Journal Article

DZNE-2020-06118

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Defective cholesterol clearance limits remyelination in the aged central nervous system.

Cantuti-Castelvetri, L. (First author)DZNE* ; Fitzner, D. ; Bosch-Queralt, M.DZNE* ; Weil, M.-T. ; Su, M.DZNE* ; Sen, P. ; Ruhwedel, T. ; Mitkovski, M. ; Trendelenburg, G. ; Lütjohann, D. ; Möbius, W. ; Simons, M. (Last author)DZNE*

2018
Assoc.60841 Washington, DC

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Please use a persistent id in citations: doi:10.1126/science.aan4183

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.

Keyword(s): Aging: metabolism (MeSH) ; Aging: physiology (MeSH) ; Animals (MeSH) ; Apolipoproteins E: genetics (MeSH) ; Apolipoproteins E: metabolism (MeSH) ; Central Nervous System: metabolism (MeSH) ; Central Nervous System: physiology (MeSH) ; Cholesterol: metabolism (MeSH) ; Crystallization (MeSH) ; Demyelinating Diseases: metabolism (MeSH) ; Lysosome-Associated Membrane Glycoproteins: metabolism (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Myelin Sheath: metabolism (MeSH) ; Myelin Sheath: pathology (MeSH) ; Phagocytes: metabolism (MeSH) ; Remyelination (MeSH) ; Apolipoproteins E ; Lamp1 protein, mouse ; Lysosome-Associated Membrane Glycoproteins ; Cholesterol

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Contributing Institute(s):

1. Molecular Neurobiology (AG Simons)

Research Program(s):

1. 341 - Molecular Signaling (POF3-341) (POF3-341)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF >= 60 ; JCR ; SCOPUS ; Web of Science Core Collection ; Zoological Record

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