Molecular Neurodegeneration (Sep 2024)
Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease
- Artem Zatcepin,
- Johannes Gnörich,
- Boris-Stephan Rauchmann,
- Laura M. Bartos,
- Stephan Wagner,
- Nicolai Franzmeier,
- Maura Malpetti,
- Xianyuan Xiang,
- Yuan Shi,
- Samira Parhizkar,
- Maximilian Grosch,
- Karin Wind-Mark,
- Sebastian T. Kunte,
- Leonie Beyer,
- Carolin Meyer,
- Desirée Brösamle,
- Ann-Christin Wendeln,
- Collins Osei-Sarpong,
- Steffanie Heindl,
- Arthur Liesz,
- Sophia Stoecklein,
- Gloria Biechele,
- Anika Finze,
- Florian Eckenweber,
- Simon Lindner,
- Axel Rominger,
- Peter Bartenstein,
- Michael Willem,
- Sabina Tahirovic,
- Jochen Herms,
- Katharina Buerger,
- Mikael Simons,
- Christian Haass,
- Rainer Rupprecht,
- Markus J. Riemenschneider,
- Nathalie L. Albert,
- Marc Beyer,
- Jonas J. Neher,
- Lars Paeger,
- Johannes Levin,
- Günter U. Höglinger,
- Robert Perneczky,
- Sibylle I. Ziegler,
- Matthias Brendel
Affiliations
- Artem Zatcepin
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Johannes Gnörich
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Boris-Stephan Rauchmann
- Institute of Neuroradiology, University Hospital LMU
- Laura M. Bartos
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Stephan Wagner
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Nicolai Franzmeier
- Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich
- Maura Malpetti
- Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge
- Xianyuan Xiang
- Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, LMU Munich
- Yuan Shi
- German Center for Neurodegenerative Diseases (DZNE)
- Samira Parhizkar
- Department of Neurology, Washington University in St. Louis
- Maximilian Grosch
- German Center for Vertigo and Balance Disorders, University Hospital of Munich, LMU Munich
- Karin Wind-Mark
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Sebastian T. Kunte
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Leonie Beyer
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Carolin Meyer
- German Center for Neurodegenerative Diseases (DZNE)
- Desirée Brösamle
- German Center for Neurodegenerative Disease (DZNE), Neuroimmunology and Neurodegenerative Diseases
- Ann-Christin Wendeln
- German Center for Neurodegenerative Disease (DZNE), Neuroimmunology and Neurodegenerative Diseases
- Collins Osei-Sarpong
- Platform for Single Cell Genomics and Epigenomics (PRECISE), German Center for Neurodegenerative Diseasesand , University of Bonn and West German Genome Center
- Steffanie Heindl
- Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich
- Arthur Liesz
- Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich
- Sophia Stoecklein
- Department of Radiology, University Hospital, LMU Munich
- Gloria Biechele
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Anika Finze
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Florian Eckenweber
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Simon Lindner
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Axel Rominger
- Department of Nuclear Medicine, Inselpital, Bern University Hospital, University of Bern
- Peter Bartenstein
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Michael Willem
- Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, LMU Munich
- Sabina Tahirovic
- German Center for Neurodegenerative Diseases (DZNE)
- Jochen Herms
- German Center for Neurodegenerative Diseases (DZNE)
- Katharina Buerger
- German Center for Neurodegenerative Diseases (DZNE)
- Mikael Simons
- German Center for Neurodegenerative Diseases (DZNE)
- Christian Haass
- German Center for Neurodegenerative Diseases (DZNE)
- Rainer Rupprecht
- Department of Psychiatry and Psychotherapy, University of Regensburg
- Markus J. Riemenschneider
- Department of Neuropathology, Regensburg University Hospital
- Nathalie L. Albert
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Marc Beyer
- Platform for Single Cell Genomics and Epigenomics (PRECISE), German Center for Neurodegenerative Diseasesand , University of Bonn and West German Genome Center
- Jonas J. Neher
- Munich Cluster for Systems Neurology (SyNergy)
- Lars Paeger
- German Center for Neurodegenerative Diseases (DZNE)
- Johannes Levin
- German Center for Neurodegenerative Diseases (DZNE)
- Günter U. Höglinger
- German Center for Neurodegenerative Diseases (DZNE)
- Robert Perneczky
- German Center for Neurodegenerative Diseases (DZNE)
- Sibylle I. Ziegler
- Department of Nuclear Medicine, University Hospital, LMU Munich
- Matthias Brendel
- Department of Nuclear Medicine, University Hospital, LMU Munich
- DOI
- https://doi.org/10.1186/s13024-024-00752-6
- Journal volume & issue
-
Vol. 19,
no. 1
pp. 1 – 25
Abstract
Abstract 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.
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