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

• Published in: Neurobiology of aging 2020-10, Vol.94, p.24-33
• Main Authors: Al-Edresi, Sarmad, Alsalahat, Izzeddin, Freeman, Sally, Aojula, Harmesh, Penny, Jeffrey
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Aβ1–42 peptide; Cleavage; MALDI-TOF; Resveratrol
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2020.04.012

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. [Display omitted] •Resveratrol disrupts amyloid beta aggregation by causing peptide fragmentation.•Resveratrol-mediated amyloid beta fragmentation is concentration-dependent.•Resveratrol reduces amyloid beta-mediated cytotoxicity towards neuroblastoma cells.•Resveratrol cleaves amyloid beta at Phe4-Arg5; representing a novel mechanism.