Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease
Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease
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DOI：
10.3233/jad-200146
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Luna-Munoz, Jose
中科院分区：
文献类型：
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作者：
Hernandes-Alejandro, Mario;Montano, Sarita;Luna-Munoz, Jose
背景：神经原纤维缠结（NFT）和淀粉样斑块是阿尔茨海默病（AD）大脑中的神经病理学标志。 tau 蛋白的翻译后修饰（例如磷酸化和截短）已被提议作为构成 NFT 的异常配对螺旋丝组装的引发剂。神经元和NFT是基质金属蛋白酶（MMP）的位点。目的：本研究的目的是分析脑样本中MMP-9和tau蛋白与AD的关系。方法：本研究对早期、中度和晚期AD患者的脑组织样本进行。通过蛋白质印迹和明胶底物酶谱分析 MMP 和 tau 水平。使用免疫荧光技术和共聚焦显微镜来分析 NFT 中两种蛋白质的存在。进一步，进行分子动力学模拟（MDS）和蛋白质-蛋白质对接来预测MMP-9和tau蛋白之间的相互作用。结果：MMP-9表达在AD中晚期最多，而MMP-2表达仅在AD晚期增加。有趣的是，共聚焦显微镜显示 NFT 中存在 MMP-9 和 tau 蛋白的共定位。 MDS 和蛋白质-蛋白质对接预测表明，MMP-9 和全长 tau 蛋白之间可以形成高亲和力复合物。结论：这些观察结果为这两种蛋白质之间的相互作用提供了初步证据。 tau 蛋白的翻译后修饰，例如 MMP-9 识别位点中氨基酸残基的 C 端截短或磷酸化，以及蛋白质的构象变化，例如 N 端序列在三重复结构域上的折叠，可能会在 NFT 发育阶段排除 MMP-9 和 tau 蛋白之间的相互作用。
Background: Neurofibrillary tangles (NFTs) and amyloid plaques are the neuropathological hallmarks in brains with Alzheimer's disease (AD). Post-translational modifications of tau, such as phosphorylation and truncation, have been proposed as initiators in the assembly of the abnormal paired helical filaments that constitute the NFTs. Neurons and NFTs are sites of matrix metalloproteinases (MMPs).Objective: The aim of this study was to analyze the relationship of MMP-9 and tau protein in brain samples with AD.Methods: This study was performed on brain tissue samples from patients with early, moderate, and late AD. MMPs and tau levels were analyzed by western blot and gelatin-substrate zymography. Immunofluorescence techniques and confocal microscopy were used to analyze the presence of both proteins in NFTs. Further, molecular dynamics simulations (MDS) and protein-protein docking were conducted to predict interaction between MMP-9 and tau protein.Results: MMP-9 expression was greatest in moderate and late AD, whereas MMP-2 expression was only increased in late-stage AD. Interestingly, confocal microscopy revealed NFTs in which there was co-localization of MMP-9 and tau protein. MDS and protein-protein docking predictions indicate that a high-affinity complex can be formed between MMP-9 and full-length tau protein.Conclusion: These observations provide preliminary evidence of an interaction between these two proteins. Post-translational modifications of tau protein, such as C-terminal truncation or phosphorylation of amino acid residues in the MMP-9 recognition site and conformational changes in the protein, such as folding of the N-terminal sequence over the three-repeat domain, could preclude the interaction between MMP-9 and tau protein during stages of NFT development.