[en] Alzheimer's disease (AD) is a neurodegenerative condition that leads to neuronal death and memory dysfunction. 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 isoforms (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) expression to similar extent and did not affect ApoE expression. Finally, GFT1803 increased insulin-degrading enzyme expression. Analysis of spatial memory formation in the Morris water maze demonstrated that both compounds were able to partially revert the phenotype of APP/PS1 mice in comparison to wild-type mice with GFT1803 being most effective. As compared to pioglitazone, GFT1803 (pan-PPAR agonist) produced 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.
Disciplines :
Neurology
Author, co-author :
Kummer, Markus P; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany
Schwarzenberger, Rafael; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany
Sayah-Jeanne, Sakina; Genfit, Parc Eurasante, Loos, France
Dubernet, Mathieu; Genfit, Parc Eurasante, Loos, France
Walczak, Robert; Genfit, Parc Eurasante, Loos, France
Hum, Dean W; Genfit, Parc Eurasante, Loos, France
Schwartz, Stephanie; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany
Axt, Daisy; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany
HENEKA, Michael ; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases, Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Pan-PPAR modulation effectively protects APP/PS1 mice from amyloid deposition and cognitive deficits.
The E7 antibody developed by M. Klymkowsky was obtained from the Developmental Studies Hybridoma Bank. This study was supported by the Deutsche Forschungsgemeinschaft (KFO177, TP4) to MTH and by grants of the INMiND project of the European Union. MTH is member of the DFG Cluster of Excellence ImmunoSensation.Sakina Sayah-Jeanne, Mathieu Dubernet, Robert Walczak, and Dean W. Hum are employees of GENFIT SA. This study was in part sponsored by GENFIT SA.
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