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

We undertook longitudinal ß-amyloid positron emission tomography (Aß-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in Aß model mice. We thus tested the hypothesis this treatment would rescue from increases of the Aß-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 Aß-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, Aß-PET and immunohistochemistry revealed a shift toward higher fibrillary composition of Aß-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 Aß-PET signal upon immunomodulatory treatments targeting Aß aggregation can thus be protective.

Asymmetry of Fibrillar Plaque Burden in Amyloid Mouse Models.

Asymmetries of amyloid-ß (Aß) burden are well known in Alzheimer disease (AD) but did not receive attention in Aß mouse models of Alzheimer disease. Therefore, we investigated Aß asymmetries in Aß mouse models examined by Aß small-animal PET and tested if such asymmetries have an association with microglial activation. Methods: We analyzed 523 cross-sectional Aß PET scans of 5 different Aß mouse models (APP/PS1, PS2APP, APP-SL70, AppNL-G-F , and APPswe) together with 136 18-kDa translocator protein (TSPO) PET scans for microglial activation. The asymmetry index (AI) was calculated between tracer uptake in both hemispheres. AIs of Aß PET were analyzed in correlation with TSPO PET AIs. Extrapolated required sample sizes were compared between analyses of single and combined hemispheres. Results: Relevant asymmetries of Aß deposition were identified in at least 30% of all investigated mice. There was a significant correlation between AIs of Aß PET and TSPO PET in 4 investigated Aß mouse models (APP/PS1: R = 0.593, P = 0.001; PS2APP: R = 0.485, P = 0.019; APP-SL70: R = 0.410, P = 0.037; AppNL-G-F : R = 0.385, P = 0.002). Asymmetry was associated with higher variance of tracer uptake in single hemispheres, leading to higher required sample sizes. Conclusion: Asymmetry of fibrillar plaque neuropathology occurs frequently in Aß mouse models and acts as a potential confounder in experimental designs. Concomitant asymmetry of microglial activation indicates a neuroinflammatory component to hemispheric predominance of fibrillary amyloidosis.

Early and Longitudinal Microglial Activation but Not Amyloid Accumulation Predicts Cognitive Outcome in PS2APP Mice.

Neuroinflammation may have beneficial or detrimental net effects on the cognitive outcome of Alzheimer disease (AD) patients. PET imaging with 18-kDa translocator protein (TSPO) enables longitudinal monitoring of microglial activation in vivo. Methods: We compiled serial PET measures of TSPO and amyloid with terminal cognitive assessment (water maze) in an AD transgenic mouse model (PS2APP) from 8 to 13 mo of age, followed by immunohistochemical analyses of microglia, amyloid, and synaptic density. Results: Better cognitive outcome and higher synaptic density in PS2APP mice was predicted by higher TSPO expression at 8 mo. The progression of TSPO activation to 13 mo also showed a moderate association with spared cognition, but amyloidosis did not correlate with the cognitive outcome, regardless of the time point. Conclusion: This first PET investigation with longitudinal TSPO and amyloid PET together with terminal cognitive testing in an AD mouse model indicates that continuing microglial response seems to impart preserved cognitive performance.

Microglial response to increasing amyloid load saturates with aging: a longitudinal dual tracer in vivo µPET-study.

BACKGROUND: Causal associations between microglia activation and ß-amyloid (Aß) accumulation during the progression of Alzheimer's disease (AD) remain a matter of controversy. Therefore, we used longitudinal dual tracer in vivo small animal positron emission tomography (µPET) imaging to resolve the progression of the association between Aß deposition and microglial responses during aging of an Aß mouse model. METHODS: APP-SL70 mice (N = 17; baseline age 3.2-8.5 months) and age-matched C57Bl/6 controls (wildtype (wt)) were investigated longitudinally for 6 months using Aß (18F-florbetaben) and 18 kDa translocator protein (TSPO) µPET (18F-GE180). Changes in cortical binding were transformed to Z-scores relative to wt mice, and microglial activation relative to amyloidosis was defined as the Z-score difference (TSPO-Aß). Using 3D immunohistochemistry for activated microglia (Iba-1) and histology for fibrillary Aß (methoxy-X04), we measure microglial brain fraction relative to plaque size and the distance from plaque margins. RESULTS: Aß-PET binding increased exponentially as a function of age in APP-SL70 mice, whereas TSPO binding had an inverse U-shape growth function. Longitudinal Z-score differences declined with aging, suggesting that microglial response declined relative to increasing amyloidosis in aging APP-SL70 mice. Microglial brain volume fraction was inversely related to adjacent plaque size, while the proximity to Aß plaques increased with age. CONCLUSIONS: Microglial activity decreases relative to ongoing amyloidosis with aging in APP-SL70 mice. The plaque-associated microglial brain fraction saturated and correlated negatively with increasing plaque size with aging.