Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation

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

doi:10.1101/2021.05.30.445761

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bioRxiv · 10.1101/2021.05.30.445761

Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation

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Abstract

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimers disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of peroxisome proliferator-activated receptor (PPAR)-{gamma} with pioglitazone in two different mouse models of AD (PS2APP, AppNL-G-F). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and {beta}-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Pioglitazone-treated female PS2APP and AppNL-G-F mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male AppNL-G-F mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R=-0.874, p<0.0001) but not in vehicle controls (R=-0.356, p=0.081). Reduced TSPO-PET signal upon treatment was associated with better spatial learning and higher fibrillar {beta}-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R=0.952, p<0.0001). TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Pre-therapeutic assessment of baseline microglial activation and sex are strong predictors of individual immunomodulation effects and could serve for responder stratification.

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Biechele, G., Blume, T., Deussing, M., Zott, B., Shi, Y., Xiang, X., Franzmeier, N., Kleinberger, G., Peters, F., Ochs, K., Focke, C., Sacher, C., Wind, K., Schmidt, C., Lindner, S., Gildehaus, F.-J., Eckenweber, F., Beyer, L., von Ungern-Sternberg, B., Bartenstein, P., Baumann, K., Dorostkar, M. M., Rominger, A., Cumming, P., Willem, M., Adelsberger, H., Herms, J., Brendel, M.. 2021-05-31. Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation. https://doi.org/10.1101/2021.05.30.445761

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