Myelin Lipid Composition in the Central Nervous System Is Regionally Distinct and Requires Mechanistic Target of Rapamycin Signaling

Cholesterol is highly enriched in the myelin sheath and is often dysregulated in neurodegenerative diseases affecting myelin integrity. Despite the prominence of promyelinating drugs targeting sterol synthesis and our increasing knowledge of oligodendrocyte heterogeneity, few studies have defined regional differences in lipid metabolism across the CNS. Previous analyses revealed that spinal cord oligodendroglia have a higher capacity for endogenous cholesterol biosynthesis compared to brain oligodendroglia. Our current findings reveal that, in contrast to spinal cord oligodendroglia, brain oligodendroglia have a higher capacity to uptake and respond to extracellular lipoproteins. Moreover, brain myelin has lower lipid concentrations compared to spinal cord myelin. Comparisons between spinal cord and subregions of the brain revealed that myelin lipid content is correlated to average axon diameter such that regions with smaller diameter axons, such as corpus callosum and cortical gray matter, have myelin with lower cholesterol and phospholipid content compared to regions containing higher diameter axons, including spinal cord and brain stem. When differentiated on synthetic nanofibers in vitro, spinal cord oligodendrocytes maintained a higher cholesterol content compared to brain oligodendrocytes irrespective of fiber diameter but displayed fiber diameter-dependent changes in fatty acid content. Establishment and maintenance of regional differences in myelin composition are supported by the mechanistic target of rapamycin (mTOR) signaling, as deletion of mTOR in oligodendroglia abolishes regional differences in myelin lipid content, with the greatest decreases in spinal cord and brain stem. These data highlight multiple differences in brain and spinal cord lipid metabolism, which result in regionally distinct myelin composition.