Cyclooxygenase 2 RNA message abundance, stability, and hypervariability in sporadic Alzheimer neocortex

Long-term treatment by nonsteroidal anti-inflammatory drugs has been shown to decrease the incidence of Alzheimer's disease (AD). Both platelet-activating factor and interleukin-1beta, potent mediators of the inflammatory and immune response, strongly induce transcription of the cyclooxygenase-2 (COX-2) gene in brain cells. Using Northern and RT-PCR analysis, we have determined in 15 control and 10 sporadic AD human neocortical samples (age range, 60-82 yr; postmortem interval [PMI] range, 0.7-16.0 hr) the levels of COX-2 RNA in relation to the constitutively expressed COX-1 and beta-actin RNA message levels. Our results indicate that in short PMI brain, COX-1 and COX-2 transcripts are relatively low abundance RNA messages, ranging from a mean of 6.8% of the beta-actin signal in controls to 8.5% of the beta-actin signal in AD-affected brain. A large variation in the signal intensity for COX-2 RNA was noted in both control and AD; although there was a trend for higher COX-2 RNA message abundance in AD neocortex to +11.5% of that of controls, it did not reach statistical significance (ANOVA = 0.45). Several human tissues, including heart, skeletal muscle, lung, kidney, and spinal cord, displayed 4.6- and 2.8-kb COX-2 RNA message isoforms; however, the 4.6-kb COX-2 RNA predominated in the hippocampus and association neocortex. COX-2 RNA message was found to be degraded at similar rates in both control and AD tissues, and a strong positive correlation between the PMI and the intensity of the COX-2 RNA signal was noted (ANOVA = 0.006). Linear regression analysis indicated that the 4.6-kb COX-2 RNA is an unstable short-lived RNA species with a half-life of not more than 3.5 hr, a feature characteristic of immediate early gene transcripts. Individual hypervariability in COX-2 RNA message abundance may reflect various degrees of expression of AD-related inflammatory processes.