Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain(553 views) Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, Storto M, Gaviraghi G, Terstappen GC, Nicoletti F
Keywords: β-Amyloid, Alzheimer, S Disease, Apoptosis, Dickkopf-1, Tau Phosphorylation, Wnt Pathway, Amyloid Beta Protein, Antisense Oligonucleotide, Dickkopf 1 Protein, Glycogen Synthase Kinase 3beta, Glycoprotein, Protein P53, Regulator Protein, Tau Protein, Tumor Suppressor Protein, Unclassified Drug, Wnt Protein, Alzheimer Disease, Animal Cell, Article, Brain Cell, Controlled Study, Dystrophy, Embryo, Enzyme Activation, Gene Expression, Human, Human Tissue, Knockout Gene, Nerve Cell Culture, Nerve Cell Degeneration, Neurite, Neurofibrillary Tangle, Neurotoxicity, Nonhuman, Priority Journal, Protein Hyperphosphorylation, Protein Induction, Protein Localization, Protein Phosphorylation, Signal Transduction, Aged, 80 And Over, Amyloid Beta-Protein, Bcl-2-Associated X Protein, Dizocilpine Maleate, Gene Expression Regulation, Glutamic Acid, Immunoenzyme Techniques, Intercellular Signaling Peptides And Proteins, Nerve Degeneration, Nerve Tissue Proteins, Oligodeoxyribonucleotides, Peptide Fragments, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins C-Bcl-2, Quinoxalines, Messenger, Tumor Suppressor Protein P53,
Affiliations: *** IBB - CNR ***
Siena Biotech., 53100 Siena, Italy
Dept. of Pharmaceutical Sciences, University of Catania, 95125 Catania, Italy
Department of Neuropathology, Academic Medical Center, University of Amsterdam Meibergdreef, Amsterdam 1105 AZ, Netherlands
Dept. Hum. Physiol. and Pharmacol., University of Rome La Sapienza, 00185 Rome, Italy
Istituto Neurologico Mediterraneo, Neuromed., 86077 Pozzilli, Isernia, Italy
Ist. di Bioimmagini e Biostrutture, CNR-95125, Catania, Italy
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Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain
We used primary cultures of cortical neurons to examine the relationship between β-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to β-amyloid peptide (βAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3β. DKK1 was induced at late times after βAP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in βAP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by β-amyloid and is critically involved in the process of tau phosphorylation.
Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain
No results.
Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain