef promoter complex, leading to activation of their target genes, which play an important role in NSC proliferation and differentiation. ETH activates PI3K·Akt, which in turn phosphorylates and inactivates GSK-3β and activates β-catenin. ETH enhances expression of Wnt pathway genes. The blockage of the Wnt·β-catenin signaling (β-catenin siRNA and Dkk-1) and PI3K·Akt pathway (LY294002) results in inhibition of ETH-induced cell proliferation and neuronal differentiation. ETH also blocks Aβ-mediated inhibition of neurogenesis through activation of PI3K/Akt/Wnt/β-catenin signaling.