Fig. 7

Wnt3a ligand regulates autophagy via the Wnt/STOP mechanism, modulating the GSK-AMPK axis in hippocampal neurons. In this scheme, we summarize our findings in conjunction with previous knowledge. Wnt3a ligand binding to the Frizzled receptor requires the presence of the LRP5/6 canonical co-receptor, leading to GSK-3β inhibition (Ser9 phosphorylation). This effect also occurs in the presence of lithium or TCS-183, which are both known inhibitors of GSK-3β. AMPK, a key regulator of cellular metabolism, was inhibited by basal GSK-3β activity; therefore, GSK-3β inhibition promotes AMPK activation. In addition, PP2Ac, the major AMPK phosphatase in the brain, did not affect this regulation mediated by the Wnt pathway (shown in gray). Lithium, rapamycin and metformin are indirect activators of AMPK through the inhibition of mitochondrial complex I, which leads to decreased ATP levels and results in an increased [AMP/ATP] ratio. The increased AMP/ATP ratio allows access to the two main upstream AMPK kinases, LKB1 and CaMKKβ. Downstream, we show that Wnt3a ligand promotes the initiation of autophagy as illustrated by LC3 maturation from LC3I to LC3II, as well as increased accumulation of autophagosome/autophagolysosome structures in cultured hippocampal neurons and the CA1 region of rat hippocampus