Scali Carla, Caraci Filippo, Gianfriddo Marco, Diodato Enrica, Roncarati Renza, Pollio Giuseppe, Gaviraghi Giovanni, Copani Agata, Nicoletti Ferdinando, Terstappen Georg C, Caricasole Andrea
Siena Biotech S.p.A., 53100 Siena, Italy.
Neurobiol Dis. 2006 Nov;24(2):254-65. doi: 10.1016/j.nbd.2006.06.016. Epub 2006 Aug 17.
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 beta-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-3beta. 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.
Wnt拮抗剂Dickkopf-1（DKK1）的表达在与阿尔茨海默病和脑缺血相关的神经退行性过程中被诱导。然而，关于DKK1对神经元的介导作用知之甚少。我们现在描述，在培养的神经元中，通过TCF报告基因检测和β-连环蛋白水平分析评估，DKK1能够抑制经典Wnt信号传导，并引发与BCL-2表达丧失、BAX诱导和TAU过度磷酸化相关的细胞死亡。在大鼠中局部注入DKK1会导致海马CA1区的神经元细胞死亡和星形细胞增生，以及基底核大细胞胆碱能神经元死亡。通过全身给予锂离子可以逆转这两种效应，锂离子通过抑制糖原合酶激酶-3β来挽救Wnt通路。DKK1抑制神经元中的Wnt信号传导并导致神经元死亡的证明支持了经典Wnt通路的抑制促成神经退行性疾病病理生理学的假说。
