Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA.
Mol Neurodegener. 2010 Dec 13;5:57. doi: 10.1186/1750-1326-5-57.
Age-related neurodegenerative diseases share a number of important pathological features, such as accumulation of misfolded proteins as amyloid oligomers and fibrils. Recent evidence suggests that soluble amyloid oligomers and not the insoluble amyloid fibrils may represent the primary pathological species of protein aggregates.
We have produced several monoclonal antibodies that specifically recognize prefibrillar oligomers and do not recognize amyloid fibrils, monomer or natively folded proteins. Like the polyclonal antisera, the individual monoclonals recognize generic epitopes that do not depend on a specific linear amino acid sequence, but they display distinct preferences for different subsets of prefibrillar oligomers. Immunological analysis of a number of different prefibrillar Aβ oligomer preparations show that structural polymorphisms exist in Aβ prefibrillar oligomers that can be distinguished on the basis of their reactivity with monoclonal antibodies. Western blot analysis demonstrates that the conformers defined by the monoclonal antibodies have distinct size distributions, indicating that oligomer structure varies with size. The different conformational types of Aβ prefibrillar oligomers can serve as they serve as templates for monomer addition, indicating that they seed the conversion of Aβ monomer into more prefibrillar oligomers of the same type.
These results indicate that distinct structural variants or conformers of prefibrillar Aβ oligomers exist that are capable of seeding their own replication. These conformers may be analogous to different strains of prions.
与年龄相关的神经退行性疾病具有许多重要的病理特征，例如错误折叠的蛋白质（如淀粉样寡聚体和纤维）的积累。最近的证据表明，可溶性淀粉样寡聚体而不是不溶性淀粉样纤维可能代表蛋白质聚集物的主要病理物种。
我们已经产生了几种特异性识别原纤维前寡聚体而不识别淀粉样纤维、单体或天然折叠蛋白的单克隆抗体。与多克隆抗血清一样，单个单克隆抗体识别通用表位，这些表位不依赖于特定的线性氨基酸序列，但它们对不同亚群的原纤维前寡聚体显示出不同的偏好。对许多不同的 Aβ 原纤维寡聚体制剂的免疫分析表明，Aβ原纤维寡聚体中存在结构多态性，可以根据它们与单克隆抗体的反应性来区分。Western blot 分析表明，单克隆抗体定义的构象具有不同的大小分布，表明寡聚物结构随大小而变化。Aβ原纤维寡聚体的不同构象类型可以作为单体添加的模板，表明它们引发 Aβ单体转化为相同类型的更多原纤维寡聚体。
这些结果表明，存在不同结构变体或原纤维前 Aβ寡聚体的构象，能够自我复制。这些构象可能类似于不同类型的朊病毒。
