| First Author | Biechele G | Year | 2021 |
| Journal | Theranostics | Volume | 11 |
| Issue | 18 | Pages | 8964-8976 |
| PubMed ID | 34522221 | Mgi Jnum | J:324397 |
| Mgi Id | MGI:6766144 | Doi | 10.7150/thno.64022 |
| Citation | Biechele G, et al. (2021) Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation. Theranostics 11(18):8964-8976 |
| abstractText | 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, App(NL-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. Results: Pioglitazone-treated female PS2APP and App(NL-G-F) mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male App(NL-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 beta-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. |
