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The Journal of Neuroscience, March 15, 1999, 19(6):1959-1964
RNA Oxidation Is a Prominent Feature of Vulnerable Neurons in Alzheimer's Disease
Akihiko Nunomura1, 2, George Perry1, Miguel A. Pappolla3, Ramon Wade1, Keisuke Hirai1, 4, Shigeru Chiba2, and Mark A. Smith1 1 Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, 2 Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa 078-8510, Japan, 3 Department of Pathology, University of South Alabama, Mobile, Alabama 36617, and 4 Pharmaceutical Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Limited, Osaka 532-8686, Japan
In this study we used an in situ approach to identify the oxidized nucleosides 8-hydroxydeoxyguanosine (8OHdG) and 8-hydroxyguanosine (8OHG), markers of oxidative damage to DNA and RNA, respectively, in cases of Alzheimer's disease (AD). The goal was to determine whether nuclear and mitochondrial DNA as well as RNA is damaged in AD. Immunoreactivity with monoclonal antibodies 1F7 or 15A3 recognizing both 8OHdG and 8OHG was prominent in the cytoplasm and to a lesser extent in the nucleolus and nuclear envelope in neurons within the hippocampus, subiculum, and entorhinal cortex as well as frontal, temporal, and occipital neocortex in cases of AD, whereas similar structures were immunolabeled only faintly in controls. Relative density measurement showed that there was a significant increase (p < 0.0001) in 8OHdG and 8OHG immunoreactivity with 1F7 in cases of AD (n = 22) as compared with senile (n = 13), presenile (n = 10), or young controls (n = 4). Surprisingly, the oxidized nucleoside was associated predominantly with RNA because immunoreaction was diminished greatly by preincubation in RNase but only slightly by DNase. This is the first evidence of increased RNA oxidation restricted to vulnerable neurons in AD. The subcellular localization of damaged RNA showing cytoplasmic predominance is consistent with the hypothesis that mitochondria may be a major source of reactive oxygen species that cause oxidative damage in AD.
Key words: Alzheimer's disease; oxidative stress; RNA oxidation; DNA oxidation; 8-hydroxyguanosine; 8-hydroxydeoxyguanosine; mitochondrial damage
Copyright © 1999 Society for Neuroscience 0270-6474/99/1961959-06$05.00/0
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