Effects of Charged Cholesterol Derivatives on Aβ40 Amyloid Formation.
Effects of Charged Cholesterol Derivatives on Aβ40 Amyloid Formation.
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DOI：
10.1021/acs.jpcb.5b09557
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发表时间：
2016-01-14
期刊：
影响因子：
--
通讯作者：
Du D
中科院分区：
文献类型：
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作者：
Elbassal EA;Liu H;Morris C;Wojcikiewicz EP;Du D
了解淀粉样β肽（Aβ）聚集的机制进展对于阐明阿尔茨海默病（AD）的潜在发病机制至关重要。在此，我们首次报道了两种胆固醇衍生物，带负电荷的胆固醇硫酸盐（胆固醇-SO4）和带正电荷的3β-[N-（二甲基氨基乙烷）氨基甲酰基]-胆固醇（DC-胆固醇）对Aβ40纤维化的影响。我们的结果表明，胆固醇-SO4 和 DC-胆固醇的两种非囊泡形式都会适度加速 Aβ40 的聚集速率。这种效应与未修饰胆固醇观察到的效应类似，表明疏水相互作用在 Aβ40 与这些类固醇分子结合中的重要性。此外，我们表明，在较高浓度的阴离子胆固醇-SO4 下形成的囊泡显着促进 Aβ40 聚集速率。相比之下，阳离子 DC-胆固醇囊泡在适当的实验条件下表现出抑制 Aβ40 原纤维形成的能力。结果表明，Aβ40 与带电囊泡之间的静电相互作用对于调节 Aβ40-囊泡相互作用非常重要。我们的结果还表明，胆固醇衍生物聚集体的结构特性，包括表面电荷和囊泡大小，对于调节这些囊泡对 Aβ40 聚集动力学的影响至关重要。
Understanding of the mechanistic progess of Amyloid-β peptide (Aβ) aggregation is critical for elucidating the underlying pathogenesis of Alzheimer’s disease (AD). Herein, we report for the first time the effects of two cholesterol derivatives, negatively charged cholesterol sulfate (cholesterol-SO4) and positively charged 3β-[N-(dimethylaminoethane)carbamoyl]-cholesterol (DC-cholesterol), on the fibrillization of Aβ40. Our results demonstrate that both of the nonvesicle forms of cholesterol-SO4 and DC-cholesterol moderately accelerate the aggregation rate of Aβ40. This effect is similar to that observed for unmodified cholesterol, indicating the importance of hydrophobic interactions in binding of Aβ40 to these steroid molecules. Furthermore, we show that the vesicles formed at higher concentrations of anionic cholesterol-SO4 facilitate Aβ40 aggregation rate markedly. In contrast, the cationic DC-cholesterol vesicles show the ability to inhibit Aβ40 fibril formation under appropriate experimental conditions. The results suggest that the electrostatic interactions between Aβ40 and the charged vesicles can be of great importance in regulating Aβ40-vesicle interaction. Our results also indicate that the structural properties of the aggregates of the cholesterol derivatives, including the surface charge and the size of the vesicles, are critical in regulating the effects of these vesicles on Aβ40 aggregation kinetics.