Chronic PPAR gamma Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition

We 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. 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 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. Surprisingly, A beta-PET and immunohistochemistry revealed a shift toward 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. These translational data suggest that a shift toward 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.