期刊
NEUROBIOLOGY OF AGING
卷 35, 期 9, 页码 2147-2160出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2014.03.025
关键词
Microglia; Priming; Aging; DNA damage; Phagocytosis; Neuroinflammation; Neuron-glia interaction; Hyperactivation
资金
- NWO [40-00506-98-9021, 175-010-2009-023]
- European commission FP7 Markage [FP7-Health-2008-200880]
- National Institute of Health (NIH)/National Institute of Aging (NIA) [1PO1 AG-17242-02]
- NIEHS [1UO1 ES011044]
- Royal Academy of Arts and Sciences of the Netherlands
- European Research Council Advanced Grant
- European Community's Seventh Framework Programme (FP7) [HEALTH-F2-2010-259893]
- Mouse Clinic for Cancer and Aging through a RoadMap grant from the Netherlands Organization for Scientific Research (NWO)
- Dutch MS Research Foundation
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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