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; von Ungern-Sternberg, Barbara; Bartenstein, Peter; ... (2021). Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation. Theranostics, 11(18), pp. 8964-8976. Ivyspring International 10.7150/thno.64022

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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)-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. 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 β-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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Clinic of Nuclear Medicine

UniBE Contributor:

Rominger, Axel Oliver and Cumming, Paul

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1838-7640

Publisher:

Ivyspring International

Language:

English

Submitter:

Daria Vogelsang

Date Deposited:

07 Jan 2022 11:36

Last Modified:

07 Jan 2022 11:36

Publisher DOI:

10.7150/thno.64022

PubMed ID:

34522221

Uncontrolled Keywords:

AppNL-G-F mice PS2APP mice TSPO-PET microglia pioglitazone prediction sex

BORIS DOI:

10.48350/161779

URI:

https://boris.unibe.ch/id/eprint/161779

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