Curcumin Dictates Divergent Fates for the Central Salt Bridges in Amyloid-β and Amyloid-β.

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 and curcumin on Aβ, and compare these with their previously reported effects on Aβ. Aβ and Aβ differ only near the C-terminus, where curcumin interacts, while Zn 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 aggregates, but not in Aβ. In contrast, we find no difference in the effects of Zn on Aβ and Aβ. In the presence of Zn, 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.