Neuronal DNA damage correlates with overexpression of interleukin-1beta converting enzyme in APPV717F mice

Transgenic APPV717F mice, homozygous for a human minigene encoding the V717F familial Alzheimer's disease mutation, develop Abeta plaques similar to those seen in Alzheimer patients and show evidence of neuronal cell drop out in CA2-3 regions of the hippocampus at 8 months of age and older. Interleukin-1 (IL-1)beta (IL-1beta) converting enzyme (ICE) is a cysteine protease (caspase-1) that processes inactive (33 kDa) pro-IL-1beta to the active (17 kDa) inflammatory cytokine. We used immunohistochemistry, RT-PCR, and DNA cleavage (TUNEL) analysis to show progressive, age-associated increases in ICE mRNA levels, in the numbers of ICE-immunoreactive glia, and in the numbers of neurons showing evidence of DNA damage in APPV717F mice that commenced months prior to the appearance of Abeta plaques. Moreover, there were significant correlations between these parameters over an age range of 1-17 months. These findings are consistent with the idea that increases in ICE activity and expression contribute to neuronal injury in Alzheimer's disease.