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

DDA Raj; Dick Jaarsma; IR Holtman; M Olah; F Marques Ferreira; W Schaafsma; N Brouwer; MMC Meijer; Monique Waard; Ingrid van der Pluijm; Renata Brandt; Karim Kreft; Jon Laman; G de Haan; KPH Biber; Jan Hoeijmakers; BJL Eggen; HWGM Boddeke

doi:10.1016/j.neurobiolaging.2014.03.025

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

DDA Raj, Dick Jaarsma, IR Holtman, M Olah, F Marques Ferreira, W Schaafsma, N Brouwer, MMC Meijer, Monique Waard, Ingrid van der Pluijm, Renata Brandt, Karim Kreft, Jon Laman, G de Haan, KPH Biber, Jan Hoeijmakers, BJL Eggen, HWGM Boddeke

Research output: Contribution to journal › Article › Academic › peer-review

92 Citations (Scopus)

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 language	Undefined/Unknown
Pages (from-to)	2147-2160
Number of pages	14
Journal	Neurobiology of Aging
Volume	35
Issue number	9
DOIs	https://doi.org/10.1016/j.neurobiolaging.2014.03.025
Publication status	Published - 2014

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10.1016/j.neurobiolaging.2014.03.025

http://hdl.handle.net/1765/72715

Cite this

Raj, DDA., Jaarsma, D., Holtman, IR., Olah, M., Marques Ferreira, F., Schaafsma, W., Brouwer, N., Meijer, MMC., Waard, M., van der Pluijm, I., Brandt, R., Kreft, K., Laman, J., de Haan, G., Biber, KPH., Hoeijmakers, J., Eggen, BJL., & Boddeke, HWGM. (2014). Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiology of Aging, 35(9), 2147-2160. https://doi.org/10.1016/j.neurobiolaging.2014.03.025

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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. (C) 2014 Elsevier Inc. All rights reserved.",

author = "DDA Raj and Dick Jaarsma and IR Holtman and M Olah and {Marques Ferreira}, F and W Schaafsma and N Brouwer and MMC Meijer and Monique Waard and {van der Pluijm}, Ingrid and Renata Brandt and Karim Kreft and Jon Laman and {de Haan}, G and KPH Biber and Jan Hoeijmakers and BJL Eggen and HWGM Boddeke",

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Raj, DDA, Jaarsma, D, Holtman, IR, Olah, M, Marques Ferreira, F, Schaafsma, W, Brouwer, N, Meijer, MMC, Waard, M , van der Pluijm, I , Brandt, R, Kreft, K, Laman, J, de Haan, G, Biber, KPH, Hoeijmakers, J, Eggen, BJL & Boddeke, HWGM 2014, 'Priming of microglia in a DNA-repair deficient model of accelerated aging', Neurobiology of Aging, vol. 35, no. 9, pp. 2147-2160. https://doi.org/10.1016/j.neurobiolaging.2014.03.025

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T1 - Priming of microglia in a DNA-repair deficient model of accelerated aging

AU - Raj, DDA

AU - Jaarsma, Dick

AU - Holtman, IR

AU - Olah, M

AU - Marques Ferreira, F

AU - Schaafsma, W

AU - Brouwer, N

AU - Meijer, MMC

AU - Waard, Monique

AU - van der Pluijm, Ingrid

AU - Brandt, Renata

AU - Kreft, Karim

AU - Laman, Jon

AU - de Haan, G

AU - Biber, KPH

AU - Hoeijmakers, Jan

AU - Eggen, BJL

AU - Boddeke, HWGM

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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DO - 10.1016/j.neurobiolaging.2014.03.025

M3 - Article

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