Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways
Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways
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DOI：
10.1016/j.cellsig.2006.12.009
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Maiese, Kenneth
中科院分区：
文献类型：
--
作者：
Chong, Zhao Zhong;Li, Faqi;Maiese, Kenneth
Wnt 1最初被描述为许多器官系统胚胎发生的调节剂，最近已与几种神经退行性疾病的发展有关，没有一种比阿尔茨海默病更重要。因此，我们研究了Wnt 1在β-淀粉样蛋白（A β（1-42））暴露期间监督负责细胞存活的重要途径的能力。在这里，我们表明，Wnt 1是关键的保护在SH-SY 5 Y神经元细胞系对基因组DNA降解，膜磷脂酰丝氨酸（PS）的曝光，和小胶质细胞活化，因为这些Wnt 1的神经保护属性在Wnt 1蛋白表达的基因沉默过程中丢失。与Wnt 1保护密切相关的是Akt 1的存在和激活。PI 3-K通路的药理学抑制或Akt 1表达的基因沉默可以消除Wnt 1的保护能力。与Wnt 1和Akt 1密切相关的是合成酶激酶-3 β（GSK-3 β）和β-连环蛋白的整合经典途径。通过Akt 1依赖性途径，Wnt 1磷酸化GSK-3 β并维持β-连环蛋白的完整性，以确保其从细胞质易位到细胞核，从而阻断细胞凋亡。我们的工作概述了Wnt 1及其与Akt 1，GSK-3 β和β-连环蛋白的整合在促进神经元细胞存活和抑制炎性小胶质细胞活化方面的一个非常新颖的作用，可以确定治疗神经退行性疾病的新途径。(c)2007年爱思唯尔公司All rights reserved.
Initially described as a modulator of embryogenesis for a number of organ systems, Wnt1 has recently been linked to the development of several neurodegenerative disorders, none being of greater significance than Alzheimer's disease. We therefore examined the ability of Wnt1 to oversee vital pathways responsible for cell survival during beta-amyloid (A beta(1-42)) exposure. Here we show that Wnt1 is critical for protection in the SH-SY5Y neuronal cell line against genomic DNA degradation, membrane phosphatidylserine (PS) exposure, and microglial activation, since these neuroprotective attributes of Wnt1 are lost during gene silencing of Wnt1 protein expression. Intimately tied to Wnt1 protection is the presence and activation of Akt1. Pharmacological inhibition of the PI 3-K pathway or gene silencing of Akt1 expression can abrogate the protective capacity of Wnt1. Closely aligned with Wnt1 and Akt1 are the integrated canonical pathways of synthase kinase-3 beta (GSK-3 beta) and beta-catenin. Through Akt1 dependent pathways, Wnt1 phosphorylates GSK-3 beta and maintains beta-catenin integrity to insure its translocation from the cytoplasm to the nucleus to block apoptosis. Our work outlines a highly novel role for Wnt1 and its integration with Akt1, GSK-3 beta, and beta-catenin to foster neuronal cell survival and repress inflammatory microglial activation that can identify new avenues of therapy against neurodegenerative disorders. (c) 2007 Elsevier Inc. All rights reserved.