| Myelin is a complex lipid membrane structure of stacked bilayers that insulates nerve axons and allows for increased nerve conduction efficiency. Myelin is attacked in a number of neurodegenerative diseases, most notably multiple sclerosis (MS). In MS, myelin degrades via a mechanism that involves loss of adhesion between adjacent myelin lamellae and subsequent degradation of the membrane into small vesicles. The loss of myelin leads to decreased sensory and motor function and disability. Developing treatments has been difficult, in part because the mechanism of demyelination is poorly understood. The goal of this research was to understand the biophysical principles that maintain normal myelin structure and to look for changes in diseased myelin that might alter the membrane stability. An initial overview of the individual lipids present in myelin using Langmuir monolayer isotherm measurements, fluorescence microscopy and atomic force microscopy revealed that the lipids had a wide variety of properties. Lipid extracts were then taken from MS normal-appearing white matter (NAWM) and myelin and from the white matter of marmosets in which a model of MS, experimental allergic encephalomyelitis (EAE), was induced. The MS NAWM is from areas of the brain where myelin is still intact, while EAE white matter contains regions of active demyelination. The lipid composition of these extracts was assessed using three techniques: Langmuir isotherms, high performance liquid chromatography, and carbon-13 magic angle spinning NMR. These techniques revealed only subtle changes in MS NAWM compared to controls, but found large changes in the EAE samples, including increases in negatively charged phosphatidylserine, increased membrane fluidity, and increased acyl chain unsaturation. These changes increase repulsive electrostatic and undulation forces at the extracellular interface (intraperiod line). A theoretical model predicts that these changes reduce or eliminate the interaction energy minimum normally maintained by an attractive van der Waals force, disrupting the balance of forces that maintain normal myelin structure. The cause of these lipid changes is unknown, but it is hoped that this better understanding of demyelination might lead to treatments, perhaps by finding and targeting the faulty point in lipid metabolism. |
