Downregulation of Wnt/β-catenin signaling causes degeneration of hippocampal neurons in vivo.

The possibility that the degeneration of hippocampal neurons can be caused by mis-regulation of Wnt/β-catenin signaling was tested. Downregulation of Wnt signaling by the inducible expression of Axin, ICAT, and dnTcf4E causes degeneration of hippocampal neurons, while upregulation of Wnt signaling by the inducible expression of Dvl and β-catenin has a negligible effect. Treatment with ICG-001, a small molecule known to inhibit Wnt signaling, causes degeneration of hippocampal neurons, while the treatment with a JNK specific inhibitor does not show any effect. The results from LDH and TUNEL assays suggest that degeneration occurs via apoptotic processes. Inhibition of Wnt signaling reduced IGF-1 expression and the addition of IGF-1 blocked degeneration, which suggests that downregulation of IGF-1/Akt signaling is partially responsible for the degeneration. Inducible expression of Axin in the hippocampal neurons isolated from Axin2P-rtTA/pBI-EGFP-Axin double transgenic mice also causes degeneration. Consistent with the findings, these mice had more neuronal cell death in hippocampus and had differences in contextual conditioning upon the inducible expression of Axin. In summary, our data strongly support the idea that downregulation of Wnt/β-catenin signaling causes degeneration of hippocampal neurons in vivo and may be a cause of neurodegenerative diseases related to an anxiety related response.