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

J Neurochem. 2010 Mar;112(6):1539-51. doi: 10.1111/j.1471-4159.2009.06566.x. Epub 2009 Dec 29.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Analysis of Variance
  • Animals
  • Antibodies, Monoclonal / metabolism
  • Brain / cytology
  • Brain / metabolism
  • Choline O-Acetyltransferase / metabolism
  • Disease Models, Animal
  • 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
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Neurons / metabolism
  • Peptide Fragments / metabolism
  • Phosphopyruvate Hydratase / metabolism
  • Presenilin-1 / genetics
  • beta Catenin / metabolism
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Antibodies, Monoclonal
  • Dkk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • LDL-Receptor Related Proteins
  • LRP5 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Lrp5 protein, mouse
  • PHF-1 monoclonal antibody
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • beta Catenin
  • tau Proteins
  • Choline O-Acetyltransferase
  • Glycogen Synthase Kinase 3
  • Phosphopyruvate Hydratase