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

Divya D. A. Raj, Dick Jaarsma, Inge R. Holtman, Marta Olah, Filipa M. Ferreira, Wandert Schaafsma, Nieske Brouwer, Michel M. Meijer, Monique C. de Waard, Ingrid van der Pluijm, Renata Brandt, Karim L. Kreft, Jon D. Laman, Gerald de Haan, Knut P. H. Biber, Jan H. J. Hoeijmakers, Bart J. L. Eggen, Hendrikus W. G. M. Boddeke*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)2147-2160
Number of pages14
JournalNeurobiology of Aging
Volume35
Issue number9
DOIs
Publication statusPublished - Sep-2014

Keywords

  • 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

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