- One of the first cognitive dysfunctions to arise with aging is memory loss, affecting an estimated 85% of elderly in the U.S. over the age of 80 with Age Associated Memory Impairment. A common feature in humans and animals experiencing memory loss with aging is the decline in N-methyl-D-aspartate (NMDA) receptorbinding densities in the brain. Variability in the effects of aging on the GluN1 subunit suggests that inflammation may play a role in NMDA receptor aging. The purpose of the present study was to determine the effects of an anti-inflammatory drug, ibuprofen, on spatial long-term & short-term memory and cognitive flexibility in male C57BL/6 mice from four different age groups (5, 14, 20, and 26 months of age at the end of testing). Mice were fed either Ibuprofen (375 ppm) in NIH31 diet or NIH31 diet alone for 6 weeks prior to testing. This dose had been shown to reduce pathology in an Alzheimer’s disease mouse model. Behavioral testing using the Morris Water Maze showed a significant effect of age on acquisition of spatial reference memory, the formation of spatial memory bias in probe trials, cognitive flexibility in reversal trials, and working memory, with 20 and 26 month old mice performing significantly worse than 5 month old mice. Ibuprofen enhanced overall performance in the working memory task when data was collapsed across naïve and test trials and ages. The oldest mice receiving ibuprofen showed significantly better delayed working memory, but near significantly (p=0.08) worse spatial reference memory, as compared to age-matched controls. In situ hybridization assays showed significant decreases over all ages in the mRNA densities for the GluN2B subunit, all GluN1 splice variants, and the GluN1-1 splice forms in the frontal lobes of mice consuming ibuprofen. The GluN1-3 splice form mRNA was significantly increased across ages in the frontal lobes of the ibuprofen-treated mice. There was no effect of ibuprofen on IL-1beta expression in the brains or spleens of these mice. These findings suggest that inflammation may play a role in working memory declines in aged animals, but the reducing effects of ibuprofen across ages on several factors, without reducing age-related increases in cytokine expression suggests that ibuprofen has effects on mRNA for the NMDA receptor that are unrelated to aging or inflammation.