Aβ40 has a subtle effect on Aβ42 protofibril formation, but to a lesser degree than Aβ42 concentration, in Aβ42/Aβ40 mixtures.
Aβ40 has a subtle effect on Aβ42 protofibril formation, but to a lesser degree than Aβ42 concentration, in Aβ42/Aβ40 mixtures.
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DOI：
10.1016/j.abb.2016.03.017
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发表时间：
2016-05-01
影响因子：
3.9
通讯作者：
Nichols MR
中科院分区：
文献类型：
--
作者：
Terrill-Usery SE;Colvin BA;Davenport RE;Nichols MR
近年来的研究表明，阿尔茨海默病患者的老年斑中可能含有可溶性淀粉样β肽（Aβ）原纤维前体沿着不溶性原纤维。这些可溶性Aβ物质（包括寡聚体和原纤维）已在体外得到充分研究，并通过Aβ单体的非共价自组装形成。虽然在人体中观察到40-和42-残基形式的Aβ，但大多数Aβ聚集工作分别对Aβ42或Aβ40进行，对混合物的研究相对较少。为了研究Aβ40和Aβ42的不同组合对原纤维形成的影响，将干燥的固体肽或纯化的Aβ40和Aβ42单体溶液的混合物混合在一起，并对原纤维/单体分布进行定量。Aβ42/Aβ40比值的增加增加了原纤维形成，但与纯Aβ42的等效溶液相比，混合Aβ溶液中Aβ40的存在对原纤维形成有显著的负面影响。原纤维大小受影响较小，但β-折叠结构随着由较高Aβ42/Aβ40比溶液形成的原纤维而增加。通过C-末端选择性ELISA直接测量Aβ42/Aβ40比值，发现Aβ40很少掺入原纤维。累积数据强调了Aβ42的关键重要性，但确定Aβ40是Aβ42聚集的调节剂。
Recent findings suggest that the senile plaques in Alzheimer’s disease may contain soluble amyloid-β peptide (Aβ) fibril precursors along with insoluble fibrils.. These soluble Aβ species, including oligomers and protofibrils, have been well-studied in vitro and are formed via non-covalent self-assembly of Aβ monomers. While both 40- and 42-residue forms of Aβ are observed in the human body, the majority of the Aβ aggregation work has been conducted on Aβ42 or Aβ40 separately, with relatively few investigations of mixtures. In order to study the effect of different combinations of Aβ40 and Aβ42 on protofibril formation, mixtures of either dry solid peptide, or purified Aβ40 and Aβ42 monomer solutions were mixed together and protofibril/monomer distributions were quantified. Increases in the Aβ42/Aβ40 ratio increased protofibril formation but the presence of Aβ40 in the mixed Aβ solutions had a significant negative impact on protofibril formation compared to equivalent solutions of pure Aβ42. Protofibril size was less affected, but β-sheet structure increased with protofibrils formed from higher Aβ42/Aβ40 ratio solutions. Direct measurement of Aβ42/Aβ40 ratios by C-terminal-selective ELISA found very little Aβ40 incorporated into protofibrils. The cumulative data emphasizes the critical importance of Aβ42, yet establishes Aβ40 as a regulator of Aβ42 aggregation.