Cholesterol metabolism in mouse models of Multiple Sclerosis
von Stefan Berghoff
Datum der mündl. Prüfung:2020-03-02
Betreuer:Dr. Gesine Saher
Gutachter:Prof. Dr. Christine Stadelmann-Nessler
Gutachter:Prof. Dr. Alexander Flügel
EnglischThe primary origin of brain cholesterol is de novo synthesis due to limited entry peripheral cholesterol across the blood-brain barrier (BBB). Most if not all brain cells contribute to central nervous system (CNS) cholesterol homeostasis. During development, oligodendrocytes produce the majority of cholesterol which is rate-limiting for myelin biogenesis while in the adult brain the role of individual cell-types in cholesterol homeostasis is not well-known. In demyelinating diseases such as multiple sclerosis (MS), CNS cholesterol homeostasis is disturbed likely contributing to disease. However, limited numbers of studies have addressed the relationship between cholesterol availability, cholesterol synthesis, inflammation and remyelination. In this study, I could demonstrate that the disruption of the BBB in the cuprizone intoxication model of de- and remyelination allows for entry of peripherally supplemented cholesterol which supports oligodendrocyte precursor cell (OPC) proliferation and differentiation, restores the balance of growth factors and thereby creates a permissive environment for remyelination. Further, I could show that persistent BBB impairment precedes demyelination characterized by induction of inflammatory mediators mainly of astroglial origin. In addition, I assessed the contribution of individual cell-types to CNS cholesterol metabolism during remyelination. Therefore, cholesterol metabolism during remyelination by tissue based and cell type specific sterol gene expression profiling was comprehensively analyzed and remyelination efficiency of cell type specific conditional cholesterol synthesis mutants during acute and chronic remyelination evaluated. Here, it could be shown that (I) chronic remyelination is driven by the capability of oligodendroglia to synthesize cholesterol, (II) cholesterol synthesis ablation in phagocytes prevents accumulation of the Liver X receptor (LXR) ligand desmosterol leading to chronic activation and lipid export deficiency thereby preventing remyelination, (III) exogenous cholesterol precursor therapy reduces disease severity by inducing LXR activation through increased abundance of desmosterol suppressing inflammation, in addition to directly supporting myelination in oligodendroglia and (IV) cholesterol precursor administration can be integrated in combination therapy. Together, my studies shed light on cholesterol metabolism during remyelination and provide evidence for lipid based therapy in promoting repair after demyelinating episodes.
Keywords: Multiple Sclerosis