Lipidome of Compact Myelin from Cortical Regions of the Aging Murine Brain

Age-related cognitive decline has been associated with neurodegeneration in cortical white matter tracts. The trajectory of white matter degeneration over the lifespan follows a similar pattern in humans, primates and rodents including the loss of myelin integrity and concomitant loss in myelinated axonal segments. Previous studies suggest that biochemical alterations in myelin begin to occur well prior to myelin loss. To better understand these biochemical determinants underlying white matter degeneration, we investigated the lipid composition of myelin isolated from young adult, middle-aged and aged murine brain. Compact myelin was enriched from cortical regions using a refined density centrifugation protocol and profiled the lipidome using LC-MS/MS. Over 2000 lipid species were identified, with the relative expression of 414 species changing over the age-span. The myelin lipidome from young mice was biochemically distinct compared to the aging cohorts. Aging was characterized by an overall decrease in high abundant species of glycerophospholipid and sphingolipids, including phosphocholine, phosphoethanolamine, sphingomyelin and cerebrosides. Pathway analysis by LipidSig 2.0 and lipid ontology analysis by LION/web highlighted alterations to lipid metabolism and membrane biophysical properties related to bilayer stability and organization. These data support the concept that myelin lipid compositional changes are apparent by middle age which underly structural changes in myelin at later ages. The findings provide greater insight into age-related biochemical alterations in the myelin sheath and may aid in strategies to mitigate white matter degeneration over the lifespan.