Contributions
Abstract: P741
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Introduction: Remyelination failure in the inflammatory demyelinating disorder multiple sclerosis (MS) contributes to persistent disability. Under physiological conditions brain cholesterol metabolism is separated from the circulation because the blood-brain barrier (BBB) precludes the entry of this sterol into the CNS. All neural cells participate in CNS cholesterol homeostasis but their contribution depends on developmental stage. During development, oligodendrocytes produce the majority of the cholesterol by cell autonomous sterol synthesis, and cholesterol is rate-limiting for myelin biogenesis.
Objectives: We aim at identifying whether and by which mechanism cholesterol insufficiency contributes to remyelination failure in mouse models of MS.
Aims: We investigate the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination.
Methods: We apply the cuprizone model of demyelination and remyelination and experimental autoimmune encephalomyelitis (EAE) to wildtype mice and conditional mutants of cholesterol synthesis, and analyze the role of cholesterol on disease expression.
Results: In the cuprizone model, inflammatory mediators mainly of astroglial origin destabilize the BBB after only few days, preceding demyelination and oligodendrocyte loss. Remarkably, cholesterol supplementation does not exacerbate disease expression in cuprizone treated mice or in EAE but enters the CNS from the circulation increasing the local cholesterol availability. Supplemented cholesterol supports oligodendroglia 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. Conditional mutants of cholesterol synthesis reveal the involvement of distinct cell types to cholesterol dependent remyelination, inflammation, and tissue repair.
Conclusions: 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.
Disclosure: nothing to disclose
Abstract: P741
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Introduction: Remyelination failure in the inflammatory demyelinating disorder multiple sclerosis (MS) contributes to persistent disability. Under physiological conditions brain cholesterol metabolism is separated from the circulation because the blood-brain barrier (BBB) precludes the entry of this sterol into the CNS. All neural cells participate in CNS cholesterol homeostasis but their contribution depends on developmental stage. During development, oligodendrocytes produce the majority of the cholesterol by cell autonomous sterol synthesis, and cholesterol is rate-limiting for myelin biogenesis.
Objectives: We aim at identifying whether and by which mechanism cholesterol insufficiency contributes to remyelination failure in mouse models of MS.
Aims: We investigate the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination.
Methods: We apply the cuprizone model of demyelination and remyelination and experimental autoimmune encephalomyelitis (EAE) to wildtype mice and conditional mutants of cholesterol synthesis, and analyze the role of cholesterol on disease expression.
Results: In the cuprizone model, inflammatory mediators mainly of astroglial origin destabilize the BBB after only few days, preceding demyelination and oligodendrocyte loss. Remarkably, cholesterol supplementation does not exacerbate disease expression in cuprizone treated mice or in EAE but enters the CNS from the circulation increasing the local cholesterol availability. Supplemented cholesterol supports oligodendroglia 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. Conditional mutants of cholesterol synthesis reveal the involvement of distinct cell types to cholesterol dependent remyelination, inflammation, and tissue repair.
Conclusions: 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.
Disclosure: nothing to disclose