Wnt/β-catenin信号通路在阿尔茨海默病神经元变性中的研究进展

Research advances in the Wnt/β-catenin signaling pathway in neuronal degeneration in Alzheimer’s Disease

摘要:

目的：阿尔茨海默病(Alzheimer’s disease，AD)是目前老年人最常见的痴呆类型，由于AD发病机制复杂，迄今尚未完全阐明。AD最重要的神经病理学特征是β淀粉样蛋白（amyloid-beta eptide, Aβ）沉积、Tau蛋白过度磷酸化形成神经纤维缠结以及脑内神经炎症反应的激活，并伴随着神经元的损伤及学习记忆功能受损。越来越多的研究指出Wnt/β-连环蛋白（Wnt/β-catenin）信号通路在神经退行性疾病中，尤其是AD中发挥了重要作用。为明确Wnt/β-catenin信号通路与AD发病、Aβ沉积、Tau 蛋白和神经炎症的相关性及其机制，对相关文献进行综述。方法：选择Wnt/β-catenin信号通路与AD、Aβ神经毒性、Tau 蛋白磷酸化及神经炎症相关的国内外相关文献进行综述。结果：研究表明Wnt/β-catenin信号通路参与AD的发生和发展，当该通路激活时可以抑制Aβ的沉积、Tau的过度磷酸化及神经炎症，反之则促进Aβ的产生、聚集以及Tau蛋白的磷酸化，神经炎症的发生。结论：本文就Wnt/β-catenin信号途径在AD发病中的重要性加以概述，为AD机制的研究提供了理论基础，也提示激活Wnt信号传导途径可以作为治疗AD的潜在治疗靶点。dismutase，SOD）、丙二醛（malondialdehyde，MDA）和过氧化氢酶（catalase，CAT）水平采用试剂盒检测。qPCR和Western blot检测血浆Klotho的表达。Klotho表达量与氧化应激的相关性采用Pearson相关性分析。甲基化特异性PCR（MS-PCR）检测Klotho甲基化水平。CpG岛甲基化率采用焦磷酸盐测序法。结果：相对于对照组[（94.56±16.40） mU/L]，观察组SOD含量[（79.86±18.24） mU/L]明显降低（t=4.487，P=0.000），观察组MDA水平[（2.87±2.26） pg/mL]与对照组[（2.52±1.06） pg/mL]无统计学差异（t=1.675，P=0.097），观察组CAT水平[（18.50±4.62） U/mg]与对照组[（25.26±3.54） U/mg]相比明显降低（t=8.605，P=0.000）。观察组（0.66±0.16）比对照组（1.04±0.10）血浆Klotho基因（t=14.93，P=0.000）降低；观察组（0.70±0.20）比对照组（1.04±0.10）血浆Klotho蛋白表达（t=10.92，P=0.000）降低，且Klotho蛋白表达量与SOD水平（r=0.768，P=0.000）和CAT水平（r=0.708，P=0.000）呈正相关。观察组Klotho启动子CpG岛甲基化水平升高。结论：Klotho甲基化可能是NSCLC患者血浆氧化应激状态的一个临床标志物。

Abstract:

Objective: Alzheimer’s disease (AD) is the most common type of dementia in the elderly, but its pathogenesis is complex and remains unclear. The most common neuropathological features of AD include amyloid β-protein (Aβ) deposition, neurofibrillary tangles due to hyperphosphorylation of Tau protein, and the activation of brain neuroinflammation, with neuronal injury and impaired learning and memory abilities. A growing number of studies have shown that the Wnt/β-catenin signaling pathway plays an important role in neurodegenerative disorders, especially in AD. This article reviews the related literature to clarify the association of the Wnt/β-catenin signaling pathway with the pathogenesis of AD, Aβ deposition, Tau protein, and neuroinflammation and related mechanism. Methods: The articles on the association of the Wnt/β-catenin signaling pathway with AD, Aβ neurotoxicity, Tau protein phosphorylation, and neuroinflammation, published in China and foreign countries, were reviewed. Results: Studies showed that the Wnt/β-catenin signaling pathway was involved in the development and progression of AD. The activation of this pathway inhibited Aβ deposition, hyperphosphorylation of Tau protein, and neuroinflammation, and on the contrary, it promoted the formation and aggregation of Aβ, the phosphorylation of Tau protein, and the development of neuroinflammation. Conclusion: This article reviews the importance of the Wnt/β-catenin signaling pathway in the pathogenesis of AD and provides a theoretical basis for the research on the pathogenesis of AD. It is pointed out that activation of the Wnt/β-catenin signaling pathway may be used as a potential target for the treatment of AD.patients，who were diagnosed with NSCLC in Sichuan Provincial People’s Hospital（as observation group），and 50 healthy people（as control group）. Assay kits were used to determine the levels of superoxide dismutase（SOD），malondialdehyde（MDA），and catalase（CAT） in plasma. The mRNA and protein expression of Klotho in plasma was measured/determined by qPCR and Western blot，respectively. Pearson correlation analysis was performed for the correlation between Klotho expression level and oxidative stress. Klotho methylation level was determined by methylation-specific PCR（MS-PCR）. The methylation rate of CpG islands was determined by pyrosequencing. Results：Compared with the control group，the observation group had significantly reduced levels of SOD[（79.86±18.24） mU/L vs. （94.56±16.40） mU/L，t=4.487，P=0.000] and CAT[（18.50±4.62） U/mg vs. （25.26±3.54） U/mg，t=8.605，P=0.000]，but there was no significant difference in MDA level between the observation group and the control group[（2.87±2.26） pg/mL vs. （2.52±1.06） pg/mL，t= 1.675，P=0.097]. The mRNA and protein expression levels of Klotho in plasma were significantly lower in the obser－vation group than in the control group（mRNA：0.66±0.16 vs. 1.04±0.10，t=14.93，P=0.000；protein：0.70±0.20 vs. 1.04±0.10，t=10.92，P= 0.000）. There was a positive correlation between the protein expression of Klotho and the levels of SOD（r=0.768，P=0.000） and CAT（r=0.708，P=0.000）. Meanwhile，the observation group had an increased methylation level of CpG islands in the Klotho promoter. Conclusion：Klotho methylation may be a clinical marker of oxidative stress in the plasma of patients with NSCLC.