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首页> 外文期刊>Biochemistry >Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease.
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Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease.

机译：Aβ淀粉样蛋白原纤维的组装：阿尔茨海默氏病可能早期事件的体外模型。

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摘要

Amyloid fibrils comprising primarily the peptides A beta 40 and A beta 42 are a defining feature of the Alzheimer's disease (AD) brain, and convergent evidence suggests that the process of their formation plays a central role in the AD pathogenic pathway. Elucidation of fibril assembly is critical for the discovery of potential AD diagnostics and therapeutics, since the pathogenic entity is not necessarily the product fibril, but could be a precursor species whose formation is linked to fibrillogenesis in vivo. Atomic force microscopy allowed the identification of an unanticipated intermediate in in vitro fibril formation, the A beta amyloid protofibril. This manuscript describes studies of the structure of the A beta 40 protofibril and its in vitro assembly and disassembly using atomic force microscopy (AFM). The A beta 40 protofibril has a height of ca. 4.3 +/- 0.5 nm and a periodicity of ca. 20 +/- 4.7 nm. The rate of its elongation depends on the total concentration of A beta 40, the temperature, and ionic strength of the medium. A beta 42 and A beta 40 protofibrils elongate at a comparable rate. Statistical analysis of AFM data reveals a decrease in the number of protofibrils with time, indicating that coalescence of smaller protofibrils contributes to protofibril elongation. Similar analysis reveals that protofibrils shorten while the number of protofibrils also decrease following dilution, indicating that protofibril disassembly does not proceed by a reverse of the assembly process. These investigations provide systematic data defining factors affecting A beta fibrillization and, thus, should be valuable in the design of high-throughput assays to identify agents which alter A beta protofibril assembly.
机译：主要包含肽A beta 40和A beta 42的淀粉样蛋白原纤维是阿尔茨海默氏病（AD）脑的定义特征，并且越来越多的证据表明它们的形成过程在AD致病性途径中起着核心作用。阐明原纤维装配对于潜在的AD诊断和治疗方法的发现至关重要，因为病原体不一定是原纤维产物，而可能是前体物质，其形成与体内原纤维形成有关。原子力显微镜可以鉴定出体外原纤维形成中未预料到的中间体，即Aβ淀粉样原纤维。该手稿描述了使用原子力显微镜（AFM）对A beta 40原型原纤维的结构及其体外组装和拆卸的研究。 A beta 40原纤维的高度约为1。 4.3 +/- 0.5 nm，周期约为20 +/- 4.7纳米其伸长率取决于A beta 40的总浓度，温度和介质的离子强度。 β42和Aβ40的原纤维以相当的速率伸长。 AFM数据的统计分析表明，原纤维的数量随时间减少，这表明较小的原纤维的聚结有助于原纤维的伸长。相似的分析表明，稀释后原纤维缩短，而原纤维数目也减少，这表明原纤维的分解不会通过相反的组装过程进行。这些研究提供了定义影响Aβ原纤维化的因素的系统数据，因此，在设计高通量试验以鉴定可改变Aβ原纤维组装的药物时，应该是有价值的。

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