Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition

Blume, T.; Deussing, M.; Biechele, G.; Peters, F.; Zott, B.; Schmidt, C.; Franzmeier, N.; Wind, K.; Eckenweber, F.; Sacher, C.; Shi, Y.; Ochs, K.; Kleinberger, G.; Xiang, X.; Focke, C.; Lindner, S.; Gildehaus, F.-J.; Beyer, L.; von Ungern-Sternberg, B.; Bartenstein, P.; Baumann, K.; Adelsberger, H.; Rominger, A.; Cumming, P.; Willem, M.; Dorostkar, M. M.; Herms, J.; Brendel, M.

doi:10.1101/2021.05.30.446348

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bioRxiv · 10.1101/2021.05.30.446348

Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition

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Abstract

BackgroundWe undertook longitudinal {beta}-amyloid positron emission tomography (A{beta}-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist pioglitazone in A{beta} model mice. We thus tested the hypothesis this treatment would rescue from increases of the A{beta}-PET signal while promoting spatial learning and preservation of synaptic density. MethodsPS2APP mice (N=23; baseline age: 8 months) and AppNL-G-F mice (N=37; baseline age: 5 months) were investigated longitudinally for five months using A{beta}-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. ResultsSurprisingly, A{beta}-PET and immunohistochemistry revealed a shift towards higher fibrillary composition of A{beta}-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. ConclusionThese translational data suggest that a shift towards higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the A{beta}-PET signal upon immunomodulatory treatments targeting A{beta} aggregation can thus be protective.

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Blume, T., Deussing, M., Biechele, G., Peters, F., Zott, B., Schmidt, C., Franzmeier, N., Wind, K., Eckenweber, F., Sacher, C., Shi, Y., Ochs, K., Kleinberger, G., Xiang, X., Focke, C., Lindner, S., Gildehaus, F.-J., Beyer, L., von Ungern-Sternberg, B., Bartenstein, P., Baumann, K., Adelsberger, H., Rominger, A., Cumming, P., Willem, M., Dorostkar, M. M., Herms, J., Brendel, M.. 2021-05-30. Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition. https://doi.org/10.1101/2021.05.30.446348

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