Author Of 1 Presentation
P0779 - Lipid handling by macrophages and microglia is impaired in the aging CNS after demyelination (ID 578)
Abstract
Background
Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating neurodegenerative disease of the central nervous system (CNS). Demyelination results in an accumulation of myelin debris, which is mostly comprised of lipids, in the extracellular space, which previous studies have shown to impair remyelination. Under optimal circumstances, the debris is cleared through phagocytosis by phagocytes, such as microglia and macrophages.
Objectives
A key determinant of progression of most neurodegenerative diseases including MS is age. Studies have reported the deficient clearance of myelin debris, and increased formation and deposition of cholesterol crystals within macrophages, in the aging CNS after demyelination. This has been associated with reduced expression of cholesterol exporter ABCA1 with age. As myelin contains about 80% of lipids, we propose that the accumulation, deficient processing and shuttling of lipids or lipid droplets contribute to the impaired myelin debris clearance in an injured aging CNS.
Methods
We have used lysolecithin demyelination in the spinal cord of young (2-3 months) and aging (8-12 months) mice. Confocal and slide scanner microscopes were utilized to investigate the abundance of lipid droplets in young and aging mice. We conducted bulk RNA sequencing of laser-microdissected lesion sites at day 3 post demyelination. In culture, we have used the macrophages and microglia to assess the effect of lipids on phagocytosis of myelin debris.
Results
In bulk RNA sequencing of laser-microdissected lesion sites at day 3 post demyelination, we found that transcripts encoding the apparatus associated with lipid processing and their degradation (such as pxmp2, cat, abcd3, rab37, lcat) are greatly reduced with aging. Confocal microscopy documented the accumulation of lipid droplets within macrophage/microglia in lesions, and this is significantly higher at day 14 and 21 in aging compared to young mice. In culture, we found that extracellular cholesterol increases the engulfment of myelin debris by macrophages and microglia, leading to appearance of foamy cells. Current experiments probe the contribution of the deficient handling of myelin associated lipids in cholesterol crystal formation and how to target therapeutically the processing of intracellular lipids.
Conclusions
The proper and efficient handling of myelin lipid is imperative for making the lesion environment more conducing for repair.