DNA damage and apoptosis in Alzheimer's disease: colocalization with c- Jun immunoreactivity, relationship to brain area, and effect of postmortem delay

Abstract

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.

Connecting TNF-α Signaling Pathways to iNOS Expression in a Mouse Model of Alzheimer's Disease: Relevance for the Behavioral and Synaptic Deficits Induced by Amyloid β Protein

“…In the present study, we demonstrate that A␤ 1-40 produced a rapid and sustained activation of JNK and its target c-Jun, via mechanisms possibly dependent on TNF-␣. These results are consistent with previous reports indicating that JNK pathways are activated in the AD brain (Anderson et al, 1996;Zhu et al, 2001). …”

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

“…However, the specificity of TUNEL for apoptosis is questionable (Portera-Cailliau et al, 1995;Anderson et al, 1996). Our data show that fragmented nuclei resulting from apoptosis are inevitably labeled with TUNEL, whereas the necrotic nuclei resulting from excitotoxicity become TUNEL-positive during the postmortem time period.…”

“…Consistent with the notion that apoptosis is a gene-directed self-destruction program, alterations in gene expression are associated with apoptosis (for review, see Bredesen, 1995). Recent studies suggest that apoptosis contributes to neuronal cell death after cerebral ischemia (Nitatori et al, 1995;Chopp and Li, 1996;Du et al, 1996), in Alzheimer's disease (Cotman and Anderson, 1995;Lassmann et al, 1995;Anderson et al, 1996), and in Huntington's disease (Portera-Cailliau et al, 1995).…”

Microglial activation by uptake of fDNA via a scavenger receptor

“…Increasing data suggest that such neurons, undergoing cell death either by a form of apoptosis or necrosis, manifest significant DNA fragmentation (Anderson et al, 1996;Sheng et al, 1998b;Smale et al, 1995;Velez-Pardo et al, 2001). The number of neurons having fragmented DNA (fDNA) correlates with the formation of neurofibrillary tangles in those neurons (Sheng et al, 1998b).…”