Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease.
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.
Rosi
Maria Cristina
MC
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
Luccarini
Ilaria
I
Grossi
Cristina
C
Fiorentini
Anna
A
Spillantini
Maria Grazia
MG
Prisco
Antonella
A
Scali
Carla
C
Gianfriddo
Marco
M
Caricasole
Andrea
A
Terstappen
Georg C
GC
Casamenti
Fiorella
F
D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; C085349:PHF-1 monoclonal antibody; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D051176:beta Catenin; D016875:tau Proteins; D002795:Choline O-Acetyltransferase; D038362:Glycogen Synthase Kinase 3; D010751:Phosphopyruvate Hydratase