Journal
SCIENCE
Volume 359, Issue 6376, Pages 684-688Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aan4183
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Funding
- European Research Council (ERC) Consolidator Grant
- German Research Foundation (DFG) [SI 746/9-1, SI 746/10-1, SPP1757, TRR128, TRR43]
- Klaus Tschira Stiftung
- Adelson Foundation
- Excellence Cluster for Systems Neurology (SyNergy)
- Excellence Cluster for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)
- ERC grant
- Boehringer Ingelheim stipend
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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.
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