Abstract
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 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Analysis of Variance
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Animals
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Antibodies, Monoclonal / metabolism
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Brain / cytology
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Brain / metabolism
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Choline O-Acetyltransferase / metabolism
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Disease Models, Animal
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Gene Expression Regulation / genetics
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Gene Expression Regulation / physiology*
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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LDL-Receptor Related Proteins / genetics
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LDL-Receptor Related Proteins / metabolism
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Low Density Lipoprotein Receptor-Related Protein-5
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics
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Neurodegenerative Diseases / genetics
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Neurodegenerative Diseases / metabolism*
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Neurodegenerative Diseases / pathology
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Neurons / metabolism
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Peptide Fragments / metabolism
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Phosphopyruvate Hydratase / metabolism
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Presenilin-1 / genetics
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beta Catenin / metabolism
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tau Proteins / metabolism
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Antibodies, Monoclonal
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Dkk1 protein, mouse
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Intercellular Signaling Peptides and Proteins
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LDL-Receptor Related Proteins
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LRP5 protein, human
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Low Density Lipoprotein Receptor-Related Protein-5
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Lrp5 protein, mouse
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PHF-1 monoclonal antibody
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Peptide Fragments
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Presenilin-1
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amyloid beta-protein (1-42)
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beta Catenin
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tau Proteins
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Choline O-Acetyltransferase
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Glycogen Synthase Kinase 3
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Phosphopyruvate Hydratase