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.

[1]  L. Murri,et al.  Causative and susceptibility genes for Alzheimer’s disease: a review , 2003, Brain Research Bulletin.

[2]  Andrea Caricasole,et al.  The Wnt pathway, cell-cycle activation and beta-amyloid: novel therapeutic strategies in Alzheimer's disease? , 2003, Trends in pharmacological sciences.

[3]  N. Inestrosa,et al.  Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by β-amyloid fibrils , 2003, Molecular Psychiatry.

[4]  N. Inestrosa,et al.  Protein kinase C inhibits amyloid β‐peptide neurotoxicity by acting on members of the Wnt pathway , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  A. Caricasole,et al.  Erratic expression of DNA polymerases by β‐amyloid causes neuronal death , 2002 .

[6]  N. Inestrosa,et al.  Wnt signaling involvement in β-amyloid-dependent neurodegeneration , 2002, Neurochemistry International.

[7]  G. Terstappen,et al.  Molecular cloning and initial characterization of the MG61/PORC gene, the human homologue of the Drosophila segment polarity gene Porcupine. , 2002, Gene.

[8]  A. LeBlanc,et al.  Selective cytotoxicity of intracellular amyloid β peptide1–42 through p53 and Bax in cultured primary human neurons , 2002, The Journal of cell biology.

[9]  Jiang Shou,et al.  Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA , 2002, Oncogene.

[10]  G. Terstappen,et al.  Lithium induces gene expression through lymphoid enhancer-binding factor/T-cell factor responsive element in rat PC12 cells , 2002, Neuroscience Letters.

[11]  R. Jope,et al.  The multifaceted roles of glycogen synthase kinase 3β in cellular signaling , 2001, Progress in Neurobiology.

[12]  A. Zorn,et al.  Wnt signalling: Antagonistic Dickkopfs , 2001, Current Biology.

[13]  S. Folstein,et al.  Evidence supporting WNT2 as an autism susceptibility gene. , 2001, American journal of medical genetics.

[14]  S. Fukumoto,et al.  Akt Participation in the Wnt Signaling Pathway through Dishevelled* , 2001, The Journal of Biological Chemistry.

[15]  Giancarlo V. De Ferrari and,et al.  Wnt signaling function in Alzheimer’s disease , 2000, Brain Research Reviews.

[16]  A D Roses,et al.  The role of apolipoprotein E in Alzheimer's disease: pharmacogenomic target selection. , 2000, Biochimica et biophysica acta.

[17]  Jian Wang,et al.  Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53 , 2000, Oncogene.

[18]  C. Duyckaerts,et al.  Microglia, amyloid and dementia in Alzheimer disease A correlative study , 2000, Neurobiology of Aging.

[19]  S. Jackson,et al.  Regulation of p53 in response to DNA damage , 1999, Oncogene.

[20]  F. Nicoletti,et al.  Mitotic signaling by β‐amyloid causes neuronal death , 1999 .

[21]  D. Chuang,et al.  Involvement of Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) and p53 in Neuronal Apoptosis: Evidence That GAPDH Is Upregulated by p53 , 1999, The Journal of Neuroscience.

[22]  E. Mandelkow,et al.  Phosphorylation of tau protein by recombinant GSK‐3β: pronounced phosphorylation at select Ser/Thr‐Pro motifs but no phosphorylation at Ser262 in the repeat domain , 1999, FEBS letters.

[23]  A. Takashima,et al.  Activation of tau protein kinase I/glycogen synthase kinase-3β by amyloid β peptide (25–35) enhances phosphorylation of tau in hippocampal neurons , 1998, Neuroscience Research.

[24]  S Lovestone,et al.  Abnormalities of Wnt signalling in schizophrenia – evidence for neurodevelopmental abnormality , 1998, Neuroreport.

[25]  R. Nusse,et al.  β-catenin: a key mediator of Wnt signaling , 1998 .

[26]  T. Dale,et al.  Signal transduction by the Wnt family of ligands. , 1998, The Biochemical journal.

[27]  C. Finch,et al.  Evidence for Apoptotic Cell Death in Alzheimer's Disease , 1995, Experimental Neurology.

[28]  H. Braak,et al.  Staging of alzheimer's disease-related neurofibrillary changes , 1995, Neurobiology of Aging.

[29]  C. Mummery,et al.  Expression of TGF-beta s and their receptors during implantation and organogenesis of the mouse embryo. , 1994, Developmental biology.

[30]  W. Nelson,et al.  Wnt-1 modulates cell-cell adhesion in mammalian cells by stabilizing beta-catenin binding to the cell adhesion protein cadherin , 1994, The Journal of cell biology.

[31]  C. Cotman,et al.  Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[32]  R. Malenka,et al.  Beta-catenin is critical for dendritic morphogenesis. , 2003, Nature neuroscience.

[33]  N. Inestrosa,et al.  Wnt signaling involvement in beta-amyloid-dependent neurodegeneration. , 2002, Neurochemistry international.

[34]  A. Caricasole,et al.  Erratic expression of DNA polymerases by beta-amyloid causes neuronal death. , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  R. Maccioni,et al.  AbetaPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. , 2002, Journal of Alzheimer's disease : JAD.

[36]  Y. Shen,et al.  p53-dependent apoptosis pathways. , 2001, Advances in cancer research.

[37]  F. Nicoletti,et al.  Mitotic signaling by beta-amyloid causes neuronal death. , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  A. Takashima,et al.  Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons. , 1998, Neuroscience research.

[39]  K Willert,et al.  Beta-catenin: a key mediator of Wnt signaling. , 1998, Current opinion in genetics & development.