DNA damage and apoptosis in Alzheimer's disease: colocalization with c-Jun immunoreactivity, relationship to brain area, and effect of postmortem delay.
Many neurons in Alzheimer's disease (AD) exhibit terminal deoxynucleotidyl transferase (TdT) labeling for DNA strand breaks with a distribution suggestive of apoptosis. We have shown previously that immunoreactivity for c-Jun is elevated in AD and found in association with neuronal pathology. In addition, cultured neurons undergoing beta-amyloid-mediated apoptosis exhibit a selective and prolonged induction of c-Jun. Consequently, we conducted double-labeling experiments to examine whether c-Jun is associated with DNA strand breaks in AD tissue; we observed a strong colocalization between these markers. As would be predicted based on the distribution of AD pathology, we also found that TdT labeling was prominent in the entorhinal cortex, but absent or at very low levels in cerebellum. Furthermore, we confirmed that postmortem delay (PMD) does not affect TdT labeling within the limits used for tissue used in this study. However, in contrast to previous studies, we report an increase in TdT labeling with more extended PMDs. Finally, gel electrophoresis of genomic DNA isolated from AD and control cases failed to reveal evidence for either an apoptotic or a necrotic mechanism of cell death in AD, possibly because of a low number of cells actually undergoing cell death at any given time. Our findings support the hypothesis that DNA damage labeled using TdT reflects neuronal vulnerability and cell loss associated with AD pathology, and that at least a portion of the cells labeled with this technique is undergoing apoptosis. Furthermore, in agreement with in vitro findings, these results suggest a relationship between the expression of c-Jun and neuronal risk and/or cell death in AD.
Anderson
A J
AJ
Institute for Brain Aging and Dementia, University of California, Irvine 92717-4550, USA.
Su
J H
JH
Cotman
C W
CW
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D017209:Apoptosis; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D004249:DNA Damage; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D004586:Electrophoresis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012016:Reference Values; D013997:Time Factors; D014018:Tissue Distribution
D016755:Proto-Oncogene Proteins c-jun; D004253:DNA Nucleotidylexotransferase