Signal transduction during amyloid-β-peptide neurotoxicity:: role in Alzheimer disease
Signal transduction during amyloid-β-peptide neurotoxicity:: role in Alzheimer disease
复制标题
DOI：
10.1016/j.brainresrev.2004.07.018
复制
发表时间：
2004-12-01
影响因子：
--
通讯作者：
Inestrosa, NC
中科院分区：
文献类型：
--
作者：
Fuentealba, RA;Farias, G;Inestrosa, NC
阿尔茨海默病（AD）是一种神经退行性疾病，具有进行性痴呆，伴有脑中的两种主要结构变化：称为神经元缠结（NFT）的细胞内蛋白质沉积和由营养不良的神经突包围的细胞外淀粉样蛋白沉积，其构成老年斑。目前，广泛认为淀粉样β肽（A β）代谢失衡是AD进展的关键。β沉积可以通过分子伴侣增强，包括铜等金属和乙酰胆碱酯酶（ACNE）等蛋白质。在神经元水平，几种AD相关蛋白与Wnt/β-连环蛋白信号传导途径的转导物相互作用，包括β-连环蛋白和糖原合成酶激酶3 β（GSK-3 β），体外和体内研究均表明Wnt/β-连环蛋白信号传导是A β毒性的靶点。因此，在AD实验动物模型或原代海马神经元中，锂或Wnt配体激活这种信号传导通过恢复β-连环蛋白水平和存活基因如bcl-2的Wnt靶基因表达来减弱A β神经毒性。另一方面，过氧化物酶体增殖物激活受体γ（PPAR γ）和毒蕈碱乙酰胆碱受体（mAChR）激动剂也激活Wnt/β-连环蛋白信号传导，并且它们对海马神经元具有神经保护作用。我们的研究与以下观点一致：Wnt信号传导组分功能的持续丧失将触发一系列事件，决定AD的发作和发展，并且通过激活交叉对话信号级联调节该途径应被视为AD治疗的可能治疗策略。(C)2004 Elsevier B.V保留所有权利。
Alzheimer's disease (AD) is a neurodegenerative disorder with progressive dementia accompanied by two main structural changes in the brain: intracellular protein deposits termed neurofibrillary tangles (NFT) and extracellular amyloid protein deposits surrounded by dystrophic neurites that constitutes the senile plaques. Currently, it is widely accepted that amyloid beta-peptide (A beta) metabolism disbalance is crucial for AD progression. A beta deposition may be enhanced by molecular chaperones, including metals like copper and proteins like acetylcholinesterase (ACNE). At the neuronal level, several AD-related proteins interact with transducers of the Wnt/beta-catenin signaling pathway, including beta-catenin and glycogen synthase kinase 3 beta (GSK-3 beta) and both in vitro and in vivo studies suggest that Wnt/beta-catenin signaling is a target for A beta toxicity. Accordingly, activation of this signaling by lithium or Wnt ligands in AD-experimental animal models or in primary hippocampal neurons attenuate A beta neurotoxicity by recovering beta-catenin levels and Wnt-target gene expression of survival genes such as bcl-2. On the other hand, peroxisomal proliferator-activated receptor gamma (PPAR gamma) and muscarinic acetylcholine receptor (mAChR) agonists also activate Wnt/beta-catenin signaling and they have neuroprotective effects on hippocampal neurons. Our studies are consistent with the idea that a sustained loss of function of Wnt signaling components would trigger a series of events, determining the onset and development of AD and that modulation of this pathway through the activation of cross-talking signaling cascades should be considered as a possible therapeutic strategy for AD treatment. (C) 2004 Elsevier B.V All rights reserved.