Abstract
There are three specific regions in the Amyloid beta (Aβ) peptide sequence where variations cause enhanced toxicity in Alzheimer's disease: the N-terminus, the central salt bridge, and the C-terminus. Here, we investigate if there is a close conformational connection between these three regions, which may suggest a concerted mechanism of toxicity. We measure the effects of Zn(2+) and curcumin on Aβ(40), and compare these with their previously reported effects on Aβ(42). Aβ(42) and Aβ(40) differ only near the C-terminus, where curcumin interacts, while Zn(2+) interacts near the N-terminus. Therefore, this comparison should help us differentiate the effect of modulating the C- and the N-termini. We find that curcumin allows fibril-like structures containing the salt bridge to emerge in the mature Aβ(40) aggregates, but not in Aβ(42). In contrast, we find no difference in the effects of Zn(+2) on Aβ(40) and Aβ(42). In the presence of Zn(+2), both of these fail to form proper fibrils, and the salt bridge remains disrupted. These results indicate that modulations of the Aβ termini can determine the fate of a salt bridge far away in the sequence, and this has significant consequences for Aβ toxicity. We also infer that small molecules can alter oligomer-induced toxicity by modulating the aggregation pathway, without substantially changing the final product of aggregation.