A new purified Lawsoniaside remodels amyloid-beta(42) fibrillation into a less toxic and non-amyloidogenic pathway

摘要

Mounting evidence indicates soluble A beta(42) oligomers as the most toxic species causing neuronal death which leads to the onset and progression of Alzheimer disease (AD). Recently, it has been found that neurotoxic A beta(42) oligomers grow from monomeric species or arise following secondary nucleation by preformed mature fibrils. Thus, the use of natural compounds such as polyphenols to hinder the growth or to remodel A beta(42) fibrils is one of the most promising strategies for AD treatment. In our previous study, we showed that 1, 2, 4-trihydroxynaphthalene-2-0-beta-o-glucopyranoside (THNG) inhibits A beta(42) aggregation during the early steps of the aggregation process, inhibits its conformational change to a beta-sheet-rich structure, decreases its polymerization, inhibits its fibrillogenisis and reduces oxidative stress and aggregate cytotoxicity. Here, we used different spectroscopic and cell culture methods to check the effect of THNG on fibrils disaggregation. We showed that THNG binds to mature A beta(42) fibrils, rearrange their secondary structure, and remodels them into non-amyloid, less toxic, species by inhibiting their interaction with the plasma membrane. Our findings reveal that THNG is a good agent to remodel amyloid fibrils and could be used as a starting molecular scaffold to design new anti AD drugs. (C) 2018 Elsevier B.V. All rights reserved.