Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition.

We undertook longitudinal β-amyloid positron emission tomography (Aβ-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in Aβ model mice. We thus tested the hypothesis this treatment would rescue from increases of the Aβ-PET signal while promoting spatial learning and preservation of synaptic density. Here, we investigated longitudinally for 5 months PS2APP mice ( N = 23; baseline age: 8 months) and App ^{NL - G - F} mice ( N = 37; baseline age: 5 months) using Aβ-PET. Groups of mice were treated with pioglitazone or vehicle during the follow-up interval. We tested spatial memory performance and confirmed terminal PET findings by immunohistochemical and biochemistry analyses. Surprisingly, Aβ-PET and immunohistochemistry revealed a shift toward higher fibrillary composition of Aβ-plaques during upon chronic pioglitazone treatment. Nonetheless, synaptic density and spatial learning were improved in transgenic mice with pioglitazone treatment, in association with the increased plaque fibrillarity. These translational data suggest that a shift toward higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the Aβ-PET signal upon immunomodulatory treatments targeting Aβ aggregation can thus be protective.
Competing Interests: GK is an employee of ISAR bioscience. KB is an employee of Roche. AR has received research support and speaker honoraria from Siemens. MB received speaker honoraria from GE healthcare, Roche, and LMI and is an advisor of LMI. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Blume, Deussing, Biechele, Peters, Zott, Schmidt, Franzmeier, Wind, Eckenweber, Sacher, Shi, Ochs, Kleinberger, Xiang, Focke, Lindner, Gildehaus, Beyer, von Ungern-Sternberg, Bartenstein, Baumann, Adelsberger, Rominger, Cumming, Willem, Dorostkar, Herms and Brendel.)