Department of Biochemical Sciences, University of Florence, Florence, Italy.
FEBS J. 2010 Nov;277(22):4602-13. doi: 10.1111/j.1742-4658.2010.07889.x.
A great deal must still be learnt on the structural features of amyloid assemblies, particularly prefibrillar aggregates, and the relationship of the latter with amyloid cytotoxicity. Presently, it is recognized that the population of unstable, heterogeneous amyloid oligomers and protofibrils is mainly responsible for amyloid cytotoxicity. Conversely, mature fibrils are considered stable, harmless reservoirs of molecular species devoid of toxicity in the polymerized state. This view has been modified by recent reports showing that mature fibrils grown at different conditions can display different structural features and stabilities, possibly leading them to undergo disassembly with the leak of toxic oligomers. Fibril polymorphism is paralleled by oligomer polymorphism and both can be traced back to amyloid growth from differently destabilized monomers with distinct structural features at differing conditions. Recent research has started to unravel oligomer structural and biophysical features and the relationship between the latter and oligomer cytotoxicity. These data have led to the proposal that, together, both oligomer and membrane physical features determine the extent of oligomer-membrane interaction with the resulting disruption of membrane integrity and cell impairment. Such a view can help to explain the variable vulnerability of different cell types to the same amyloids and the lack of relationship between amyloid load and the severity of clinical symptoms. It also stresses the importance, for cell/tissue impairment, of the presence, in tissue, in addition to toxic oligomers, of fibrils conformers of reduced stability as a possible source of toxic oligomers, whose leakage can be favoured upon interaction with suitable surfaces or by other environmental conditions.
在淀粉样蛋白组装体的结构特征方面，特别是原纤维前聚集体，以及后者与淀粉样蛋白细胞毒性的关系方面，仍有许多需要学习的地方。目前，人们认识到，不稳定的、异质的淀粉样蛋白寡聚物和原纤维的群体主要负责淀粉样蛋白的细胞毒性。相反，成熟的纤维被认为是不稳定的、无害的分子物种的储存库，在聚合状态下没有毒性。最近的研究报告表明，在不同条件下生长的成熟纤维可以显示出不同的结构特征和稳定性，这可能导致它们发生解聚，从而释放出有毒的寡聚物，这一观点已经被修改。纤维的多态性与寡聚物的多态性平行，两者都可以追溯到从不同去稳定化的单体以不同的条件下具有不同结构特征的方式进行淀粉样蛋白的生长。最近的研究已经开始揭示寡聚物的结构和物理特征，以及后者与寡聚物细胞毒性之间的关系。这些数据导致了这样一种观点，即寡聚物和膜的物理特征共同决定了寡聚物与膜相互作用的程度，从而导致膜完整性的破坏和细胞损伤。这种观点可以帮助解释为什么不同类型的细胞对相同的淀粉样蛋白具有不同的易感性，以及淀粉样蛋白负荷与临床症状严重程度之间缺乏关系。它还强调了在组织中，除了有毒的寡聚物之外，还存在稳定性降低的纤维构象体作为有毒寡聚物的可能来源的重要性，其泄漏可能会由于与合适的表面相互作用或其他环境条件而得到促进，从而对细胞/组织造成损伤。
