Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 34, Pages 8624-8634Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1957-08.2008
Keywords
mitochondria DNA; transcription factor A; oxidative stress; aging; memory impairment; microglia
Categories
Funding
- Ministry for Education, Science, and Culture, Japan
- Comprehensive Research in Aging and Health Labor and Welfare of Japan
- Uehara Research Foundation
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Mitochondrial DNA (mtDNA) is highly susceptible to injury induced by reactive oxygen species (ROS). During aging, mutations of mtDNA accumulate to induce dysfunction of the respiratory chain, resulting in the enhanced ROS production. Therefore, age-dependent memory impairment may result from oxidative stress derived from the respiratory chain. Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. We herein report that an overexpression of TFAM in HeLa cells significantly inhibited rotenone-induced mitochondrial ROS generation and the subsequent NF-kappa B (nuclear factor-kappa B) nuclear translocation. Furthermore, TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain. In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1 beta(IL-1 beta) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. The IL-1 beta amount markedly increased in the brain of the TG mice after treatment with lipopolysaccharide (LPS), whereas its mean amount was significantly lower than that of the LPS-treated aged wild-type mice. At the same time, an increased mtDNA damage in microglia and an impaired hippocampal LTP were also observed in the LPS-treated aged TG mice. Together, an overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia.
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