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The Journal of Neuroscience, June 30, 2004, 24(26):6021-6027; doi:10.1523/JNEUROSCI.1381-04.2004

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Neurobiology of Disease
Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain

Andrea Caricasole,^1 * Agata Copani,^2,6 * Filippo Caraci,² Eleonora Aronica,³ Annemieke J. Rozemuller,³ Alessandra Caruso,⁴ Marianna Storto,⁵ Giovanni Gaviraghi,¹ Georg C. Terstappen,¹ and Ferdinando Nicoletti^4,5

¹Siena Biotech, 53100 Siena, Italy, ²Department of Pharmaceutical Sciences, University of Catania, 95125 Catania, Italy, ³Department of Neuropathology, Academic Medical Center, Univeristy of Amsterdam Meibergdreef, Amsterdam 1105 AZ, The Netherlands, ⁴Department of Human Physiology and Pharmacology, University of Rome La Sapienza, 00185 Rome, Italy, ⁵Istituto Neurologico Mediterraneo, Neuromed, 86077 Pozzilli, Isernia, Italy, and ⁶Istituto di Bioimmagini e Biostrutture, CNR-95125 Catania, Italy

We used primary cultures of cortical neurons to examine the relationship between -amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to -amyloid peptide (AP) 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-3. DKK1 was induced at late times after AP 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 AP-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 -amyloid and is critically involved in the process of tau phosphorylation.

Key words: Alzheimer's disease; -amyloid; Wnt pathway; Dickkopf-1; tau phosphorylation; apoptosis

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Received Feb 2, 2004; revised May 19, 2004; accepted May 20, 2004.

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