• Maria Cristina Rosi, Ilaria Luccarini, Cristina Grossi, Anna Fiorentini, Maria Grazia Spillantini, Antonella Prisco, Carla Scali, Marco Gianfriddo, Andrea Caricasole, Georg C Terstappen, and Fiorella Casamenti.
• Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
• J. Neurochem. 2010 Mar 1;112(6):1539-51.

AbstractTo investigate the role of the Wnt inhibitor Dickkopf-1 (DKK-1) in the pathophysiology of neurodegenerative diseases, we analysed DKK-1 expression and localization in transgenic mouse models expressing familial Alzheimer's disease mutations and a frontotemporal dementia mutation. A significant increase of DKK-1 expression was found in the diseased brain areas of all transgenic lines, where it co-localized with hyperphosphorylated tau-bearing neurons. In TgCRND8 mice, DKK-1 immunoreactivity was detected in neurons surrounding amyloid deposits and within the choline acetyltransferase-positive neurons of the basal forebrain. Active glycogen synthase kinase-3 (GSK-3) was found to co-localize with DKK-1 and phospho-tau staining. Downstream to GSK-3, a significant reduction in beta-catenin translocation to the nucleus, indicative of impaired Wnt signaling functions, was found as well. Cumulatively, our findings indicate that DKK-1 expression is associated with events that lead to neuronal death in neurodegenerative diseases and support a role for DKK-1 as a key mediator of neurodegeneration with therapeutic potential.

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