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Transglutaminase bonds in neurofibrillary tangles and paired helical filament tau early in Alzheimer's disease.

机译:阿尔茨海默氏病早期,神经原纤维缠结中的转谷氨酰胺酶键和成对的螺旋丝状tau。

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Transglutaminase-catalyzed epsilon(gamma-glutamyl)lysine cross-links exist in Alzheimer's disease (AD) paired helical filament (PHF) tau protein but not normal soluble tau. To test the hypothesis that these cross-links could play a role in the formation of neurofibrillary tangles (NFT), we used single- and double-label immunofluorescence confocal microscopy and immunoaffinity purification and immunoblotting to examine epsilon(gamma-glutamyl)lysine cross-links in AD and control brains. The number of neurons that are immunoreactive with an antibody directed at the epsilon-(gamma-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with epsilon(gamma-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains epsilon(gamma-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II, epsilon(gamma-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with epsilon(gamma-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT.
机译:转谷氨酰胺酶催化的ε(γ-谷氨酰)赖氨酸交联存在于阿尔茨海默氏病(AD)配对螺旋丝(PHF)tau蛋白中,但不存在正常的可溶性tau蛋白。为了检验这些交联可能在神经原纤维缠结(NFT)形成中起作用的假设,我们使用了单标签和双标签免疫荧光共聚焦显微镜以及免疫亲和纯化和免疫印迹技术来检查ε(γ-谷氨酰)赖氨酸交叉链接和控制大脑。与年龄匹配的对照和精神分裂症患者相比,AD皮质中与针对ε-(γ-谷氨酰胺基)赖氨酸键的抗体发生免疫反应的神经元数量明显更高。 PHF tau定向抗体AT8,MC-1和PHF-1与ε(γ-谷氨酰基)赖氨酸免疫标记在AD NFT中共定位。免疫亲和纯化和免疫印迹实验表明,PHF tau在AD的顶叶和额叶皮层中包含ε(γ-谷氨酰基)赖氨酸键。在内嗅皮层和海马中存在NFT的对照病例中,表明存在Braak和Braak II期,顶叶和额叶皮层的PHF tau中存在ε(γ-谷氨酰)赖氨酸键,尽管缺乏显微镜下可检测到的NFT或老年斑在这些皮质区域。在阶段II缺乏NFT的大脑区域中存在带有ε(γ-谷氨酰胺基)赖氨酸键的PHF tau(但有望在阶段III包含NFT的大脑区域)表明这些键早于NFT的形成。

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