Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski H M
Neurological Institute, University of Vienna, Austria.
Brain Res. 1989 Jan 16;477(1-2):90-9. doi: 10.1016/0006-8993(89)91396-6.
The intraneuronal accumulation of paired helical filaments in the form of neurofibrillary tangles is one hallmark of the brain pathology in Alzheimer's disease. At certain predilection sites, a small number of similar lesions are also present in the brains of the majority of aged non-demented individuals. As suggested by several studies before, these abnormal cytoskeletal structures contain determinants of microtubule-associated protein tau and ubiquitin. The present study uses a morphological classification of neurofibrillary tangles into different stages of maturation, as suggested by Alzheimer in 1911, and shows by quantitative immunocytochemistry that early stages of neurofibrillary degeneration contain abnormally phosphorylated tau. Immunoreactivity for the altered tau is seen not only in tangles but also in the cytoplasm of some nerve cells lacking neurofibrillary tangles. Similar numbers of such immunoreactive neurons without tangles are present in age-matched non-demented individuals as in Alzheimer cases, but are absent in young controls. In contrast, incorporation of an epitope, recognized by a monoclonal antibody (3-39) raised to paired helical filaments, which is directed against a determinant residing in the 50-65 amino acid residue region of ubiquitin occurs late in the process of tangle maturation and is most pronounced in extracellular 'ghost tangles'. It is suggested that the accumulation of abnormally phosphorylated tau is one of the earliest cytoskeletal changes in the process of tangle formation. Exposure of certain ubiquitin epitopes in the pathological fibers may reflect an unsuccessful attempt of proteolytic degradation.
以神经原纤维缠结形式存在的成对螺旋丝在神经元内的积累是阿尔茨海默病脑病理学的一个标志。在某些偏好部位，大多数老年非痴呆个体的大脑中也存在少量类似病变。如之前几项研究所表明的，这些异常的细胞骨架结构包含微管相关蛋白tau和泛素的决定因素。本研究采用了阿尔茨海默在1911年提出的将神经原纤维缠结按成熟的不同阶段进行形态学分类，并通过定量免疫细胞化学显示神经原纤维变性的早期阶段含有异常磷酸化的tau。改变的tau的免疫反应性不仅见于缠结中，也见于一些没有神经原纤维缠结的神经细胞的细胞质中。在年龄匹配的非痴呆个体中，没有缠结的此类免疫反应性神经元数量与阿尔茨海默病患者相似，但在年轻对照中不存在。相反，一种针对成对螺旋丝产生的单克隆抗体（3-39）所识别的表位的掺入，该表位针对泛素50-65氨基酸残基区域中的一个决定因素，发生在缠结成熟过程的后期，并且在细胞外“幽灵缠结”中最为明显。有人提出，异常磷酸化的tau的积累是缠结形成过程中最早的细胞骨架变化之一。病理纤维中某些泛素表位的暴露可能反映了蛋白水解降解的一次不成功尝试。
