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The Journal of Neuroscience, May 1, 2001, 21(9):3017-3023
Mitochondrial Abnormalities in Alzheimer's Disease
Keisuke Hirai1, 4, Gjumrakch Aliev2, Akihiko Nunomura1, 5, Hisashi Fujioka1, Robert L. Russell1, Craig S. Atwood1, Anne B. Johnson6, Yvonne Kress6, Harry V. Vinters7, Massimo Tabaton8, Shun Shimohama9, Adam D. Cash1, Sandra L. Siedlak1, Peggy L. R. Harris1, Paul K. Jones3, Robert B. Petersen1, George Perry1, and Mark A. Smith1 1 Institute of Pathology, 2 Department of Neurology, and 3 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, 4 Pharmaceutical Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Osaka, 532-8686 Japan, 5 Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa, 078-8510 Japan, 6 Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, 7 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90024, 8 Department of Neuroscience, University of Genova, 16132 Genova, Italy, and 9 Department of Neurology, Kyoto University, Kyoto, 606-8507 Japan
The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we used in situ hybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.
Key words: Alzheimer's disease; free radicals; metabolism; mitochondria; neurodegeneration; oxidative stress
Copyright © 2001 Society for Neuroscience 0270-6474/01/2193017-07$05.00/0
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