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The Journal of Neuroscience, August 20, 2008, 28(34):8624-8634; doi:10.1523/JNEUROSCI.1957-08.2008

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Behavioral/Systems/Cognitive
Reverse of Age-Dependent Memory Impairment and Mitochondrial DNA Damage in Microglia by an Overexpression of Human Mitochondrial Transcription Factor A in Mice

Yoshinori Hayashi,^1 * Masayoshi Yoshida,^2,4 * Mayumi Yamato,^3 * Tomomi Ide,² Zhou Wu,¹ Mayumi Ochi-Shindou,¹ Tomotake Kanki,⁴ Dongchon Kang,⁴ Kenji Sunagawa,² Hiroyuki Tsutsui,⁵ and Hiroshi Nakanishi¹

¹Laboratory of Oral Aging Science, Faculty of Dental Sciences, ²Department of Cardiovascular Medicine, Graduate School of Medical Sciences, ³Department of REDOX Medicinal Science, Graduate School of Pharmaceutical Sciences, ⁴Department of Clinical Chemistry and Laboratory Medicine, Kyushu University, Fukuoka 812-8582, Japan, and ⁵Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan

Correspondence should be addressed to either of the following: Dr. Tomomi Ide, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Email: tomomi_i{at}cardiol.med.kyushu-u.ac.jp; or Dr. Hiroshi Nakanishi, Laboratory of Oral Aging Science, Faculty of Dental Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Email: nakan{at}dent.kyushu-u.ac.jp

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-B (nuclear factor-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-1β (IL-1β) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. The IL-1β 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.

Key words: mitochondria DNA; transcription factor A; oxidative stress; aging; memory impairment; microglia

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Received March 3, 2008; revised July 7, 2008; accepted July 15, 2008.

Correspondence should be addressed to either of the following: Dr. Tomomi Ide, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Email: tomomi_i{at}cardiol.med.kyushu-u.ac.jp; or Dr. Hiroshi Nakanishi, Laboratory of Oral Aging Science, Faculty of Dental Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan, Email: nakan{at}dent.kyushu-u.ac.jp

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