Abstract
Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes.
Highlights
Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability
We previously showed that cholesterol is rate limiting for CNS myelination[17] and that nutritional cholesterol supplementation can stimulate developmental myelination in a mouse model of leukodystrophy[18]
At the peak of the clinical symptoms, dietary cholesterol did not influence the level of inflammation: histopathological lesions in the lumbar spinal cord white matter as well as the immune cell infiltration and characteristics of the pro-inflammatory milieu were comparable in extent and composition (Fig. 1c; Supplementary Fig. 2)
Summary
Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. In experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes. In demyelinating diseases such as multiple sclerosis (MS), the failure to remyelinate contributes to axonal damage[1], a major factor in persistent disability. Dietary cholesterol modulates the profile of growth factors, simultaneously enhancing OPC proliferation and oligodendrocyte differentiation, thereby facilitating remyelination and reducing axonal injury These data have implications for the treatment of demyelinating diseases
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