Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation

Biechele, Gloria; Blume, Tanja; Deussing, Maximilian; Zott, Benedikt; Shi, Yuan; Xiang, Xianyuan; Franzmeier, Nicolai; Kleinberger, Gernot; Peters, Finn; Ochs, Katharina; Focke, Carola; Sacher, Christian; Wind, Karin; Schmidt, Claudio; Lindner, Simon; Gildehaus, Franz-Josef; Eckenweber, Florian; Beyer, Leonie; Ungern-Sternberg, Barbara von; Bartenstein, Peter; Baumann, Karlheinz; Dorostkar, Mario M.; Rominger, Axel; Cumming, Paul; Willem, Michael; Adelsberger, Helmuth; Herms, Jochen und Brendel, Matthias (2021): Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation. In: Theranostics, Bd. 11, Nr. 18: S. 8964-8976

Abstract

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's 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. Methods: Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of the 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 (3-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Results: 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 pharmacological treatment was associated with better spatial learning despite higher fibrillar (3-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R = 0.952, p < 0.0001). Conclusion: TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Sex and pre-therapeutic assessment of baseline microglial activation predict individual immunomodulation effects and may serve for responder stratification.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1838-7640
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198