Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity

Wen Jie Du, Jing Jing Guo, Ming Tao Gao, Sheng Quan Hu, Xiao Yan Dong, Yifan Han, Fu Feng Liu, Shaoyi Jiang, Yan Sun

Research output: Journal article publicationJournal articleAcademic researchpeer-review

103 Citations (Scopus)

Abstract

Soluble amyloid β-protein (Aβ) oligomers, the main neurotoxic species, are predominantly formed from monomers through a fibril-catalyzed secondary nucleation. Herein, we virtually screened an in-house library of natural compounds and discovered brazilin as a dual functional compound in both Aβ 42 fibrillogenesis inhibition and mature fibril remodeling, leading to significant reduction in Aβ 42 cytotoxicity. The potent inhibitory effect of brazilin was proven by an IC 50 of 1.5 ± 0.3 μM, which was smaller than that of (-)-epigallocatechin gallate in Phase III clinical trials and about one order of magnitude smaller than those of curcumin and resveratrol. Most importantly, it was found that brazilin redirected Aβ 42 monomers and its mature fibrils into unstructured Aβ aggregates with some β-sheet structures, which could prevent both the primary nucleation and the fibril-catalyzed secondary nucleation. Molecular simulations demonstrated that brazilin inhibited Aβ 42 fibrillogenesis by directly binding to Aβ 42 species via hydrophobic interactions and hydrogen bonding and remodeled mature fibrils by disrupting the intermolecular salt bridge Asp23-Lys28 via hydrogen bonding. Both experimental and computational studies revealed a different working mechanism of brazilin from that of known inhibitors. These findings indicate that brazilin is of great potential as a neuroprotective and therapeutic agent for Alzheimer's disease.
Original languageEnglish
Article number7992
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - 1 Jan 2015

ASJC Scopus subject areas

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