Wnt-pathway activation during the early stage of neurodegeneration in FTDP-17 mice.

Glycogen synthase kinase-3beta (GSK-3beta), a key component of the Wnt signaling pathway, has been recognized as an important tau kinase with a potential pathogenic role in dementia. We have previously shown that GSK-3beta-induced tau-hyperphosphorylation and Wnt-activation enhance tau-induced degeneration in Drosophila. Here, we demonstrate that Wnt-activation occurs prior to 3 months of age in the JNPL3 mouse model of frontotemporal dementia (FTD). We observed that GSK-3beta becomes associated with insoluble tau, concomitant with the increase in the downstream Wnt-pathway component beta-catenin. We demonstrate that this induces downstream Wnt signaling via the activation of nuclear transcription factors associated with beta-catenin, suggesting that Wnt-pathway activation is an early feature of the neurodegenerative process.