The Membrane Stability of Model Myelin Lipids Modulated By the Presence of Cholesterol

The myelin sheath is a multilamellar lipid membrane wrapped around axons of neurons in the central nervous system (CNS) that facilitates rapid nerve impulse transmission, which is essential for the proper functioning of the CNS. Myelin destruction, called demyelination, causes Multiple Sclerosis (MS), a neurodegenerative disorder that results in the loss of sensory and motor functions due to nerve impulse leakage.

In healthy subjects, the amphipathic lipids that compose myelin form a remarkably stable membrane. The major lipids include the phospholipids L-alpha-phosphatidylcholine (Brain PC), L-alpha-phosphatidylethanolamine (Brain PE), and L-alpha-phosphatidylserine (Brain PS), and cholesterol. Lipid extracts of animal models of remyelination show changes in the lipidome; however, the details of how this lipidome alteration changes the mechanical properties of the myelin sheath is not currently understood. The role of lipids in MS progression has recently been identified; however, the details of these changes and the role of the lipidome change are not currently understood, limiting the treatments for MS. This work addresses the critical need to understand the relationship between structure and function of lipids in the myelin sheath. Using a Langmuir-Pockels trough, surface pressure (SP) versus area isotherms were measured to quantify mechanical properties of lipids extracted from the myelin sheath in the brains of mice with and without MS. Our results showed a significant learning of the compressibility modulus in the lipid films formed from the remyelinated myelin lipid extracts compared to the healthy lipid extracts. In addition, lipidomic studies showed significant differences in the phospholipid and cholesterol composition between the healthy and “sick” animals, establishing the role of the lipidome in MS. To better understand the role of the lipidome alteration on the membrane mechanical properties, further exploration was done using model membrane compositions with varying content of the three phospholipid classes and cholesterol. Careful analysis using several different compositions demonstrate that the largest difference in the monolayer’s area compressibility modulus is seen for cholesterol compositions that reflect the native and diseased cholesterol content. Since the area compressibility modulus of monolayers is correlated to the membrane’s rigidity, our results conclusively prove the importance of cholesterol in maintaining the structural integrity of the myelin sheath.