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Journal Article

Defective cholesterol clearance limits remyelination in the aged central nervous system

MPS-Authors
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Cantuti-Castelvetri,  Ludovico
Cellular neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Fitzner,  Dirk
Cellular neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Bosch-Queralt,  Mar
Max Planck Institute of Experimental Medicine, Max Planck Society;

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Weil,  Marie-Theres
Cellular neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Su,  Minhui
Max Planck Institute of Experimental Medicine, Max Planck Society;

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Ruhwedel,  Torben
Electron microscopy, Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Mitkovski,  Miso
Light microscopy facility, Wiss. Servicegruppen, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Möbius,  Wiebke
Electron microscopy, Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Simons,  Mikael
Cellular neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Citation

Cantuti-Castelvetri, L., Fitzner, D., Bosch-Queralt, M., Weil, M.-T., Su, M., Sen, P., et al. (2018). Defective cholesterol clearance limits remyelination in the aged central nervous system. Science, 359(6376), 684-688. doi:10.1126/science.aan4183.


Cite as: https://hdl.handle.net/21.11116/0000-0000-2F49-B
Abstract
Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation and phagolysosomal membrane rupture and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters, including apolipoprotein E. Stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals and thereby inducing a maladaptive immune response that impedes tissue regeneration.