Priming of microglia in a DNA-repair deficient model of accelerated aging

被引：108

作者：

Raj, Divya D. A. ^{[1
]}

Jaarsma, Dick ^{[2
]}

Holtman, Inge R. ^{[1
]}

Olah, Marta ^{[1
]}

Ferreira, Filipa M. ^{[2
]}

Schaafsma, Wandert ^{[1
]}

Brouwer, Nieske ^{[1
]}

Meijer, Michel M. ^{[1
]}

de Waard, Monique C. ^{[3
]}

van der Pluijm, Ingrid ^{[3
]}

Brandt, Renata ^{[3
]}

Kreft, Karim L. ^{[4
,5
,6
]}

Laman, Jon D. ^{[4
,5
]}

de Haan, Gerald ^{[7
]}

Biber, Knut P. H. ^{[1
,8
]}

Hoeijmakers, Jan H. J. ^{[3
]}

Eggen, Bart J. L. ^{[1
]}

Boddeke, Hendrikus W. G. M. ^{[1
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, Sect Med Physiol, NL-9713 AV Groningen, Netherlands

[2] Erasmus Univ, Med Ctr, Dept Neurosci, Rotterdam, Netherlands

[3] Erasmus Univ, Med Ctr, Canc Genom Ctr, Dept Genet, Rotterdam, Netherlands

[4] Erasmus Univ, Med Ctr, Dept Immunol, Rotterdam, Netherlands

[5] MS Ctr ErasMS, Rotterdam, Netherlands

[6] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands

[7] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, European Res Inst Biol Aging, NL-9713 AV Groningen, Netherlands

[8] Univ Med Ctr, Dept Psychiat & Psychotherapy, Freiburg, Germany

来源：

NEUROBIOLOGY OF AGING | 2014年 / 35卷 / 09期

基金：

欧洲研究理事会;

关键词：

Microglia; Priming; Aging; DNA damage; Phagocytosis; Neuroinflammation; Neuron-glia interaction; Hyperactivation; COEXPRESSION NETWORK ANALYSIS; NUCLEOTIDE EXCISION-REPAIR; CHRONIC NEURODEGENERATION; DAMAGE RESPONSE; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; OXIDATIVE DAMAGE; GROWTH FAILURE; IMMUNE-SYSTEM; NER PROGERIA;

D O I：

10.1016/j.neurobiolaging.2014.03.025

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

030301 [社会学]; 100201 [内科学];

摘要：

Aging is associated with reduced function, degenerative changes, and increased neuroinflammation of the central nervous system (CNS). Increasing evidence suggests that changes in microglia cells contribute to the age-related deterioration of the CNS. The most prominent age-related change of microglia is enhanced sensitivity to inflammatory stimuli, referred to as priming. It is unclear if priming is due to intrinsic microglia ageing or induced by the ageing neural environment. We have studied this in Ercc1 mutant mice, a DNA repair-deficient mouse model that displays features of accelerated aging in multiple tissues including the CNS. In Ercc1 mutant mice, microglia showed hallmark features of priming such as an exaggerated response to peripheral lipopolysaccharide exposure in terms of cytokine expression and phagocytosis. Specific targeting of the Ercc1 deletion to forebrain neurons resulted in a progressive priming response in microglia exemplified by phenotypic alterations. Summarizing, these data show that neuronal genotoxic stress is sufficient to switch microglia from a resting to a primed state. (C) 2014 Elsevier Inc. All rights reserved.

引用

页码：2147 / 2160

页数：14

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