Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease

• Published in: Journal of neurochemistry Vol. 112; no. 6; pp. 1539 - 1551
• Main Authors: Rosi, Maria Cristina, Luccarini, Ilaria, Grossi, Cristina, Fiorentini, Anna, Spillantini, Maria Grazia, Prisco, Antonella, Scali, Carla, Gianfriddo, Marco, Caricasole, Andrea, Terstappen, Georg C, Casamenti, Fiorella
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.03.2010; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: active glycogen synthase kinase-3; Adult and adolescent clinical studies; Age Factors; Alzheimer disease; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Analysis of Variance; Animals; Antibodies, Monoclonal - metabolism; beta Catenin - metabolism; Biological and medical sciences; Brain - cytology; Brain - metabolism; Choline O-Acetyltransferase - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dickkopf-1; Disease Models, Animal; frontotemporal dementia; Gene expression; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Glycogen Synthase Kinase 3 - metabolism; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; LDL-Receptor Related Proteins - genetics; LDL-Receptor Related Proteins - metabolism; Low Density Lipoprotein Receptor-Related Protein-5; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation - genetics; Neurodegeneration; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurology; Neurons - metabolism; Organic mental disorders. Neuropsychology; Peptide Fragments - metabolism; Phosphopyruvate Hydratase - metabolism; Physiology; Presenilin-1 - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rodents; tau Proteins - metabolism; transgenic mice; β-catenin; Animal model; Dickkopf-1; Alzheimer disease; Glycogen synthase kinase-3; Central nervous system; Encephalon; Signal transduction; β-catenin; Familial disease; transgenic mice; Degenerative disease; Localization; Alzheimer's disease; Nervous system diseases; Pathophysiology; Rodentia; Cerebral disorder; active glycogen synthase kinase-3; Vertebrata; Mammalia; Neuron; Mouse; Cell death; Choline; Central nervous system disease; Mutation; Frontotemporal dementia
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06566.x

J. Neurochem. (2010) 112, 1539-1551. To 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 β-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.