Intra-subject analysis of LRP-1 expression in neurons and glia from both active and inactive MS lesions in comparison to unlesioned contra- lateral brain tissue

Background: Multiple Sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system (CNS) of variable clinical course often beginning as a relapsing-remitting form and progressing into a secondary progressive disorder7. Remyelination of denuded axons in the CNS is usually rapid and efficient, and even MS lesions show some ability to remyelinate in remission stages of relapsing-remitting MS. However, as the pathological hallmark of chronic MS is demyelinated plaque, this repair process somehow eventually fails in MS patients8. The classical perception of MS is that it is a T-cell mediated autoimmune disorder initiated by the breakdown of the blood-brain barrier (BBB) leading to inflammatory cell infiltration and myelin destruction2. However, recent evidence suggests that immune cell infiltration and activation within lesion sites of the CNS may not be the primary cause of MS both as an initiator of chronic forms of the disease and as the trigger for new lesions in the relapsing-remitting form3,4,5. These recent studies indicate that widespread oligodendrocyte apoptosis and subsequent microglial activation can preceed immune response indicating that, at least in some cases, immune cell infiltration and activation may actually be a response to demyelination and not the primary cause. Recent studies in our lab have demonstrated that low-density lipoprotein receptor-related protein (LRP-1) is a novel receptor mediating the phagocytosis of myelin debris in the CNS1. These studies also demonstrate that oligodendrocytes have the greatest expression of LRP-1 and the greatest capacity for the clearance of myelin debris. Therefore, widespread death of oligodendrocytes in a CNS lesion site would not only lead to myelin debris accumulation, but would greatly impair the ability of glial cells in that area to clear debris so remyelination could take place. Additionally, glial activation that takes place upon oligodendrocyte apoptosis and precedes immune infiltration can also impede the ability of oligodendrocyte progenitor cells (OPCs) to migrate into the lesion site, which has been shown to have the capacity to restore function in inactive lesion sites2,5.