Further supporting the possible benefits of targeting PPARδ in the treatment of AD, administration of GW0742 significantly reduced amyloid plaque burden in the subiculum of 5xFAD mice. These mice overexpress the amyloid precursor protein and presenilin 1, display plaques and inflammation, and develop neuronal damage and cognitive impairment. Interestingly, the decrease in amyloid burden in GW0742 treated 5xFAD mice was associated with increased expression of neprilysin, an amyloid-degrading enzyme. Furthermore, GW0742 could activate a neprilysin promoter driving luciferase expression in vitro. GW0742 also led to a decrease in astrocyte activation in the 5xFAD mice, as assessed by GFAP staining [22].
