Gloria Biechele1, Karin Wind2, Tanja Blume3, Christian Sacher2, Leonie Beyer2, Florian Eckenweber2, Nicolai Franzmeier4, Michael Ewers5, Benedikt Zott6, Simon Lindner2, Franz-Josef Gildehaus2, Barbara von Ungern-Sternberg2, Sabina Tahirovic7, Michael Willem8, Peter Bartenstein9, Paul Cumming10, Axel Rominger11, Jochen Herms12, Matthias Brendel13. 1. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany. Electronic address: gloria.biechele@med.uni-muenchen.de. 2. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany. 3. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany; DZNE - German Center for Neurodegenerative Diseases, Munich, Germany. 4. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University Munich. 5. DZNE - German Center for Neurodegenerative Diseases, Munich, Germany; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University Munich. 6. Institute of Neuroscience, Technical University of Munich, Munich, Germany; Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 7. DZNE - German Center for Neurodegenerative Diseases, Munich, Germany. 8. Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, LMU Munich, Munich, Germany. 9. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 10. Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland; School of Psychology and Counselling, Queensland University of Technology, Brisbane, Australia. 11. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany; Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland. 12. DZNE - German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Center of Neuropathology and Prion Research, University of Munich, Munich Germany. 13. Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Electronic address: matthias.brendel@med.uni-muenchen.de.
Abstract
BACKGROUND: In Alzheimer`s disease (AD), regional heterogeneity of β-amyloid burden and microglial activation of individual patients is a well-known phenomenon. Recently, we described a high incidence of inter-individual regional heterogeneity in terms of asymmetry of plaque burden and microglial activation in β-amyloid mouse models of AD as assessed by positron-emission-tomography (PET). We now investigate the regional associations between amyloid plaque burden, microglial activation, and impaired spatial learning performance in transgenic mice in vivo. METHODS: In 30 AppNL-G-F mice (15 female, 15 male) we acquired cross-sectional 18 kDa translocator protein (TSPO-PET, 18F-GE-180) and β-amyloid-PET (18F-florbetaben) scans at ten months of age. Control data were obtained from age- and sex-matched C57BI/6 wild-type mice. We assessed spatial learning (i.e. Morris water maze) within two weeks of PET scanning and correlated the principal component of spatial learning performance scores with voxel-wise β-amyloid and TSPO tracer uptake maps in AppNL-G-F mice, controlled for age and sex. In order to assess the effects of hemispheric asymmetry, we also analyzed correlations of spatial learning performance with tracer uptake in bilateral regions of interest for frontal cortex, entorhinal/piriform cortex, amygdala, and hippocampus, using a regression model. We tested the correlation between regional asymmetry of PET biomarkers with individual spatial learning performance. RESULTS: Voxel-wise analyses in AppNL-G-F mice revealed that higher TSPO-PET signal in the amygdala, entorhinal and piriform cortices, the hippocampus and the hypothalamus correlated with spatial learning performance. Region-based analysis showed significant correlations between TSPO expression in the right entorhinal/piriform cortex and the right amygdala and spatial learning performance, whereas there were no such correlations in the left hemisphere. Right lateralized TSPO expression in the amygdala predicted better performance in the Morris water maze (β = -0.470, p = 0.013), irrespective of the global microglial activation and amyloid level. Region-based results for amyloid-PET showed no significant associations with spatial learning. CONCLUSION: Elevated microglial activation in the right amygdala-entorhinal-hippocampal complex of AppNL-G-F mice is associated with better spatial learning. Our findings support a protective role of microglia on cognitive function when they highly express TSPO in specific brain regions involved in spatial memory.
BACKGROUND: In Alzheimer`s disease (AD), regional heterogeneity of β-amyloid burden and microglial activation of individual patients is a well-known phenomenon. Recently, we described a high incidence of inter-individual regional heterogeneity in terms of asymmetry of plaque burden and microglial activation in β-amyloid mouse models of AD as assessed by positron-emission-tomography (PET). We now investigate the regional associations between amyloid plaque burden, microglial activation, and impaired spatial learning performance in transgenic mice in vivo. METHODS: In 30 AppNL-G-F mice (15 female, 15 male) we acquired cross-sectional 18 kDa translocator protein (TSPO-PET, 18F-GE-180) and β-amyloid-PET (18F-florbetaben) scans at ten months of age. Control data were obtained from age- and sex-matched C57BI/6 wild-type mice. We assessed spatial learning (i.e. Morris water maze) within two weeks of PET scanning and correlated the principal component of spatial learning performance scores with voxel-wise β-amyloid and TSPO tracer uptake maps in AppNL-G-F mice, controlled for age and sex. In order to assess the effects of hemispheric asymmetry, we also analyzed correlations of spatial learning performance with tracer uptake in bilateral regions of interest for frontal cortex, entorhinal/piriform cortex, amygdala, and hippocampus, using a regression model. We tested the correlation between regional asymmetry of PET biomarkers with individual spatial learning performance. RESULTS: Voxel-wise analyses in AppNL-G-F mice revealed that higher TSPO-PET signal in the amygdala, entorhinal and piriform cortices, the hippocampus and the hypothalamus correlated with spatial learning performance. Region-based analysis showed significant correlations between TSPO expression in the right entorhinal/piriform cortex and the right amygdala and spatial learning performance, whereas there were no such correlations in the left hemisphere. Right lateralized TSPO expression in the amygdala predicted better performance in the Morris water maze (β = -0.470, p = 0.013), irrespective of the global microglial activation and amyloid level. Region-based results for amyloid-PET showed no significant associations with spatial learning. CONCLUSION: Elevated microglial activation in the right amygdala-entorhinal-hippocampal complex of AppNL-G-F mice is associated with better spatial learning. Our findings support a protective role of microglia on cognitive function when they highly express TSPO in specific brain regions involved in spatial memory.
Authors: Tanja Blume; Maximilian Deussing; Gloria Biechele; Finn Peters; Benedikt Zott; Claudio Schmidt; Nicolai Franzmeier; Karin Wind; Florian Eckenweber; Christian Sacher; Yuan Shi; Katharina Ochs; Gernot Kleinberger; Xianyuan Xiang; Carola Focke; Simon Lindner; Franz-Josef Gildehaus; Leonie Beyer; Barbara von Ungern-Sternberg; Peter Bartenstein; Karlheinz Baumann; Helmuth Adelsberger; Axel Rominger; Paul Cumming; Michael Willem; Mario M Dorostkar; Jochen Herms; Matthias Brendel Journal: Front Aging Neurosci Date: 2022-03-30 Impact factor: 5.750
Authors: Vasil Kecheliev; Francesco Spinelli; Adrienne Herde; Ahmed Haider; Linjing Mu; Jan Klohs; Simon M Ametamey; Ruiqing Ni Journal: Front Aging Neurosci Date: 2022-09-30 Impact factor: 5.702