Fundamental membrane interactions of copper generated oligomers, profibrils and amyloid fibres

背景资料：有一组疾病，包括疯牛病和密切相关的阿尔茨海默病，其特征是蛋白质分子粘在一起形成低聚物和长纤维积聚，称为淀粉样蛋白斑块。这些物质存在于患有这些疾病的患者（或疯牛病的动物）的大脑中。正是这种特定蛋白质的粘附，特别是阿尔茨海默病中的淀粉样β肽（Ab），导致了一系列事件，最终导致细胞死亡和痴呆。这种被称为Ab的小肽分子只有40或42个氨基酸长，但却是所有痴呆症中最常见的一种。有强有力的证据表明，Ab 42的寡聚体对细胞的毒性最大。Ab-寡聚体是5至100个Ab分子结合在一起的特异性束。寡聚体引起细胞毒性的机制尚不清楚，然而，一个流行的观点是寡聚体破坏细胞膜壁的完整性。有趣的是，必需的矿物质（如铜等金属离子）会干扰抗体粘附在一起的方式和可能性。表现出类似于AD症状的转基因小鼠，在铜代谢受到影响时表现出更快的症状。此外，铜被发现与大脑中的淀粉样蛋白斑块结合。目的：本提案的主要目的是研究不同Ab聚集体与细胞膜壁的基本相互作用。我们将使用必需的矿物质，特别是铜，其影响形成的Ab聚集体的类型，特别是铜使Ab 42的毒性更强的寡聚体形式稳定。意义：我们的初步观察表明，Ab 40和Ab 42之间的细胞毒性的充分记录的差异可能是由于这两种肽在铜存在下形成寡聚体或纤维的方式非常不同。铜几乎专门产生Ab 42的低聚物而不是纤维的能力将有助于研究这种形式的Ab 42，否则它通常是不稳定的。铜稳定的Ab-寡聚物对细胞膜的影响将促进Ab-寡聚物破坏脂质膜的第一个3D图像的产生。铜抗体低聚物毒性的细胞研究将首次与神经元突触健康的测量相关。

Background: There are a group of diseases including Mad-cow, and the closely related Alzheimer's disease, that are characterised by protein molecules which stick together to form oligomers and long fibrous accumulations, called amyloid plaques. These are found in the brains of patients (or animals in the case of mad-cow disease) suffering from these diseases. It is this sticking together of specific proteins, in particular amyloid beta peptide (Ab) in the case of Alzheimer's disease, which causes a cascade of events culminating in cell-death and dementia. The small peptide molecule, called Ab, is only 40 or 42 amino acids long but is responsible for the most common of all dementias. There is strong evidence that oligomers of Ab42 are the most toxic to cells. Ab-oligomers are specific bundles of between 5 to 100 Ab molecules bound together. The mechanism by which the oligomers cause cell toxicity is not clearly understood, however, one popular idea involves oligomers damaging the integrity of the celluar membrane wall. Interestingly, essential minerals (metal ions such as copper) perturb the way and likelihood that Ab will stick together. Genetically modified mice that show symptoms similar to AD, show symptoms more rapidly when copper metabolism is affected. Furthermore, copper is found bound to the amyloid plaques in the brain. Aims: The broad aim of this proposal is to investigate the fundamental interaction of different Ab aggregates with cellular membrane walls. We will use essential minerals, in particular copper, which influence the type of Ab aggregate formed, specifically copper stabilises the more toxic oligomeric form of Ab42.Significance: Our preliminary observation suggests that well documented differences in the cellular toxicity between Ab40 and Ab42 may be due to the very different ways these two peptides form oligomers or fibres in the presence of copper. The ability of copper to almost exclusively generate oligomers of Ab42, rather than fibres, will facilitate studying this form of Ab42, which is otherwise typically unstable. The effect of copper stabilized Ab-oligomers on cell-membranes will facilitate the generation of the first 3D images of lipid membrane disruption by Ab-oligomers. Cellular studies of copper-Ab-oligomer toxicity will, for the first time, be related to measures of synaptic health in neurons.