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

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 Zn²⁺ and curcumin on Aβ₄₀, and compare these with their previously reported effects on Aβ₄₂. Aβ₄₂ and Aβ₄₀ 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 Aβ₄₀ aggregates, but not in Aβ₄₂. In contrast, we find no difference in the effects of Zn⁺² on Aβ₄₀ and Aβ₄₂. 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.