Curcumin Dictates Divergent Fates for the Central Salt Bridges in Amyloid-β40 and Amyloid-β42

There are three specific regions in the Amyloid beta (A beta) 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 Zn2+ and curcumin on A beta(40), and compare these with their previously reported effects on A beta(42). A beta(42) and A beta(40) differ only near the C-terminus, where curcumin interacts, while Zn2+ 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 A beta(40) aggregates, but not in A beta(42). In contrast, we find no difference in the effects of Zn+2 on A beta(40) and A beta(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 A beta termini can determine the fate of a salt bridge far away in the sequence, and this has significant consequences for A beta 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.