Importance of Apolipoprotein A-I in Multiple Sclerosis

Abstract

Jean-Martin Charcot has first described multiple sclerosis (MS) as a disease of the central nervous system (CNS) over a century ago. MS remains incurable today, and treatment options are limited to disease modifying drugs. Over the years, significant advances in understanding disease pathology have been made in autoimmune and neurodegenerative components. Despite the fact that brain is the most lipid rich organ in human body, the importance of lipid metabolism has not been extensively studied in this disorder. In MS, the CNS is under attack by a person's own immune system. Autoantigens and autoantibodies are known to cause devastation of myelin through up regulation of T-cells and cytokines, which penetrate through the blood-brain barrier to cause inflammation and myelin destruction. The anti-inflammatory role of high-density lipoproteins (HDLs) has been implicated in a plethora of biological processes: vasodilation, immunity to infection, oxidation, inflammation, and apoptosis. However, it is not known what role HDL plays in neurological function and myelin repair in MS. Understanding of lipid metabolism in the CNS and in the periphery might unveil new therapeutic targets and explain the partial success of some existing MS therapies.

Keywords: ATP- binding cassette transporter A1; ApoA-I; CNS; FTY720 (fingolimod; Gilenya); HDL; multiple sclerosis; sphingosine 1 phosphate.

FIGURE 1

ApoA-I reduces inflammation in the CNS by preventing contact between the T cells and macrophages. HDL produced in the periphery has access to the CNS whereas LDL has no ability to enter the CNS from the circulation. The membrane associated ATP-binding cassette subfamily A member 1 (ABCA1) and ABCA G1 act as the primary sterol transporters for ApoA-I/HDL. HDL associated ApoA-I is then recognized by the lipoprotein receptors (LDL, SR-BI) in the CNS. Brain cholesterol homeostasis is supported by the reverse cholesterol transport and efflux of 24 (24S-OH) and 27 (27-OH) hydroxysterols through the blood–brain barrier (BBB).