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

Theranostics. 2021 Aug 19;11(18):8964-8976. doi: 10.7150/thno.64022. PMID: 34522221; PMCID: PMC8419052.

Authors/Editors: 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 FJ, Eckenweber F, Beyer L, von Ungern-Sternberg B, Bartenstein P, Baumann K, Dorostkar MM, Rominger A, Cumming P, Willem M, Adelsberger H, Herms J, Brendel M.
Publication Date: 2021

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. Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of peroxisome proliferator-activated receptor (PPAR)-γ 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 β-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 β-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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