Abstract
BackgroundMultiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS) commonly affecting young adults. There is increasing evidence that environmental factors are important in the development and course of MS. The metabolic syndrome (MetS) which comprises dyslipidemia has been associated with a worse outcome in MS disease. Furthermore, the lipid-lowering drug class of statins has been proposed to improve MS disease course. However, cholesterol is also rate-limiting for myelin biogenesis and promotes remyelination in MS animal models. Thus, the impact of circulating blood cholesterol levels during the disease remains debated and controversial.MethodsWe assessed the role of circulating cholesterol on the murine model of MS, the experimental autoimmune encephalomyelitis (EAE) disease using two different approaches: (1) the mouse model of familial hypercholesterolemia induced by low-density lipoprotein receptor (LDLr) deficiency, and (2) the use of the monoclonal anti-PCSK9 neutralizing antibody alirocumab, which reduces LDLr degradation and consequently lowers blood levels of cholesterol.ResultsElevated blood cholesterol levels induced by LDLr deficiency did not worsen clinical symptoms of mice during EAE. In addition, we observed that the anti-PCSK9 antibody alirocumab did not influence EAE disease course, nor modulate the immune response in EAE.ConclusionsThese findings suggest that blood cholesterol level has no direct role in neuro-inflammatory diseases and that the previously shown protective effects of statins in MS are not related to circulating cholesterol.
Highlights
Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS) commonly affecting young adults
Blood was collected from WT and low-density lipoprotein receptor (LDLr)−/− female mice before induction of EAE. LDLr−/− mice had a significant twofold elevation of total cholesterol compared to WT mice (Fig. 1A)
Monoclonal anti‐Proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralizing antibody decreases circulating cholesterol without alleviating EAE symptoms As we observed that LDLr deficiency did not affect EAE disease progression, we further explored the inverse, whether reducing circulating cholesterol would attenuate the disease as described for statin treatment
Summary
Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS) commonly affecting young adults. There is increasing evidence that environmental factors are important in the development and course of MS. Multiple sclerosis (MS) is a chronic inflammatory and autoimmune disease affecting the central nervous system (CNS) leading to neuronal damage and disabling neurological deficits [1] It is a common disorder affecting young adults; its mortality is low, but it is a lifelong disease with high morbidity. The etiology of MS is multifactorial and environmental factors play a major role in disease causation [2]. In line with this concept, obesity, defined as a body mass index ≥ 30 kg/m2, is associated with increased risk of MS [3, 4].
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