Site of Cholesterol Oxidation Impacts Its Localization and Domain Formation in the Neuronal Plasma Membrane

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.