Cholesterol Dysregulation in Multiple Sclerosis: Implications for Pathogenesis and Opportunities for Monitoring and Treating Progressive Disease

Multiple sclerosis (MS) is characterised by demyelination, neuroinflammation and neurodegeneration that contributes to a progressively worsening condition over time. Ongoing, chronic demyelination is an important hallmark of MS pathobiology; however the underlying drivers of progression have not been fully elucidated. Microglia mediate demyelination and contribute to continued lesion expansion.Phagocytosis and processing of myelin by microglia and macrophages results in the release of myelin-lipids – including cholesterol, and dysregulation of cholesterol homeostasis may drive a damaging microglial/macrophage response. The oxidised metabolites of cholesterol – oxysterols – are important ligands implicated in myelination, neuroinflammation and neuron survival and may represent a druggable target. Little is known about the abundance and location of cholesterol and the oxysterols in the MS brain, or how their dysregulation may contribute to a worsening progressive MS.