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Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes
Nature Chemistry ( IF 21.8 ) Pub Date : 2018-05-07 , DOI: 10.1038/s41557-018-0031-x
Johnny Habchi , Sean Chia , Céline Galvagnion , Thomas C. T. Michaels , Mathias M. J. Bellaiche , Francesco Simone Ruggeri , Michele Sanguanini , Ilaria Idini , Janet R. Kumita , Emma Sparr , Sara Linse , Christopher M. Dobson , Tuomas P. J. Knowles , Michele Vendruscolo

Alzheimer’s disease is a neurodegenerative disorder associated with the aberrant aggregation of the amyloid-β peptide. Although increasing evidence implicates cholesterol in the pathogenesis of Alzheimer’s disease, the detailed mechanistic link between this lipid molecule and the disease process remains to be fully established. To address this problem, we adopt a kinetics-based strategy that reveals a specific catalytic role of cholesterol in the aggregation of Aβ42 (the 42-residue form of the amyloid-β peptide). More specifically, we demonstrate that lipid membranes containing cholesterol promote Aβ42 aggregation by enhancing its primary nucleation rate by up to 20-fold through a heterogeneous nucleation pathway. We further show that this process occurs as a result of cooperativity in the interaction of multiple cholesterol molecules with Aβ42. These results identify a specific microscopic pathway by which cholesterol dramatically enhances the onset of Aβ42 aggregation, thereby helping rationalize the link between Alzheimer’s disease and the impairment of cholesterol homeostasis.



中文翻译:

脂质膜存在下胆固醇通过异种成核途径催化Aβ42聚集

阿尔茨海默氏病是与淀粉样β肽异常聚集有关的神经退行性疾病。尽管越来越多的证据表明胆固醇与阿尔茨海默氏病的发病机理有关,但该脂质分子与疾病过程之间的详细机理联系尚待完全确立。为了解决这个问题,我们采用动力学为基础的策略,揭示了A的聚集胆固醇的具体推动作用β 42(的淀粉状蛋白的42个残基的形式β 肽)。更具体地说,我们表明,含胆固醇脂膜促进β通过异质成核途径将其主要成核速率提高多达20倍来实现42聚集。进一步的研究表明此过程中发生,如结合的多胆固醇分子的相互作用的协同的结果β 42这些结果识别特定的微观途径,其中胆固醇显着提高A的发病β 42聚集,从而有助于合理化之间的链路阿尔茨海默氏病和胆固醇稳态的损害。

更新日期:2018-05-08
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