Yusaku Nakabeppu and Sugako Oka
Scientific Tracks Abstracts: J Neurol Neurophysiol
Mitochondrial dysfunction is considered to have a pivotal role for developing Alzheimer?s disease (AD). Accumulation of Amyloid β (Aβ) in neurons induces mitochondrial dysfunction and reactive oxygen species (ROS) production. It has been reported that 8-oxoguanine (8-oxoG), one of the major oxidation products in DNA/RNA and nucleotides, accumulates in AD brain. Oxidative DNA damage especially in mitochondria can lead to synaptic dysfunction and neuronal loss, and thereby causing neurodegenation. In the present study, we examined effects of human mitochondrial transcriptional factor A (hTFAM) transgene on the pathology of a mouse model of AD (3xTg-AD) harboring PS1M146V, APP (Swe), and MAPT (P301L) transgenes. TFAM is now known to contribute not only in transcription of mitochondrial DNA but also its maintenance, and thus protecting mitochondria from oxidative stress. In the Morris Water Maze test, 13-month-old 3xTg-AD hemizygous mice carrying hemizygoush TFAM transgene exhibited significant improvement of learning and memory deficit compared to 3xTg-AD hemizygous mice. Accumulation of Aβ was markedly decreased in cerebral cortices and hippocampi of the 3xTg- AD/hTFAM mice. Moreover, 3xTg-AD/hTFAM mice exhibited much less 8-oxo-dG immunoreactivity in cerebral cortices and hippocampi in comparison to 3xTg-AD mice which accumulated higher level of 8-oxo-dG. To clarify the mechanism of improvement of AD phenotype by hTFAM, we are currently performing gene expression profiling using hippocampal RNA prepared from these animals. These results will provide the new insight to understand the molecular mechanisms of AD pathology and possible new strategies for the therapy of AD.
Yusaku Nakabeppu is a Professor at the Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Japan. He is now serving as the Director of Research Center for Nucleotide Pool, Kyushu University. He graduated from Graduate School of Sciences, Kyushu University, with a Doctor of Science degree in 1984. He has performed Postdoctoral work at Johns Hopkins University School of Medicine from 1987 to 1990. In 1997, he was appointed as a Professor at the Medical Institute of Bioregulation, Kyushu University, and was elected as a Distinguished Professor at Kyushu University in 2010.