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

Aggregation of amyloid β1-42 (Aβ1-42) 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 antioxidant but has also been reported to bind to Aβ1-42 peptide, thereby reducing aggregation. However, little is known of the precise mechanism by which resveratrol reduces Aβ1-42 peptide aggregation. Using the thioflavin-T assay, the ability of resveratrol to reduce the extent of Aβ1-42 peptide aggregation was investigated. The findings of the present study demonstrate that interaction of resveratrol with Aβ1-42 peptide resulted in the cleavage of Aβ1-42 peptide into smaller fragments, as detected by matrix assisted laser desorption ionization-time of flight mass spectrometry. Atomic force microscopy analyses revealed Aβ1-42 peptide, under control conditions, aggregated into oligomers, protofibrils, and fibrils, whereas there was a distinct lack of these structures when Aβ1-42 peptide was incubated with resveratrol. Following 10 days incubation of Aβ1-42 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 Aβ1-42 peptide toward SH-SY5Y human neuroblastoma cells, suggesting a protective effect of the polyphenol. We therefore propose a novel mechanism by which resveratrol disrupts Aβ1-42 aggregation by mediating fragmentation of Aβ1-42 into smaller peptides, which have no propensity to aggregate further.