Conformational change as one of the earliest alterations of tan in Alzheimer's disease
Conformational change as one of the earliest alterations of tan in Alzheimer's disease
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DOI：
10.1016/s0197-4580(00)00157-3
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发表时间：
2000-09-01
影响因子：
4.2
通讯作者：
Davies, P
中科院分区：
文献类型：
--
作者：
Weaver, CL;Espinoza, M;Davies, P
在阿尔茨海默病（AD）中发现的成对螺旋丝（PHF）主要由异常形式的tau（PHF-tau）组成，其经历了几种翻译后修饰。先前的研究表明，单克隆抗体MC 1识别AD中tau的独特构象。我们已经评估了MC 1识别的tau构象的时间和空间发生，并在Braak I期和II期病例中发现其出现在海马神经元中易受神经元缠结（NFT）形成的影响。电子显微镜已经清楚地表明，这种构象先于PHF的形成。MC 1免疫亲和层析也鉴定了这种异常tau的非丝状可溶性池。ELISA和免疫印迹显示，这种物质与NFT中发现的物质无法区分。这种可溶性组分具有以浓度依赖性方式自组装成PHF的能力。由于MC 1识别的构象变化出现在PHF的组装之前，并且在PHF中发现，但不存在于正常脑中，因此我们认为MC 1表位的形成是AD中tau的最早病理改变之一。(C)2000 Elsevier Science Inc. All rights reserved.
Paired helical filaments (PHFs) found in Alzheimer's disease (AD) are mainly comprised of an abnormal form of tau (PHF-tau) that has undergone several post-translational modifications. Previous studies have shown that the monoclonal antibody MC1 identifies a distinct conformation of tau in AD. We have assessed the temporal and spatial occurrence of the tau conformation recognized by MC1, and found its appearance in hippocampal neurons vulnerable to neurofibrillary tangle (NFT) formation in Braak Stage I and II cases. Electron microscopy has clearly demonstrated that this conformation precedes the formation of PHF. MC1 immunoaffinity chromatography also has identified a nonfilamentous, soluble pool of this abnormal tau. ELISA and immunoblotting have shown that this material is indistinguishable from that found in NFTs. This soluble component has the ability to self-assemble into PHFs in a concentration-dependent manner. Because the conformational change recognized by MC1 appears before the assembly of and is found in PHF, but is not present in the normal brain, we suggest that the formation of the MC1 epitope is one of the earliest pathological alterations of tau in AD. (C) 2000 Elsevier Science Inc. All rights reserved.