Research School of Chemistry, College of Science, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
ACS Chem Neurosci. 2021 Oct 20;12(20):3873-3884. doi: 10.1021/acschemneuro.1c00395. Epub 2021 Oct 11.
Cholesterol is integral to the structure of mammalian cell membranes. Oxidation of cholesterol alters how it behaves in the membrane and influences the membrane biophysical properties. Elevated levels of oxidized cholesterol are associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. Previous work has investigated the impact of oxidized cholesterol in the context of simple model membrane systems. However, there is a growing body of literature that shows that complex membranes possessing physiological phospholipid distributions have different properties from those of binary or trinary model membranes. In the current work, the impact of oxidized cholesterol on the biophysical properties of a complex neuronal plasma membrane is investigated using coarse-grained Martini molecular dynamics simulations. Comparison of the native neuronal membrane to neuronal membranes containing 10% tail-oxidized or 10% head-oxidized cholesterol shows that the site of oxidization changes the behavior of the oxidized cholesterol in the membrane. Furthermore, species-specific domain formation is observed between each oxidized cholesterol and minor lipid classes. Although both tail-oxidized and head-oxidized cholesterols modulate the biophysical properties of the membrane, smaller changes are observed in the complex neuronal membrane than seen in the previous work on simple binary or trinary model membranes. This work highlights the presence of compensatory effects of lipid diversity in the complex neuronal membrane. Overall, this study improves our molecular-level understanding of the effects of oxidized cholesterol on the properties of neuronal tissue and emphasizes the importance of studying membranes with realistic lipid compositions.
胆固醇是哺乳动物细胞膜结构的重要组成部分。胆固醇的氧化会改变其在膜中的行为，并影响膜的生物物理特性。氧化胆固醇水平升高与神经退行性疾病有关，如阿尔茨海默病、帕金森病、多发性硬化症和亨廷顿病。以前的工作已经研究了氧化胆固醇在简单模型膜系统中的影响。然而，越来越多的文献表明，具有生理磷脂分布的复杂膜与二元或三元模型膜具有不同的性质。在当前的工作中，使用粗粒度的马蒂尼分子动力学模拟研究了氧化胆固醇对复杂神经元质膜生物物理特性的影响。将天然神经元膜与含有 10%尾氧化或 10%头氧化胆固醇的神经元膜进行比较表明，氧化部位改变了氧化胆固醇在膜中的行为。此外，在每种氧化胆固醇和少量脂质类之间观察到特定物种的域形成。尽管尾氧化和头氧化胆固醇都调节膜的生物物理特性，但在复杂神经元膜中观察到的变化比以前在简单二元或三元模型膜上的研究要小。这项工作强调了脂质多样性在复杂神经元膜中存在补偿效应。总的来说，这项研究提高了我们对氧化胆固醇对神经元组织性质影响的分子水平理解，并强调了研究具有真实脂质组成的膜的重要性。
