(112i) Thermodynamic and Rheological Impacts of the Lipid Composition in Healthy Versus Diseased Myelin and Their Implications for Demyelination

The myelin sheath is a critical component of the central nervous system (CNS) and peripheral nervous system (PNS). It is a multilamellar membrane consisting of a coiled bilayer that acts as an electrical insulator for nerve impulses traveling along axons between nerve cells. Myelin’s effectiveness as an electrical insulator is correlated with its thickness and compactness, and its ability to closely pack both the cytoplasmic faces within and the extracellular faces outside of each layer is critical for proper function, otherwise leading to serious neurological diseases including multiple sclerosis.

Compared to other membranes in the body, the myelin sheath contains a large lipid fraction in the range of 75-80% of the dry mass, compared to about 50% in other membranes, consisting of many different lipids falling primarily within the classes of glycerophospholipids, sphingolipids, and sterols. The lipids in the myelin sheath play a critical role in membrane stability and compaction, and it has been shown that the lipid composition differs significantly between healthy specimens and those sensitized with experimental autoimmune encephalomyelitis (EAE). While previous investigations have used model lipid bilayers and monolayers to study their interactions with important proteins including myelin basic protein (MBP) and proteolipid protein (PLP), our understanding of the role of lipid composition on membrane formation thermodynamics and rheology, particularly when comparing healthy versus diseased membranes, is lacking.

In this presentation we study the formation and interfacial dilatational rheology of lipid monolayers modeling the cytoplasmic and extracellular sides of healthy and EAE myelin. We use a Langmuir trough for both surface pressure versus area isotherms and oscillating area interfacial rheology measurements, all performed at approximately body temperature (37°C). From isotherm data, we calculate differences in the Gibbs free energy of mixing between the four monolayers to show differences in intermolecular interactions and miscibility. These results are used to support observations in interfacial rheology results, where EAE extracellular monolayers are substantially stiffer than their healthy counterparts, and both cytoplasmic monolayers are significantly softer than the extracellular side. We also analyze the nonlinear rheological behavior of the monolayers, for example observing in general film softening during compression and expansion. These first oscillatory interfacial rheology measurements of model myelin monolayers, coupled with the thermodynamic analysis of film formation, improve our understanding of the implications of the different lipid compositions on the film properties, and provide clues to how the changes in lipid composition may lead to demyelination.