Investigating the Role of Cholesterol Ester Regulation Towards Successful Remyelination

Multiple sclerosis is a chronic autoimmune, neurodegenerative disease where myelin sheaths are subjected to a series of inflammatory episodes of demyelination. The myelin sheath is a lipid-rich membrane where more than 70% of the dry weight is lipids. Since lipids are the main component in myelin, our goal is to identify changes in lipid populations during demyelination and remyelination that may highlight lipid pathways crucial in either promoting or impairing successful remyelination. In this study, we have used the induced conditional knockout- myelin regulatory factor (iCKO-Myrf) mouse model which features defined stages of global demyelination followed by remyelination. The model also features a measurable motor disability that correlates with peak brain demyelination. Unbiased full profile lipidomics analysis performed on brain and spinal cord samples collected from iCKO-Myrf mouse model have revealed large changes in cholesterol ester (CE) populations during myelin damage compared to normal physiological conditions. In the brain a 30-fold increase of CEs was observed during peak myelin damage and CE accumulation decreased with myelin repair. In contrast in the spinal cord, a 130-fold accumulation of CEs was observed chronically with persistent accumulation of CEs throughout the timepoints. Furthermore, histology characterization revealed that brain remyelinates faster than the spinal cord. Collectively, these results suggest that CE accumulation and clearance are correlated with myelin damage and repair with a strong possibility that CE regulatory pathways are highly involved in the myelin damage & repair process. ACAT1, LCAT, Apoe and nCEH are some of the proteins that have been implicated in the regulation of CEs in the brain. We are characterizing the expression levels of these proteins during demyelination and remyelination to understand how CEs are regulated during myelin damage and repair which may reveal new targets for therapeutic approaches.