Tabaton M, Cammarata S, Mancardi G, Manetto V, Autilio-Gambetti L, Perry G, Gambetti P
Department of Neurology, University of Genoa, Italy.
Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2098-102. doi: 10.1073/pnas.88.6.2098.
Neurofibrillary tangles (NFTs), a hallmark of Alzheimer disease, are commonly located in perikarya of neurons. In advanced cases of Alzheimer disease, however, NFTs are observed also in the extracellular space. As extracellular NFTs (E-NFTs), and occasionally intracellular NFTs (I-NFTs), are recognized by antibodies to beta-amyloid protein (beta AP), beta AP may be present not only in amyloid deposits but also in paired helical filaments (PHFs), the primary components of NFTs. We compared the antigenic characteristics of I-NFTs and E-NFTs with light- and electron-microscopic immunocytochemistry by using several antibodies to noncontiguous epitopes of the microtubule-associated protein tau and of ubiquitin (Ub) as well as an antiserum to beta AP. At variance with I-NFTs, E-NFTs were made predominantly of straight filaments (SFs), rather than PHFs, that were often separated by astroglial processes and in close association with small beta AP deposits. Occasionally, E-NFTs were made of bundles of amorphous material, which showed no resemblance to SFs, PHFs, or amyloid fibrils. The antigenic changes in E-NFTs suggest that when NFTs become extracellular they lose the N and, possibly, the C termini of tau while maintaining the intermediate region of the molecule; they also lose the N-terminal two-thirds of Ub while the C-terminal conjugation site of Ub is preserved. A small subset of E-NFTs reacted with antibodies to both beta AP and tau. Although in most E-NFTs, the epitopes recognized by tau and Ub antibodies were located in typical PHFs and SFs, the epitopes recognized in this subset of anti-beta AP and anti-tau-positive E-NFTs were located exclusively in the bundles of amorphous material. It is suggested that either beta AP epitopes are present but inaccessible in PHFs and SFs and become exposed after conformational changes occurring in the extracellular space or PHFs and SFs become closely associated with beta AP in the extracellular space.
神经原纤维缠结（NFTs）是阿尔茨海默病的一个标志，通常位于神经元的胞体中。然而，在阿尔茨海默病的晚期病例中，也可在细胞外空间观察到NFTs。由于细胞外NFTs（E-NFTs），偶尔还有细胞内NFTs（I-NFTs），可被β-淀粉样蛋白（β-AP）抗体识别，β-AP可能不仅存在于淀粉样沉积物中，还存在于NFTs的主要成分双螺旋丝（PHFs）中。我们使用几种针对微管相关蛋白tau和泛素（Ub）非连续表位的抗体以及一种β-AP抗血清，通过光镜和电镜免疫细胞化学比较了I-NFTs和E-NFTs的抗原特性。与I-NFTs不同，E-NFTs主要由直丝（SFs）而非PHFs组成，这些直丝常被星形胶质细胞突起分隔，并与小的β-AP沉积物紧密相连。偶尔，E-NFTs由无定形物质束组成，与SFs、PHFs或淀粉样纤维丝毫无相似之处。E-NFTs的抗原变化表明，当NFTs进入细胞外时，它们失去了tau的N端，可能还有C端，同时保留了分子的中间区域；它们还失去了Ub的N端三分之二，而Ub的C端结合位点得以保留。一小部分E-NFTs与β-AP和tau的抗体都发生反应。尽管在大多数E-NFTs中，tau和Ub抗体识别的表位位于典型的PHFs和SFs中，但在这一小部分抗β-AP和抗tau阳性的E-NFTs中识别的表位仅位于无定形物质束中。有人认为，要么β-AP表位存在于PHFs和SFs中但无法接近，在细胞外空间发生构象变化后暴露出来，要么PHFs和SFs在细胞外空间与β-AP紧密结合。
