Your browser doesn't support javascript.
loading
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; Baumann, Karlheinz; Dorostkar, Mario M; Rominger, Axel; Cumming, Paul; Willem, Michael; Adelsberger, Helmuth; Herms, Jochen; Brendel, Matthias.
Afiliación
  • Biechele G; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Blume T; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Deussing M; DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
  • Zott B; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Shi Y; Institute of Neuroscience, Technical University of Munich, Munich, Germany.
  • Xiang X; Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • Franzmeier N; DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
  • Kleinberger G; Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Peters F; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Ochs K; ISAR Bioscience GmbH, 82152 Planegg, Germany.
  • Focke C; DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
  • Sacher C; DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
  • Wind K; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Schmidt C; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Lindner S; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Gildehaus FJ; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Eckenweber F; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Beyer L; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • von Ungern-Sternberg B; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Bartenstein P; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Baumann K; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Dorostkar MM; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Rominger A; SyNergy, University of Munich, Munich, Germany.
  • Cumming P; Roche Pharma Research and Early Development, Neuroscience Discovery, Roche, Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Willem M; DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
  • Adelsberger H; Center for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Munich, Germany.
  • Herms J; Dept. of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
  • Brendel M; SyNergy, University of Munich, Munich, Germany.
Theranostics ; 11(18): 8964-8976, 2021.
Article en En | MEDLINE | ID: mdl-34522221
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 ß-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 ß-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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de GABA / Microglía / Enfermedad de Alzheimer Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Theranostics Año: 2021 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Australia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de GABA / Microglía / Enfermedad de Alzheimer Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Theranostics Año: 2021 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Australia