Journal
NEUROBIOLOGY OF AGING
Volume 30, Issue 1, Pages 14-21Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2007.05.015
Keywords
Dementia; Transgenic animal model; Wnt-pathway
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Funding
- John Douglas French Alzheimer's Foundation
- UCLA Alzheimer*s disease research center (ADRC)
- NIH [K08 NS002240]
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Glycogen synthase kinase-3beta (GSK-3 beta), 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-3 beta-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-3 beta 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. (C) 2007 Elsevier Inc. All rights reserved.
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