Characterization of β amyloid assemblies in drusen:: the deposits associated with aging and age-related macular degeneration
Characterization of β amyloid assemblies in drusen:: the deposits associated with aging and age-related macular degeneration
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DOI：
10.1016/j.exer.2003.10.011
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发表时间：
2004-02-01
影响因子：
3.4
通讯作者：
Johnson, LV
中科院分区：
文献类型：
--
作者：
Anderson, DH;Talaga, KC;Johnson, LV
目的.最近的研究强烈表明，玻璃疣，与年龄相关性黄斑变性（AMD）相关的细胞外沉积物，是局部炎症事件的表现。新的证据表明，玻璃疣内的亚结构元件含有活化的补体成分以及淀粉样蛋白β（Abeta），这是阿尔茨海默病斑块的主要促炎成分。我们表征了这些含Abeta的元素的超微结构组织和组织化学染色特性，以进一步评估它们在玻璃疣形成和AMD发病机制中的意义。我们使用微分干涉对比光学，激光扫描共聚焦免疫荧光，和免疫金电子显微镜来表征玻璃疣中含有Abeta的元素的结构特性和分子组成。我们从152只年龄从9岁到91岁的人类供体眼睛收集的电子显微照片的蒙太奇中获得了其频率的估计。通常组织为同心环状结构的球形含Abeta元件是玻璃疣的常见亚结构组分。它们用硫磺素T染色，但不被刚果红染色;它们也不结合阳离子、亲脂性或核酸结合荧光染料。在超微结构上，它们由一个中心核、一个或多个中间有电子透明层的同心内环和一个电子致密的外壳组成。免疫金标记表明，大多数Abeta免疫反应性与外层组成的密集包装的球形亚基。没有明显的大脑中聚集的淀粉样纤维的特征性的纵向纤维阵列。其他主要的玻璃疣相关蛋白包括末端补体复合物C5 b-9、玻连蛋白、载脂蛋白E、血清淀粉样蛋白P组分和泛素均被排除在球体之外。嵌在玻璃疣中的这些结构似乎代表了一种新型的大分子组装体，其含有Abeta以及活化的补体成分。这些细胞外沉积物中存在Abeta是另一个指示，即引起玻璃疣和AMD的一些致病途径可能与以错误折叠蛋白质沉积和聚集为特征的其他神经退行性疾病共有。(C)2003 Elsevier Ltd.保留所有权利。
Purpose. Recent studies strongly suggest that drusen, the extracellular deposits associated with age-related macular degeneration (AMD), are a manifestation of local inflammatory events. New evidence indicates that substructural elements within drusen contain activated complement components as well as amyloid beta (Abeta), a major pro-inflammatory component of Alzheimer's disease plaques. We characterized the ultrastructural organization and histochemical staining properties of these Abeta-containing elements in order to further assess their significance in drusen formation and AMD pathogenesis.Methods. We used differential interference contrast optics, laser scanning confocal immunofluorescence, and immunogold electron microscopy to characterize the structural properties and molecular composition of Abeta-containing elements in drusen. We obtained estimates of their frequency from montages of electron micrographs gathered from 152 human donor eyes ranging from 9 to 91 years of age.Results. Spherical Abeta-containing elements, which are typically organized as concentric ring-like structures, are common substructural components of drusen. They stain with thioflavin T, but are not stained by Congo red; nor do they bind cationic, lipophilic, or nucleic acid-binding fluorescent dyes. Ultrastructurally, they are composed of a central core, one or more concentric inner rings with intervening electron lucent layers, and an electron dense outer shell. Immunogold labeling indicates that most Abeta immunoreactivity is associated with the outer layers that consist of densely-packed spherical subunits. No longitudinally-oriented fibril arrays, characteristic of aggregated amyloid fibrils in the brain, are evident. Other prominent drusen-associated proteins including the terminal complement complex C5b-9, vitronectin, apolipoprotein E, serum amyloid P component, and ubiquitin are excluded from the spheres.Conclusions. These structures embedded in drusen appear to represent a new type of macromolecular assembly that contains Abeta as well as activated complement components. The presence of Abeta in these extracellular deposits is an additional indication that some of the pathogenic pathways that give rise to drusen and AMD may be shared with other neurodegenerative diseases characterized by misfolded protein deposition and aggregation. (C) 2003 Elsevier Ltd. All rights reserved.