Format

Send to

Choose Destination
Science. 2018 Feb 9;359(6376):684-688. doi: 10.1126/science.aan4183. Epub 2018 Jan 4.

Defective cholesterol clearance limits remyelination in the aged central nervous system.

Author information

1
Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
2
Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
3
Institute of Neuronal Cell Biology, Technical University Munich, 80805 Munich, Germany.
4
German Center for Neurodegenerative Disease (DZNE), 81377 Munich, Germany.
5
Department of Neurology, University of Göttingen Medical Center, 37075 Göttingen, Germany.
6
Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37075 Göttingen, Germany.
7
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
8
Light Microscopy Facility, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
9
Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53127 Bonn, Germany.
10
Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany. msimons@gwdg.de.

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.

PMID:
29301957
DOI:
10.1126/science.aan4183
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center