Curcumin dictates divergent fates for the central salt bridges in amyloid- β40 and amyloid- β42

Chandra, Bappaditya ; Mithu, Venus Singh ; Bhowmik, Debanjan ; Das, Anand Kant ; Sahoo, Bankanidhi ; Maiti, Sudipta ; Madhu, Perunthiruthy K. (2017) Curcumin dictates divergent fates for the central salt bridges in amyloid- β40 and amyloid- β42 Biophysical Journal, 112 (8). pp. 1597-1608. ISSN 0006-3495

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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.

Item Type:Article
Source:Copyright of this article belongs to Elsevier Science.
ID Code:112894
Deposited On:24 May 2018 11:03
Last Modified:24 May 2018 11:07

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