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Updated: May 28, 2026
Sub-acute Cerebral Microhemorrhages Induced by Lipopolysaccharide Injection in Rats
Published on: October 17, 2018
The role of microglial mtDNA damage in age-dependent prolonged LPS-induced sickness behavior
Hiroshi Nakanishi1, Yoshinori Hayashi, Zhou Wu
1Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan. nakan@dent.kyushu-u.ac.jp
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.
Insights
Aging microglia contribute to neuroinflammation and memory deficits via mitochondrial DNA damage and reactive oxygen species (ROS). Overexpressing TFAM in microglia mitigates these age-related effects, improving behavioral outcomes.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Microglia, the brain's immune cells, are key sources of inflammation and oxidative stress during aging.
- Accumulated mitochondrial DNA (mtDNA) damage in aging microglia elevates reactive oxygen species (ROS) production.
- This ROS surge activates nuclear factor-κB (NF-κB), driving neuroinflammation and cognitive deficits.
Purpose of the Study:
- To investigate the role of mitochondrial transcription factor A (TFAM) in age-related microglial dysfunction.
- To determine if TFAM overexpression can ameliorate lipopolysaccharide (LPS)-induced neuroinflammation and behavioral deficits in aging mice.
Main Methods:
- Assessed mtDNA oxidative damage and ROS levels in aging microglia.
- Examined NF-κB pathway activation following LPS stimulation.
- Evaluated the impact of TFAM overexpression on LPS-induced sickness behaviors and inflammatory responses.
Main Results:
- Aging microglia exhibit increased mtDNA damage and ROS, leading to heightened NF-κB activation and neuroinflammation.
- LPS exacerbates these effects in aged microglia.
- Overexpression of TFAM in microglia reduced mtDNA damage, decreased ROS production, and attenuated LPS-induced inflammatory responses and prolonged sickness behaviors.
Conclusions:
- Microglial aging significantly contributes to age-dependent neuroinflammation and cognitive impairment.
- TFAM plays a crucial role in maintaining mtDNA integrity and regulating redox balance in microglia.
- TFAM represents a potential therapeutic target for mitigating age-related neuroinflammation and its behavioral consequences.
