Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

<p>Abstract</p> <p>Background</p> <p>Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified <it>R</it>-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic <it>R</it>-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice.</p> <p>Results</p> <p>A four-month preventative treatment regimen with <it>R</it>-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of <it>R</it>-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning.</p> <p>Conclusion</p> <p>We have found that chronic administration of <it>R</it>-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its ability to selectively target Aβ42 production and improve cognitive impairments in transgenic APP mice, as well as promising data from a phase 2 human clinical trial, future studies are needed to investigate the utility of <it>R</it>-flurbiprofen as an AD therapeutic and its possible mechanisms of action.</p

Emergence of a Cue Strategy Preference on the Water Maze Task in Aged C57B6 × SJL F1 Hybrid Mice

The effects of age on cue learning, spatial reference memory, and strategy preference were assessed in B6 × SJL F1 mice by using the Morris water maze. This mouse strain is of particular interest because it is the background strain for a common transgenic model of Alzheimer's disease, the Tg2576 mouse, which develops plaques and other neurobiological markers of pathology beginning at 8 mo and increasing in severity with advanced age. In the current study, 12- and 23-mo-old C57B6 × SJL F1 mice were serially trained in cue and place versions of the Morris water maze task. At the completion of training, mice received a strategy probe test in which place (hidden) and cue (visible) strategies were in competition. Cue and spatial learning ability was maintained between 12 and 23 mo of age; however, on the strategy preference probe test, the 23-mo-old mice exhibited a significant bias toward the selection of a cue strategy. There was no relationship between strategy preference in the probe test and spatial learning ability, but the 23-mo-old mice did exhibit a strong trend toward shorter latencies during visible platform training, possibly reflecting the enhanced function of striatal-based neural systems in aging. These data demonstrate that 23-mo-old C57B6 × SJL F1 mice are capable of effective place learning, but if a place strategy is pitted against the use of a cue strategy, the use of a cue strategy predominates in the aged mice. The strategy preference observed here may reflect an emergence of differential processing in underlying brain circuitry with age in the B6 × SJL F1 mouse strain

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice-0

<p><b>Copyright information:</b></p><p>Taken from "Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice"</p><p>BMC Neuroscience 2007;8():54-54.</p><p>Published online 24 Jul 2007</p><p>PMCID:PMC1948891.</p><p></p>formance of any of the groups. 1B shows the search error during the acquisition of the spatial reference memory task. The 2-week -flurbiprofen-treated mice (Therapeutic group) performed more poorly than the other groups (Preventative group) on days 4, 7, 8, 9 and 10. 1C shows that only the Tg2576 mice treated for 16 weeks (Preventative group) with -flurbiprofen developed a spatial bias for the training quadrant. 1D shows representative swim paths of the Control and the Preventative groups during Probe Trial 3. Note that the -flurbiprofen-treated mice focus their search in the training quadrant that contained the hidden escape platform (bottom left quadrant). 1E shows the percent of subjects that preferred using a cue or place strategy during the strategy competition. 80% of the Tg2576 mice in the Preventative group preferred using a place strategy compared to only 30% of the Control and 31% of the Therapeutic group (Chi-square = 11.23, p < .01)

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice-1

<p><b>Copyright information:</b></p><p>Taken from "Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice"</p><p>BMC Neuroscience 2007;8():54-54.</p><p>Published online 24 Jul 2007</p><p>PMCID:PMC1948891.</p><p></p> mice from the three water mazes are plotted as percent control. The mean Aβ levels +/- the standard error from control mice are shown below each graph. The absolute values (pmoles/gram tissue) of formic acid soluble Aβ40 and Aβ42 levels from individual animals are plotted against one another to show the distribution of individual animals from experimental groups. "Preventative 1 and Preventative 2" refers to two different experiments examining the effects of 4 months of administration of -flurbiprofen to Tg2576 mice. "Therapeutic" refers to 2 weeks administration of -flurbiprofen

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice-2

<p><b>Copyright information:</b></p><p>Taken from "Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice"</p><p>BMC Neuroscience 2007;8():54-54.</p><p>Published online 24 Jul 2007</p><p>PMCID:PMC1948891.</p><p></p>crifice) were stained for Aβ plaques using antibody 33.1.1 (A) and thioflavin (B). In (C), the level of Aβ plaque burden (quantified as % Aβ immunoreactive area) in Control compared to R-flurbiprofen treated-Tg2576 mice from Experiments 2 and 3 are compared. Note the significant reduction in plaque burden in the R-flurbiprofen treated mice from Experiment 3 (*** p < 0.0001)