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Wnt信号通路在阿尔茨海默病中的作用。

Wnt signaling function in Alzheimer's disease.

作者信息

De Ferrari G V, Inestrosa N C

机构信息

Centro de Regulación Celular y Patología, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

出版信息

Brain Res Brain Res Rev. 2000 Aug;33(1):1-12. doi: 10.1016/s0165-0173(00)00021-7.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease with progressive dementia accompanied by three main structural changes in the brain: diffuse loss of neurons; intracellular protein deposits termed neurofibrillary tangles (NFT) and extracellular protein deposits termed amyloid or senile plaques, surrounded by dystrophic neurites. Two major hypotheses have been proposed in order to explain the molecular hallmarks of the disease: The 'amyloid cascade' hypothesis and the 'neuronal cytoskeletal degeneration' hypothesis. While the former is supported by genetic studies of the early-onset familial forms of AD (FAD), the latter revolves around the observation in vivo that cytoskeletal changes - including the abnormal phosphorylation state of the microtubule associated protein tau - may precede the deposition of senile plaques. Recent studies have suggested that the trafficking process of membrane associated proteins is modulated by the FAD-linked presenilin (PS) proteins, and that amyloid beta-peptide deposition may be initiated intracellularly, through the secretory pathway. Current hypotheses concerning presenilin function are based upon its cellular localization and its putative interaction as macromolecular complexes with the cell-adhesion/signaling beta-catenin molecule and the glycogen synthase kinase 3beta (GSK-3beta) enzyme. Developmental studies have shown that PS proteins function as components in the Notch signal transduction cascade and that beta-catenin and GSK-3beta are transducers of the Wnt signaling pathway. Both pathways are thought to have an important role in brain development, and they have been connected through Dishevelled (Dvl) protein, a known transducer of the Wnt pathway. In addition to a review of the current state of research on the subject, we present a cell signaling model in which a sustained loss of function of Wnt signaling components would trigger a series of misrecognition events, determining the onset and development of AD.

摘要

阿尔茨海默病(AD)是一种神经退行性疾病,伴有进行性痴呆,同时大脑会出现三种主要结构变化:神经元弥漫性丧失;细胞内蛋白质沉积物称为神经原纤维缠结(NFT),以及细胞外蛋白质沉积物称为淀粉样蛋白或老年斑,周围环绕着营养不良性神经突。为了解释该疾病的分子特征,人们提出了两种主要假说:“淀粉样蛋白级联反应”假说和“神经元细胞骨架变性”假说。前者得到早发性家族性AD(FAD)遗传研究的支持,而后者则围绕体内观察结果,即细胞骨架变化——包括微管相关蛋白tau的异常磷酸化状态——可能先于老年斑的沉积。最近的研究表明,膜相关蛋白的运输过程受与FAD相关的早老素(PS)蛋白调节,并且淀粉样β肽沉积可能通过分泌途径在细胞内启动。目前关于早老素功能的假说基于其细胞定位以及它作为大分子复合物与细胞黏附/信号β-连环蛋白分子和糖原合酶激酶3β(GSK-3β)酶的假定相互作用。发育研究表明,PS蛋白在Notch信号转导级联反应中起作用,而β-连环蛋白和GSK-3β是Wnt信号通路的转导子。这两种通路都被认为在大脑发育中起重要作用,并且它们已通过Dishevelled(Dvl)蛋白连接起来,Dvl蛋白是Wnt通路的已知转导子。除了对该主题的当前研究状况进行综述外,我们还提出了一个细胞信号模型,其中Wnt信号通路成分的持续功能丧失将引发一系列错误识别事件,从而决定AD的发病和发展。

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