Amyloid β-protein:: Monomer structure and early aggregation states of Aβ42 and its Pro19 alloform
Amyloid β-protein:: Monomer structure and early aggregation states of Aβ42 and its Pro19 alloform
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DOI：
10.1021/ja044531p
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发表时间：
2005-02-23
影响因子：
15
通讯作者：
Bowers, MT
中科院分区：
文献类型：
--
作者：
Bernstein, SL;Wyttenbach, T;Bowers, MT
淀粉样β蛋白（Abeta）是阿尔茨海默病（AD）中的一种重要的神经病因子。最近的证据表明，可溶性Abeta低聚物可能是神经毒性物质。在天然存在的Abeta肽中，42-残基形式的Abeta 42与AD特别强地连接，即使其以更丰富的40-残基形式的Abeta 40的约10%的水平产生。在这里，我们应用质谱和离子迁移率的研究Abeta 42和它的Pro（19）异形体。Phe（19）-> Pro（19）取代阻断[Pro（19）] Abeta 42的原纤维形成。有证据表明，溶液样结构的Abeta单体的电喷雾和特征。未过滤的Abeta 42溶液仅产生单体和大的寡聚体，而[Pro（19）] Abeta 42溶液产生大量的单体、二聚体、三聚体和四聚体，但不产生大的寡聚体。当通过10，000 amu过滤器并立即取样时，Abeta 42溶液产生单体、二聚体、四聚体、六聚体和两个六聚体的聚集体，这可能是原纤维形成的第一步。这些结果与最近发表的光化学交联数据一致，并支持Bitan、Teplow及其同事提出的最近聚集机制[J. Biol. Chem. 2003，278，34882-34889]。
The amyloid beta-protein (Abeta) is a seminal neuropathic agent in Alzheimer's disease (AD). Recent evidence points to soluble Abeta oligomers as the probable neurotoxic species. Among the naturally occurring Abeta peptides, the 42-residue form Abeta42 is linked particularly strongly with AD, even though it is produced at approximately 10% of the levels of the more abundant 40-residue form Abeta40. Here, we apply mass spectrometry and ion mobility to the study of Abeta42 and its Pro(19) alloform. The Phe(19) --> Pro(19) substitution blocks fibril formation by [Pro(19)]Abeta42. Evidence indicates that solution-like structures of Abeta monomers are electrosprayed and characterized. Unfiltered solutions of Abeta42 produce only monomers and large oligomers, whereas [Pro(19)]Abeta42 solutions produce abundant monomers, dinners, trimers, and tetramers; but no large oligomers. When passed through a 10,000 amu filter and immediately sampled, Abeta42 solutions produce monomers, dimers, tetramers, hexamers, and an aggregate of two hexamers that may be the first step in protofibril formation. These results are consistent with recently published photochemical cross-linking data and lend support to recent aggregation mechanisms proposed by Bitan, Teplow, and co-workers [J. Biol. Chem. 2003, 278, 34882-34889].