Kummer Markus P, Schwarzenberger Rafael, Sayah-Jeanne Sakina, Dubernet Mathieu, Walczak Robert, Hum Dean W, Schwartz Stephanie, Axt Daisy, Heneka Michael T
Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.
Mol Neurobiol. 2015 Apr;51(2):661-71. doi: 10.1007/s12035-014-8743-4. Epub 2014 May 17.
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.
阿尔茨海默病（AD）是一种导致神经元死亡和记忆功能障碍的神经退行性疾病。过去，曾对特定的过氧化物酶体增殖物激活受体（PPAR）γ激动剂，如吡格列酮进行过测试，以改善AD病理，但成效有限。在此，我们研究了GFT1803的治疗效果，GFT1803是一种新型强效PPAR激动剂，与选择性PPARγ激动剂吡格列酮相比，它能激活APP/PS1小鼠模型中的所有三种PPAR亚型（α/δ/γ）。在本研究使用的剂量下，尽管与吡格列酮相比，GFT1803在全身和大脑中的暴露量显著较低，但两种化合物显示出相似的脑/血浆分配比。用GFT1803口服治疗APP/PS1小鼠可降低小胶质细胞活化、淀粉样β（Aβ）斑块面积以及十二烷基硫酸钠和甲酸可溶性部分中的Aβ水平，且呈浓度依赖性。除了通过酶联免疫吸附测定法（ELISA）测量的Aβ38和Aβ40水平外，在吡格列酮治疗的小鼠中未观察到这些效果。两种配体均以相似程度降低胶质纤维酸性蛋白（GFAP）表达，且不影响载脂蛋白E（ApoE）表达。最后，GFT1803增加胰岛素降解酶表达。在莫里斯水迷宫中对空间记忆形成的分析表明，与野生型小鼠相比，两种化合物都能够部分逆转APP/PS1小鼠的表型，其中GFT1803最为有效。与吡格列酮相比，GFT1803（泛PPAR激动剂）在全身和大脑暴露率显著较低的情况下，在淀粉样斑块负荷、不溶性Aβ含量和神经炎症方面产生了数量上更优且质量上不同的治疗效果。
