STAT Signal transducer and activator of transcription-1

Abstract Alzheimer’s disease (AD) is a neurodegenerative condition that leads to neuronal death and memory dysfunc-tion. In the past, specific peroxisome proliferator-activated receptor (PPAR)γ-agonists, such as pioglitazone, have been tested with limited success to improve AD pathology. Here, we investigated the therapeutic efficacy of GFT1803, a novel potent PPAR agonist that activates all the three PPAR iso-forms (α/δ/γ) in the APP/PS1 mouse model in comparison to the selective PPARγ-agonist pioglitazone. Both compounds showed similar brain/plasma partitioning ratios, although whole body and brain exposure to GFT1803 was significantly lower as compared to pioglitazone, at doses used in this study. Oral treatment of APP/PS1 mice with GFT1803 decreased microglial activation, amyloid β (Aβ) plaque area, Aβ levels in sodium dodecyl sulfate- and formic acid-soluble fractions in a concentration-dependent manner. With a single exception of Aβ38 and Aβ40 levels, measured by ELISA, these effects were not observed in mice treated with pioglitazone. Both ligands decreased glial fibrillary acidic protein (GFAP) ex-pression to similar extent and did not affect ApoE expression. Finally, GFT1803 increased insulin-degrading enzyme ex-pression. Analysis of spatial memory formation in the Morris water maze demonstrated that both compounds were able to partially revert the phenotype of APP/PS1mice in comparison to wild-type mice with GFT1803 being most effective. As compared to pioglitazone, GFT1803 (pan-PPAR agonist) pro-duced both quantitatively superior and qualitatively different therapeutic effects with respect to amyloid plaque burden, insoluble Aβ content, and neuroinflammation at significantly lower whole body and brain exposure rates