title: Priming of microglia in a DNA-repair deficient model of accelerated aging.
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.
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Divya D A
authors.initials: DD
authors.lastname: Raj
authors.affiliation: Department of Neuroscience, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Jaarsma
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Inge R
authors.initials: IR
authors.lastname: Holtman
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Marta
authors.initials: M
authors.lastname: Olah
authors.affiliation: Department of Neuroscience, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Filipa M
authors.initials: FM
authors.lastname: Ferreira
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Wandert
authors.initials: W
authors.lastname: Schaafsma
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Nieske
authors.initials: N
authors.lastname: Brouwer
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Michel M
authors.initials: MM
authors.lastname: Meijer
authors.affiliation: Department of Genetics, Cancer Genomics Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.affiliation: Department of Genetics, Cancer Genomics Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
authors.affiliation: Department of Genetics, Cancer Genomics Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Renata
authors.initials: R
authors.lastname: Brandt
authors.affiliation: Department of Immunology, Erasmus University Medical Center and MS Center ErasMS, Rotterdam, the Netherlands; Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Karim L
authors.initials: KL
authors.lastname: Kreft
authors.affiliation: Department of Immunology, Erasmus University Medical Center and MS Center ErasMS, Rotterdam, the Netherlands.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.affiliation: Department of Cell Biology, European Research Institute on the Biology of Aging, University of Groningen, University Medical Center, Groningen, the Netherlands.
authors.forename: Gerald
authors.initials: G
authors.lastname: de Haan
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Psychiatry and Psychotherapy, University Medical Center, Freiburg, Germany.
authors.forename: Knut P H
authors.initials: KP
authors.lastname: Biber
authors.affiliation: Department of Genetics, Cancer Genomics Center, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: h.w.g.m.boddeke@umcg.nl.
authors.forename: Hendrikus W G M
authors.initials: HW
authors.lastname: Boddeke
mesh_terms: D000375:Aging / Q000473:pathology*; D019588:Aging, Premature / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D004720:Endonucleases / Q000235:genetics; D007249:Inflammation / Q000473:pathology*; D008070:Lipopolysaccharides; D008817:Mice, Mutant Strains; D017628:Microglia / Q000473:pathology*; D009154:Mutation; D010587:Phagocytosis; D016548:Prosencephalon / Q000473:pathology
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D004720:Endonucleases; C499360:Ercc1 protein, mouse
keywords: Aging; DNA damage; Hyperactivation; Microglia; Neuroinflammation; Neuron-glia interaction; Phagocytosis; Priming