N ofExp Neurol. Author manuscript; accessible in PMC 2017 June 01.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptDiBattista et al.Pageibuprofen relied on its activity as a COX-2 inhibitor or as a PPAR- agonist, we fed new cohorts of APOE4 mice using the selective COX-2 inhibitor celecoxib, or the PPAR- agonist pioglitazone, determined by previously reported dosages to minimize glial inflammation in an animal model of AD (Heneka et al., 2005; Varvel et al., 2009). Especially, control diets or diets containing 240 ppm pioglitazone were fed to one particular cohort for 1 week (n=6 per group), and yet another cohort was fed manage diets or diets containing 120 ppm celecoxib for 2 months (n=6 per group). Animals were once again euthanized at 6 months of age, and APOE was measured in hippocampal brain extracts. Similar to ibuprofen, pioglitazone therapy resulted within a redistribution of APOE in between TBS and TBSX brain fractions, such that there was a important reduce in the ratio of APOE within the TBS versus TBSX fractions (t=2.076, p=0.032) (Figure 5B, D, F, I). Even though celecoxib treatment didn’t result in a important redistribution of APOE amongst TBS and TBSX fractions, there was a trend toward a lower within the ratio of TBS to TBSX soluble APOE (t=1.87, p=0.09) (Figure 5C, D, G, J). These results recommend that both the COX-2 inhibiting and PPAR- activating actions of ibuprofen are contributing to its effects on APOE expression, and that modifications to both the TBS- and TBSX-soluble APOE fractions are altered by drug treatment options. Ibuprofen and pioglitazone promote dendritic spine density in 6-month-old APOE4 mice APOE4 is related with lowered dendritic spine density in human hippocampus (Ji et al.Formula of 111819-71-7 , 2003), mouse motor cortex (Dumanis et al.1438382-15-0 Price , 2009) and mouse medial entorhinal cortex (MEC) (Rodriguez et al.PMID:24576999 , 2013). APOE4 can also be connected with deficits in grid-cell-like representations inside the entorhinal cortex in young adult humans (Kunz et al., 2015). As a result, as well as measuring brain biochemical phenotypes and their modifications with ibuprofen, we investigated no matter if ibuprofen could also boost dendritic spine density, focusing on the MEC (Figure 6A). Remedy with ibuprofen for 1 week or two months each substantially increased apical oblique (F=29.37, p0.0001; post-hoc, p0.001) (Figure 6B) and basal shaft (F=35.66, p0.0001, post-hoc, p0.001) (Figure 6E) dendritic spine density inside the entorhinal cortex of APOE4 mice in comparison to those treated using a control diet. Therefore, ibuprofen had a significant effect rising total dendritic spine density (F=86.54, p0.0001, post-hoc, p0.001) (Figure 6H). Similarly, pioglitazone also enhanced apical oblique (t=10.73, p0.0001) (Figure 6C) and basal shaft (t=6.642, p0.0006) (Figure 6F) dendritic spine density, causing total dendritic spine density to raise (t=15.75, p0.0001) (Figure 6I). Celecoxib drastically enhanced basal shaft (t=2.604, p=0.04) (Figure 6G), but had no substantial effect on apical oblique (t=0.601, p=0.57) (Figure 6D) or total (t=1.768, p=0.128) (Figure 6J), dendritic spine density. General, these findings recommend that the PPAR- activity of ibuprofen might drive its effects on dendritic spine density more than the COX-2 inhibiting effects of ibuprofen.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptDiscussionAccumulating proof suggests that APOE impacts typical brain function, independent of AD pathology (Caselli et al., 2004; Filippini et al., 200.