TY - JOUR T1 - Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain JF - The Journal of Neuroscience JO - J. Neurosci. SP - 6021 LP - 6027 DO - 10.1523/JNEUROSCI.1381-04.2004 VL - 24 IS - 26 AU - Andrea Caricasole AU - Agata Copani AU - Filippo Caraci AU - Eleonora Aronica AU - Annemieke J. Rozemuller AU - Alessandra Caruso AU - Marianna Storto AU - Giovanni Gaviraghi AU - Georg C. Terstappen AU - Ferdinando Nicoletti Y1 - 2004/06/30 UR - http://www.jneurosci.org/content/24/26/6021.abstract N2 - 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. ER -