Polyphenolic Biflavonoids Inhibit Amyloid-Beta Fibrillation and Disaggregate Preformed Amyloid-Beta Fibrils.

Alzheimer's disease (AD) is a devastating neurodegenerative disease and a major cause of dementia in elderly individuals worldwide. Increased deposition of insoluble amyloid beta (A beta) fibrils in the brain is thought be a key neuropathological hallmark of AD. Many recent studies show that natural products such as polyphenolic flavonoids inhibit the formation of insoluble A beta fibrils and/or destabilize beta-sheet-rich A beta fibrils to form non-cytotoxic aggregates. In the present study, we explored the structure-activity relationship of naturally-occurring biflavonoids on A beta amyloidogenesis utilizing an in vitro thioflavin T assay with A beta 1-42 peptide which is prone to aggregate more rapidly to fibrils than A beta 1-40 peptide. Among the biflavonoids we tested, we found amentoflavone revealed the most potent effects on inhibiting A beta 1-42 fibrillization (IC50: 0.26 mu M), as well as on disassembling preformed A beta 1-42 fibrils (EC50: 0.59 mu M). Our structure-activity relationship study suggests that the hydroxyl groups of biflavonoid compounds play an essential role in their molecular interaction with the dynamic process of A beta 1-42 fibrillization. Our atomic force microscopic imaging analysis demonstrates that amentoflavone directly disrupts the fibrillar structure of preformed A beta 1-42 fibrils, resulting in conversion of those fibrils to amorphous A beta 1-42 aggregates. These results indicate that amentoflavone affords the most potent anti-amyloidogenic effects on both inhibition of A beta 1-42 fibrillization and disaggregation of preformed mature A beta 1-42 fibrils.