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[摘要]：Recently, certain C-terminal fragments (CTFs) of A beta 42 have been shown to be effective inhibitors of A beta 42 toxicity. Here, we examine the interactions between the shortest CTF in the original series, A beta(39-42), and full-length A beta. Mass spectrometry results indicate that A beta(39-42) binds directly to A beta monomers and to the n = 2, 4, and 6 oligomers. The A beta 42:A beta(39-42) complex is further probed using molecular dynamics simulations. Although the CTF was expected to bind to the hydrophobic C-terminus of A beta 42, the simulations show that A beta(39-42) binds at several locations on A beta 42, 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 A beta(39-42) disrupts the early assembly of full-length A beta. Specifically, the ion-mobility results show that A beta(39-42) prevents the formation of large decamer/dodecamer A beta 42 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 A beta form responsible for toxicity. The results emphasize the role of small, soluble assemblies in A beta-induced toxicity and suggest that A beta(39-42) inhibits A beta-induced toxicity by a unique mechanism, modulating early assembly into nontoxic hetero-oligomers, without preventing fibril formation. |
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