Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1

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• 作者：Carla Scali ; Filippo Caraci ; Marco Gianfriddo ; Enrica Diodato ; Renza Roncarati ; Giuseppe Pollio ; Giovanni Gaviraghi ; Agata Copani ; Ferdinando Nicoletti ; Georg C. Terstappen and Andrea Caricasole
• 刊名：Neurobiology of Disease
• 出版年：2006
• 出版时间：November 2006
• 年：2006
• 卷：24
• 期：2
• 页码：254-265
• 全文大小：1600 K

文摘

Expression of the Wnt antagonist Dickkopf-1 (DKK1) is induced during neurodegenerative processes associated with Alzheimer's Disease and brain ischemia. However, little is known about DKK1-mediated effects on neurons. We now describe that, in cultured neurons, DKK1 is able to inhibit canonical Wnt signaling, as assessed by TCF reporter assay and analysis of β-catenin levels, and to elicit cell death associated with loss of BCL-2 expression, induction of BAX, and TAU hyperphosphorylation. Local infusion of DKK1 in rats caused neuronal cell death and astrocytosis in the CA1 region of the hippocampus and death of cholinergic neurons in the nucleus basalis magnocellularis. Both effects were reversed by systemic administration of lithium ions, which rescue the Wnt pathway by inhibiting glycogen synthase kinase-3β. The demonstration that DKK1 inhibits Wnt signaling in neurons and causes neuronal death supports the hypothesis that inhibition of the canonical Wnt pathway contributes to the pathophysiology of neurodegenerative disorders.