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The role of microglial mtDNA damage in age-dependent prolonged LPS-induced sickness behavior

Published online by Cambridge University Press:  28 October 2011

Hiroshi Nakanishi ,
Yoshinori Hayashi  and
Zhou Wu
Hiroshi Nakanishi*
Affiliation:
Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan
Yoshinori Hayashi
Affiliation:
Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan
Zhou Wu
Affiliation:
Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan
*
Correspondence should be addressed to: Hiroshi Nakanishi, Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan phone: (+81)-92-642-6413 email: [email protected]
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Abstract

Microglia are the main cellular source of oxidation products and inflammatory molecules in the brain during aging. The accumulation of mitochondrial DNA (mtDNA) oxidative damage in microglia during aging results in the increased production of reactive oxygen species (ROS). The increased intracellular ROS, in turn, activates a redox-sensitive nuclear factor-κB (NF-κB) to provoke excessive neuroinflammation, resulting in memory deficits and the prolonged behavioral consequence of infection. Besides its role in regulating the gene copy number, mitochondrial transcription factor A (TFAM) is closely associated with the stabilization of mtDNA structures. Lipopolysaccharide (LPS) induces the generation of ROS from the actively respirating mitochondria as well as NADPH oxidase, and leads to the subsequent activation of the NF-κB-dependent inflammatory pathway in aging microglia. The overexpression of human TFAM improves the age-dependent prolonged LPS-induced sickness behaviors by ameliorating the mtDNA damage and reducing the resultant redox-regulated inflammatory responses. Therefore, ‘microglia-aging’ plays important roles in the age-dependent enhanced behavioral consequences of infection.

Keywords

Brain agingmicroglial agingmitochontrial transcription factor Areactive oxygen speciessickness behavior
Type
Research Article
Information
Neuron Glia Biology , Volume 7 , Special Issue 1: The Physiological Function of Microglia , February 2011 , pp. 17 - 23
Copyright
Copyright © Cambridge University Press 2012

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