Pan-PPAR Modulation Effectively Protects APP/PS1 Mice from Amyloid Deposition and Cognitive Deficits

Abstract

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.

By suppressing the expression of anterior pharynx‐defective‐1α and ‐1β and inhibiting the aggregation of β‐amyloid protein, magnesium ions inhibit the cognitive decline of amyloid precursor protein/presenilin 1 transgenic mice

“…In view of the essential role of APH-1 in Ab production, our data further revealed that MgT treatment disrupted the binding between APH-1a/-1b and PS1, leading to the reduction of Ab in a PPARg-dependent manner. Consistent with our observations, Kummer et al (28) recently reported that oral treatment of APP/PS1 mice with a novel PPARa/b/g agonist, GFT1803, decreases Ab levels and the area affected by APs. More specifically, the PPARg agonist treatment was shown to improve cognitive decline in Figure 9.…”

The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders

“…4). Some other data of Kummer et al [52] have detected that the new PPAR agonist activates all PPARs receptors (GFT1803) decreases significantly Aβ plaques/Aβ level and microglia activation in AD mice (APP/PS1). The data suggested the role of these receptors in Aβ degradation or clearance by i.e.…”

Insulin resistance and cognitive dysfunction

“…The ApoE ε4 allele frequency in IR patients is significantly higher than controls, with IR index and ApoE ε4 gene positively correlated, suggesting that IR is related to MCI and ApoE ε4, and that IR and ApoE ε4 have clinical application in predicting MCI occurrence and transformation into AD [106].…”