Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1
Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1
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DOI：
10.1016/j.nbd.2006.06.016
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发表时间：
2006-11-01
影响因子：
6.1
通讯作者：
Caricasole, Andrea
中科院分区：
文献类型：
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作者：
Scali, Carla;Caraci, Filippo;Caricasole, Andrea
Wnt拮抗剂Dickkopf-1（DKK 1）的表达在与阿尔茨海默病和脑缺血相关的神经变性过程中被诱导。然而，关于DKK 1介导的对神经元的影响知之甚少。我们现在描述，在培养的神经元中，DKK 1能够抑制典型的Wnt信号传导，如通过TCF报告基因测定和β-连环蛋白水平分析所评估的，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。在大鼠中局部输注DKK 1引起海马CAI区域中的神经元细胞死亡和星形胶质细胞增生以及基底核大细胞中胆碱能神经元的死亡。这两种作用都被全身给予锂离子逆转，锂离子通过抑制糖原合成酶激酶-3p来拯救Wnt通路。DKK 1抑制神经元中Wnt信号传导并导致神经元死亡的证明支持了经典Wnt通路的抑制有助于神经退行性疾病的病理生理学的假说。(c)2006年爱思唯尔公司All rights reserved.
Expression of the Wnt antagonist Dickkopf-1 (DKK1) is induced during neurodegenerative processes associated with Alzheimer's Disease and brain ischernia. 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 CAI 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-3p. The demonstration that DKK1 inhibits Wnt signaling in neurons and causes neuronal death supports the hyp9thesis that inhibition of the canonical Wnt pathway contributes to the pathophysiology of neurodegenerative disorders. (c) 2006 Elsevier Inc. All rights reserved.