KMID : 0606920200280020145
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Biomolecules & Therapeutics 2020 Volume.28 No. 2 p.145 ~ p.151
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Polyphenolic Biflavonoids Inhibit Amyloid-Beta Fibrillation and Disaggregate Preformed Amyloid-Beta Fibrils
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Choi Erika Y.
Kang Sam-Sik Lee Sang-Kook Han Byung-Hee
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Abstract
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Alzheimer¡¯s disease (AD) is a devastating neurodegenerative disease and a major cause of dementia in elderly individuals worldwide. Increased deposition of insoluble amyloid ¥â (A¥â) 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¥â fibrils and/or destabilize ¥â-sheet-rich A¥â fibrils to form non-cytotoxic aggregates. In the present study, we explored the structure-activity relationship of naturally-occurring biflavonoids on A¥â amyloidogenesis utilizing an in vitro thioflavin T assay with A¥â1-42 peptide which is prone to aggregate more rapidly to fibrils than A¥â1-40 peptide. Among the biflavonoids we tested, we found amentoflavone revealed the most potent effects on inhibiting A¥â1-42 fibrillization (IC50: 0.26 ¥ìM), as well as on disassembling preformed A¥â1-42 fibrils (EC50: 0.59 ¥ìM). 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¥â1-42 fibrillization. Our atomic force microscopic imaging analysis demonstrates that amentoflavone directly disrupts the fibrillar structure of preformed A¥â1-42 fibrils, resulting in conversion of those fibrils to amorphous A¥â1-42 aggregates. These results indicate that amentoflavone affords the most potent anti-amyloidogenic effects on both inhibition of A¥â1-42 fibrillization and disaggregation of preformed mature A¥â1-42 fibrils.
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KEYWORD
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Alzheimer¡¯s disease, Amyloid ¥â (A¥â), Fibrillization, Disaggregation, Structure-activity relationship, Biflavonoids
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