Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer's disease.

Autor: Zatcepin A; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany. Artem.Zatcepin@med.uni-muenchen.de.; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Artem.Zatcepin@med.uni-muenchen.de., Gnörich J; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Rauchmann BS; Institute of Neuroradiology, University Hospital LMU, Munich, Germany.; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany., Bartos LM; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany., Wagner S; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany., Franzmeier N; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany.; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Malpetti M; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, UK., Xiang X; Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, LMU Munich, Munich, Germany.; CAS Key Laboratory of Brain Connectome and Manipulation, the Brain Cognition and Brain Disease Institute, Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, ShenzhenShenzhen, 518055, China., Shi Y; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Parhizkar S; Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA., Grosch M; German Center for Vertigo and Balance Disorders, University Hospital of Munich, LMU Munich, Munich, Germany., Wind-Mark K; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Kunte ST; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany., Beyer L; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany., Meyer C; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Brösamle D; German Center for Neurodegenerative Disease (DZNE), Neuroimmunology and Neurodegenerative Diseases, Göttingen, Germany.; Dept. of Cellular Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany.; Metabolic Biochemistry, Faculty of Medicine, Biomedical Center Munich (BMC), LMU Munich, Munich, Germany., Wendeln AC; German Center for Neurodegenerative Disease (DZNE), Neuroimmunology and Neurodegenerative Diseases, Göttingen, Germany.; Dept. of Cellular Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany., Osei-Sarpong C; Platform for Single Cell Genomics and Epigenomics (PRECISE), German Center for Neurodegenerative Diseasesand , University of Bonn and West German Genome Center, Bonn, Germany.; German Center for Neurodegenerative Diseases (DZNE), Immunogenomics & Neurodegeneration, Bonn, Germany., Heindl S; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany., Liesz A; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Stoecklein S; Department of Radiology, University Hospital, LMU Munich, Munich, Germany., Biechele G; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.; Department of Radiology, University Hospital, LMU Munich, Munich, Germany., Finze A; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany., Eckenweber F; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany., Lindner S; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany., Rominger A; Department of Nuclear Medicine, Inselpital, Bern University Hospital, University of Bern, Bern, Switzerland., Bartenstein P; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany., Willem M; Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, LMU Munich, Munich, Germany., Tahirovic S; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Herms J; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany., Buerger K; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany., Simons M; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany., Haass C; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, LMU Munich, Munich, Germany., Rupprecht R; Department of Psychiatry and Psychotherapy, University of Regensburg, Molecular Neurosciences, Regensburg, Germany., Riemenschneider MJ; Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany., Albert NL; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.; German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Munich, 69120, Heidelberg, Germany.; Bavarian Cancer Research Center (BZKF), 91054, Erlangen, Germany., Beyer M; Platform for Single Cell Genomics and Epigenomics (PRECISE), German Center for Neurodegenerative Diseasesand , University of Bonn and West German Genome Center, Bonn, Germany.; German Center for Neurodegenerative Diseases (DZNE), Immunogenomics & Neurodegeneration, Bonn, Germany., Neher JJ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; German Center for Neurodegenerative Disease (DZNE), Neuroimmunology and Neurodegenerative Diseases, Göttingen, Germany.; Dept. of Cellular Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany.; Metabolic Biochemistry, Faculty of Medicine, Biomedical Center Munich (BMC), LMU Munich, Munich, Germany., Paeger L; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Levin J; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Department of Neurology, University Hospital, LMU Munich, Munich, Germany., Höglinger GU; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Department of Neurology, University Hospital, LMU Munich, Munich, Germany.; Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany., Perneczky R; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, W6 8RP, UK.; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, S10 2HQ, UK., Ziegler SI; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany., Brendel M; Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Jazyk: angličtina
Zdroj: Molecular neurodegeneration [Mol Neurodegener] 2024 Sep 05; Vol. 19 (1), pp. 64. Date of Electronic Publication: 2024 Sep 05.
DOI: 10.1186/s13024-024-00752-6
Abstrakt: Background: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker.
Methods: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization.
Results: Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia.
Conclusion: Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.
(© 2024. The Author(s).)
Databáze: MEDLINE
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