Aβ(39-42) modulates Aβ oligomerization but not fibril formation.
Aβ(39-42) modulates Aβ oligomerization but not fibril formation.
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DOI：
10.1021/bi201520b
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发表时间：
2012-01-10
期刊：
影响因子：
2.9
通讯作者：
Bowers, Michael T.
中科院分区：
文献类型：
--
作者：
Gessel, Megan Murray;Wu, Chun;Li, Huiyuan;Bitan, Gal;Shea, Joan-Emma;Bowers, Michael T.
最近，Aβ42的某些C末端片段(CTF)被证明是Aβ42毒性的有效抑制剂。在这里，我们研究了原始系列中最短的CTF Aβ(39-42)和全长Aβ之间的相互作用。质谱学结果表明，Aβ(39-42)直接与Aβ单体和n=2，4，6低聚物结合。在分子动力学模拟中进一步探讨了Aβ42：aβ(39-42)络合物。虽然CTF被认为与Aβ42的疏水C-末端结合，但模拟表明Aβ(39-42)与Aβ42上的几个位置结合，包括C-末端、其他疏水区域，并优先在N-末端结合。离子迁移率质谱仪(IM-MS)和电子显微镜实验表明，Aβ(39-42)破坏了全长Aβ的早期组装。具体来说，离子迁移率结果表明，Aβ(39-42)阻止了大的十聚体/十二聚体Aβ42物种的形成，并且可以从溶液中去除这些结构。同时，硫代黄素T荧光和电子显微镜结果表明，CTF不抑制原纤维的形成，这有力地支持了低聚物而不是淀粉样原纤维是导致毒性的Aβ形式的假说。结果强调了小的、可溶的组装在Aβ诱导的毒性中的作用，并表明Aβ(39-42)通过一种独特的机制抑制Aβ诱导的毒性，调节早期组装成无毒的杂寡体，而不阻止纤维的形成。
Recently, certain C-terminal fragments (CTFs) of Aβ42 have been shown to be effective inhibitors of Aβ42 toxicity. Here, we examine the interactions between the shortest CTF in the original series, Aβ(39–42) and full-length Aβ. Mass spectrometry results indicate that Aβ(39–42) binds directly to Aβ monomers and to the n=2,4, and 6 oligomers. The Aβ42:Aβ(39–42) complex is further probed using in molecular dynamics simulations. Although the CTF was expected to bind to the hydrophobic C-terminus of Aβ42, the simulations show that Aβ(39–42) binds at several locations on Aβ42, including the C-terminus, other hydrophobic regions, and preferentially in the N-terminus. Ion mobility-mass spectrometry (IM-MS) and electron microscopy experiments indicate that Aβ(39–42) disrupts the early assembly of full-length Aβ. Specifically, the ion-mobility results show that Aβ(39–42) prevents the formation of large decamer/dodecamer Aβ42 species and, moreover, can remove these structures from solution. At the same time, thioflavin T fluorescence and electron microscopy results show that the CTF does not inhibit fibril formation, lending strong support to the hypothesis that oligomers and not amyloid fibrils are the Aβ form responsible for toxicity. The results emphasize the role of small, soluble assemblies in Aβ-induced toxicity and suggest that Aβ(39–42) inhibits Aβ-induced toxicity by a unique mechanism, modulating early assembly into non-toxic heterooligomers, without preventing fibril formation.
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