Abstract
Millions of people around the world suffer from amyloid-related disorders, including Alzheimer’s and Parkinson’s diseases. Despite significant and sustained efforts, there are still no disease-modifying drugs available for the majority of amyloid-related disorders, and the overall failure rate in clinical trials is very high, even for compounds that show promising anti-amyloid activity in vitro. In this study, we demonstrate that even small changes in the chemical environment can strongly modulate the inhibitory effects of anti-amyloid compounds. Using one of the best-established amyloid inhibitory compounds, epigallocatechin-3-gallate (EGCG), as an example, and two amyloid-forming proteins, insulin and Parkinson’s disease-related -synuclein, we shed light on the previously unexplored sensitivity to solution conditions of the action of this compound on amyloid fibril formation. In the case of insulin, we show that the classification of EGCG as an amyloid inhibitor depends on the experimental conditions select, on the method used for the evaluation of the efficacy, and on whether or not EGCG is allowed to oxidise before the experiment. For -synuclein, we show that a small change in pH value, from 7 to 6, transforms EGCG from an efficient inhibitor to completely ineffective, and we were able to explain this behaviour by the increased stability of EGCG against oxidation at pH 6.
Highlights
The onset and progression of more than 50 human disorders, including the neurodegenerativeAlzheimer’s and Parkinson’s diseases (AD and PD), is associated with the failure of peptides and proteins to adopt or remain in their native functional and soluble states, and their subsequent conversion into amyloid fibrils [1,2]
In the Supplementary Material, we show time-resolved UV–Vis data of EGCG that demonstrates the lack of oxidation under the conditions of these kinetic experiments (Figure S2)
EGCG and its auto-oxidation products (EGCGox) on the process of amyloid fibril formation by both insulin and α-synuclein performed under distinct environmental conditions were assessed using both aforementioned approaches (Figures 1 and S7), and the conclusions are presented in (Table 1)
Summary
Alzheimer’s and Parkinson’s diseases (AD and PD), is associated with the failure of peptides and proteins to adopt or remain in their native functional and soluble states, and their subsequent conversion into amyloid fibrils [1,2]. Distinct peptides and proteins are associated with these particular human disorders; the formation and accumulation of insoluble fibrillar aggregates are common among these diseases [1,2]. Whether extracted from patients or generated in vitro, amyloid fibrils formed from different proteins seem to be remarkably similar in overall morphology. Mature amyloid fibrils tend to appear as unbranched, thread-like, elongated structures, several nanometres in diameter and with lengths of the order of micrometres [1,2]. The corresponding fibrils all contain a β-sheet-rich structure, termed “cross-β,” according to the pattern in X-ray fibre diffraction studies [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
