The Wnt Antagonist, Dickkopf-1, As a Target for the Treatment of Neurodegenerative Disorders

Overview

Journal Neurochem Res

Specialties Chemistry
Neurology

Date 2008 Apr 23

PMID 18427981

Citations 35

Authors

Filippo Caraci

Carla Busceti

Francesca Biagioni

Eleonora Aronica

Federica Mastroiacovo

Irene Cappuccio

Giuseppe Battaglia

Valeria Bruno

Andrea Caricasole

Agata Copani

Ferdinando Nicoletti

Affiliations

Soon will be listed here.

Abstract

The canonical Wnt pathway contributes to the regulation of neuronal survival and homeostasis in the CNS. Recent evidence suggests that an increased expression of Dickkopf-1 (Dkk-1), a secreted protein that negatively modulates the canonical Wnt pathway, is causally related to processes of neurodegeneration in a number of CNS disorders, including Alzheimer's disease (AD), brain ischemia and temporal lobe epilepsy (TLE). Dkk-1 induction precedes neuronal death in cellular and animal models of excitotoxicity, beta-amyloid toxicity, transient global ischemia, and kainate-induced epilepsy. In addition, Dkk-1, which is barely visible in the healthy brain, is strongly induced in brain tissue from AD patients or from patients with TLE associated with hippocampal sclerosis. These data raise the attractive possibility that Dkk-1 antagonists or neutralizing antibodies behave as neuroprotective agents by rescuing the activity of the canonical Wnt pathway.

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References

Takashima A . GSK-3 is essential in the pathogenesis of Alzheimer's disease. J Alzheimers Dis. 2006; 9(3 Suppl):309-17. DOI: 10.3233/jad-2006-9s335. View

Mlodzik M . Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation?. Trends Genet. 2002; 18(11):564-71. DOI: 10.1016/s0168-9525(02)02770-1. View

Zipfel G, Babcock D, Lee J, Choi D . Neuronal apoptosis after CNS injury: the roles of glutamate and calcium. J Neurotrauma. 2000; 17(10):857-69. DOI: 10.1089/neu.2000.17.857. View

Prunier C, Hocevar B, Howe P . Wnt signaling: physiology and pathology. Growth Factors. 2004; 22(3):141-50. DOI: 10.1080/08977190410001720860. View

Mao B, Niehrs C . Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene. 2003; 302(1-2):179-83. DOI: 10.1016/s0378-1119(02)01106-x. View

Zhou J, Liyanage U, Medina M, Ho C, Simmons A, Lovett M . Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Neuroreport. 1997; 8(6):1489-94. DOI: 10.1097/00001756-199704140-00033. View

Wang J, Shou J, Chen X . Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53. Oncogene. 2000; 19(14):1843-8. DOI: 10.1038/sj.onc.1203503. View

Kuhl M, Sheldahl L, Park M, Miller J, Moon R . The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet. 2000; 16(7):279-83. DOI: 10.1016/s0168-9525(00)02028-x. View

Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller A, Caruso A . Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci. 2004; 24(26):6021-7. PMC: 6729239. DOI: 10.1523/JNEUROSCI.1381-04.2004. View

10.

Huang H, Klein P . Multiple roles for glycogen synthase kinase-3 as a drug target in Alzheimer's disease. Curr Drug Targets. 2006; 7(11):1389-97. DOI: 10.2174/1389450110607011389. View

11.

Moon R, Bowerman B, Boutros M, Perrimon N . The promise and perils of Wnt signaling through beta-catenin. Science. 2002; 296(5573):1644-6. DOI: 10.1126/science.1071549. View

12.

Dale T . Signal transduction by the Wnt family of ligands. Biochem J. 1998; 329 ( Pt 2):209-23. PMC: 1219034. DOI: 10.1042/bj3290209. View

13.

Grotewold L, Ruther U . The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death. EMBO J. 2002; 21(5):966-75. PMC: 125884. DOI: 10.1093/emboj/21.5.966. View

14.

Takashima A, Honda T, Yasutake K, Michel G, Murayama O, Murayama M . Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res. 1998; 31(4):317-23. DOI: 10.1016/s0168-0102(98)00061-3. View

15.

Kang D, Soriano S, Xia X, Eberhart C, De Strooper B, Zheng H . Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 2002; 110(6):751-62. DOI: 10.1016/s0092-8674(02)00970-4. View

16.

Jope R . Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci. 2003; 24(9):441-3. DOI: 10.1016/S0165-6147(03)00206-2. View

17.

Salinas P . Wnt factors in axonal remodelling and synaptogenesis. Biochem Soc Symp. 1999; 65:101-9. View

18.

Oddo S, Caccamo A, Kitazawa M, Tseng B, LaFerla F . Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging. 2003; 24(8):1063-70. DOI: 10.1016/j.neurobiolaging.2003.08.012. View

19.

Bruno V, Battaglia G, Copani A, DOnofrio M, Di Iorio P, De Blasi A . Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J Cereb Blood Flow Metab. 2001; 21(9):1013-33. DOI: 10.1097/00004647-200109000-00001. View

20.

De Ferrari G, Inestrosa N . Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev. 2000; 33(1):1-12. DOI: 10.1016/s0165-0173(00)00021-7. View