Taniguchi S, McDonagh A M, Pickering-Brown S M, Umeda Y, Iwatsubo T, Hasegawa M, Mann D M A
Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, Kamikitazawa, Setagaya-ku, Tokyo, Japan.
Neuropathol Appl Neurobiol. 2004 Feb;30(1):1-18. doi: 10.1046/j.0305-1846.2003.00481.x.
Pathological examinations, using a panel of tau and other antibodies, were performed on the brains from 55 consecutively acquired cases of frontotemporal lobar degeneration (FTLD). Clinically, these comprised 31 cases of frontotemporal dementia (FTD), 10 cases of motor neurone disease inclusion dementia (MNDID), seven cases of progressive aphasia (PA), four cases of semantic dementia (SD) and three cases of progressive apraxia (PAX). Tau pathology, in the form of neurofibrillary tangles (NFTs) and glial cell tangles, was present in six cases of FTD with parkinsonism linked to chromosome 17, five of these cases resulting from +16 splice-site mutation and one from +13 mutation in the tau gene. The insoluble tau proteins were comprised mostly of four-repeat (4-R) isoforms. Eight other cases of FTD, one of PA and all three cases of PAX showed tau-positive inclusions (Pick bodies) and swollen cells (Pick cells), characteristic of Pick's disease. In these cases, the insoluble tau proteins were present in most instances as three-repeat (3-R) tau isoforms, although two cases with a mixture of 3-R and 4-R isoforms were seen. One other case of FTD showed an unusual pathology characterized by massive extracellular deposition of tau protein, composed of 4-R tau isoforms, within white matter without neuronal or glial cell inclusions. However, 33 (60%) of 55 FTLD cases showed no tau pathology in the brain, except for the rare NFTs, composed of a mix of 3-R and 4-R isoforms, in some of the more elderly cases. Of these 33 cases, 13 had FTD, 10 had MNDID, six had PA and four had SD. The pathological changes present were those of a superficial cortical laminar microvacuolation with mild subpial and subcortical gliosis; the 10 MNDID cases had ubiquitin-positive inclusions in the cerebral cortex and hippocampus. These 33 nontau FTLD cases, along with five Alzheimer's disease (AD) and six Huntington's disease (HD) cases with severe pathology, showed a variable loss of soluble tau proteins, broadly comparable with the extent of neuronal loss from the cortex and loss of the intracortical perikaryal marker, NeuN, but unrelated to proteins within afferent projection fibres such as neurofilament and alpha-synuclein. Levels of tau mRNA were decreased in parallel in the tau-negative FTLD cases and in the severe AD and HD cases. Hence, the loss of tau from these 33 nontau FTLD cases is just one aspect of a neurodegenerative process that destroys many components of the nerve cell machinery and does not represent a specific disordering of the cell's ability to form tau proteins or incorporate these into microtubules.
使用一组tau蛋白及其他抗体，对连续获取的55例额颞叶变性（FTLD）患者的大脑进行了病理检查。临床上，这些病例包括31例额颞叶痴呆（FTD）、10例运动神经元病包涵体痴呆（MNDID）、7例进行性失语（PA）、4例语义性痴呆（SD）和3例进行性失用症（PAX）。tau蛋白病理改变，以神经原纤维缠结（NFTs）和胶质细胞缠结的形式存在于6例与17号染色体相关的帕金森综合征型FTD中，其中5例由tau基因的+16剪接位点突变导致，1例由+13突变导致。不溶性tau蛋白主要由四重复（4-R）异构体组成。另外8例FTD、1例PA和所有3例PAX病例显示有tau阳性包涵体（Pick小体）和肿胀细胞（Pick细胞），这是Pick病的特征。在这些病例中，大多数情况下不溶性tau蛋白以三重复（3-R）tau异构体形式存在，不过也有2例同时存在3-R和4-R异构体混合物。另一例FTD显示出一种不寻常的病理改变，其特征是在白质中存在大量由4-R tau异构体组成的细胞外tau蛋白沉积，而无神经元或胶质细胞包涵体。然而，55例FTLD病例中有33例（60%）大脑中未显示tau蛋白病理改变，除了在一些年龄较大的病例中有罕见的由3-R和4-R异构体混合物组成的NFTs。在这33例病例中，13例为FTD，10例为MNDID，6例为PA，4例为SD。存在的病理改变为浅层皮质层状微空泡形成伴轻度软脑膜下和皮质下胶质增生；10例MNDID病例在大脑皮质和海马中有泛素阳性包涵体。这33例非tau蛋白FTLD病例，连同5例阿尔茨海默病（AD）和6例有严重病理改变的亨廷顿病（HD）病例，显示出可溶性tau蛋白有不同程度的丢失，大致与皮质神经元丢失程度及皮质内神经元胞体标记物NeuN的丢失程度相当，但与传入投射纤维内的蛋白如神经丝蛋白和α-突触核蛋白无关。tau mRNA水平在tau蛋白阴性的FTLD病例以及严重的AD和HD病例中平行下降。因此，这33例非tau蛋白FTLD病例中tau蛋白的丢失只是神经退行性过程的一个方面，该过程破坏了神经细胞机制的许多成分，并不代表细胞形成tau蛋白或将其整合到微管中的能力出现特异性紊乱。
