Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation
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 andAppNL-G-Fmice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated maleAppNL-G-Fmice 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..
Medienart: |
Preprint |
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Erscheinungsjahr: |
2023 |
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Erschienen: |
2023 |
Enthalten in: |
bioRxiv.org - (2023) vom: 04. Nov. Zur Gesamtaufnahme - year:2023 |
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Sprache: |
Englisch |
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Beteiligte Personen: |
Biechele, Gloria [VerfasserIn] |
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Links: |
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Themen: |
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doi: |
10.1101/2021.05.30.445761 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
XBI031897703 |
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520 | |a 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 andAppNL-G-Fmice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated maleAppNL-G-Fmice 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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700 | 1 | |a Blume, Tanja |4 aut | |
700 | 1 | |a Deussing, Maximilian |4 aut | |
700 | 1 | |a Zott, Benedikt |4 aut | |
700 | 1 | |a Shi, Yuan |4 aut | |
700 | 1 | |a Xiang, Xianyuan |4 aut | |
700 | 1 | |a Franzmeier, Nicolai |4 aut | |
700 | 1 | |a Kleinberger, Gernot |4 aut | |
700 | 1 | |a Peters, Finn |4 aut | |
700 | 1 | |a Ochs, Katharina |4 aut | |
700 | 1 | |a Focke, Carola |4 aut | |
700 | 1 | |a Sacher, Christian |4 aut | |
700 | 1 | |a Wind, Karin |4 aut | |
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700 | 1 | |a Lindner, Simon |4 aut | |
700 | 1 | |a Gildehaus, Franz-Josef |4 aut | |
700 | 1 | |a Eckenweber, Florian |4 aut | |
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700 | 1 | |a von Ungern-Sternberg, Barbara |4 aut | |
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700 | 1 | |a Baumann, Karlheinz |4 aut | |
700 | 1 | |a Dorostkar, Mario M. |4 aut | |
700 | 1 | |a Rominger, Axel |4 aut | |
700 | 1 | |a Cumming, Paul |4 aut | |
700 | 1 | |a Willem, Michael |4 aut | |
700 | 1 | |a Adelsberger, Helmuth |4 aut | |
700 | 1 | |a Herms, Jochen |4 aut | |
700 | 1 | |a Brendel, Matthias |4 aut | |
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