Defective cholesterol clearance limits remyelination in the aged central 
nervous system

Cantuti-Castelvetri, Ludovico; Fitzner, Dirk; Bosch-Queralt, Mar; Weil, Marie-Theres; Su, Minhui; Sen, Paromita; Ruhwedel, Torben; Mitkovski, Miso; Trendelenburg, George; Lütjohann, Dieter; Möbius, Wiebke; Simons, Mikael

doi:10.1126/science.aan4183

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Defective cholesterol clearance limits remyelination in the aged central nervous system

MPG-Autoren

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

/persons/resource/persons192408

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

/persons/resource/persons214239

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

/persons/resource/persons182479

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

/persons/resource/persons214241

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

/persons/resource/persons182382

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

/persons/resource/persons182305

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

/persons/resource/persons182306

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

/persons/resource/persons182410

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

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Zitation

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.

Zitierlink: https://hdl.handle.net/21.11116/0000-0000-2F49-B

Zusammenfassung

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.