Defective cholesterol clearance limits remyelination in the aged central nervous system

被引：402

作者：

Cantuti-Castelvetri, Ludovico ^{[1
,2
,3
,4
]}

Fitzner, Dirk ^{[1
,5
]}

Bosch-Queralt, Mar ^{[1
,2
,3
,4
]}

Weil, Marie-Theres ^{[1
,6
]}

Su, Minhui ^{[1
,2
,3
,4
]}

Sen, Paromita ^{[1
]}

Ruhwedel, Torben ^{[7
]}

Mitkovski, Miso ^{[8
]}

Trendelenburg, George ^{[5
]}

Luetjohann, Dieter ^{[9
]}

Moebius, Wiebke ^{[6
,7
]}

Simons, Mikael ^{[1
,2
,3
,4
]}

机构：

[1] Max Planck Inst Expt Med, D-37075 Gottingen, Germany

[2] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany

[3] Tech Univ Munich, Inst Neuronal Cell Biol, D-80805 Munich, Germany

[4] German Ctr Neurodegenerat Dis DZNE, D-81377 Munich, Germany

[5] Univ Gottingen, Dept Neurol, Med Ctr, D-37075 Gottingen, Germany

[6] Ctr Nanoscale Microscopy & Mol Physiol Brain CNMP, D-37075 Gottingen, Germany

[7] Max Planck Inst Expt Med, Dept Neurogenet, D-37075 Gottingen, Germany

[8] Max Planck Inst Expt Med, Light Microscopy Facil, D-37075 Gottingen, Germany

[9] Univ Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany

来源：

SCIENCE | 2018年 / 359卷 / 6376期

基金：

欧洲研究理事会;

关键词：

LIVER X RECEPTORS; MULTIPLE-SCLEROSIS; CNS REMYELINATION; APOLIPOPROTEIN-E; DIFFERENTIATION; MACROPHAGES; MICROGLIA; CELLS;

D O I：

10.1126/science.aan4183

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：684 / 688

页数：5

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