Resveratrol-mediated cleavage of amyloid β1-42 peptide: potential relevance to Alzheimer's disease

Aggregation of amyloid beta(1-42) (A beta(1-42)) peptide within the brain is considered one of the main causes of the neuropathological changes associated with Alzheimer's disease. Resveratrol is a well-known anti-oxidant but has also been reported to bind to A beta(1-42) peptide, thereby reducing aggregation. However, little is known of the precise mechanism by which resveratrol reduces A beta(1-42) peptide aggregation. Using the thioflavin-T assay, the ability of resveratrol to reduce the extent of A beta(1-42) peptide aggregation was investigated. The findings of the present study demonstrate that interaction of resveratrol with A beta(1-42) peptide resulted in the cleavage of A beta(1-42) peptide into smaller fragments, as detected by matrix assisted laser desorption ionization-time of flight mass spectrometry. Atomic force microscopy analyses revealed A beta(1-42) peptide, under control conditions, aggregated into oligomers, protofibrils, and fibrils, whereas there was a distinct lack of these structures when A beta(1-42) peptide was incubated with resveratrol. Following 10 days incubation of A beta(1-42) peptide with resveratrol, particles with a mean z-height of 1.940 nm (range 0.675-3.275 nm) were observed, which are characteristic of shorter peptide species. In cell-based studies, resveratrol significantly reduced the cytotoxicity of A beta(1-42) peptide toward SH-SY5Y human neuroblastoma cells, suggesting a protective effect of the polyphenol. We therefore propose a novel mechanism by which resveratrol disrupts A beta(1-42) aggregation by mediating fragmentation of A beta(1-42) into smaller peptides, which have no propensity to aggregate further. (C) 2020 Elsevier Inc. All rights reserved.