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

Animals Microglia / metabolism Alzheimer Disease / metabolism Mice Cognitive Dysfunction / metabolism Humans Brain / metabolism Disease Models, Animal Positron-Emission Tomography Receptors, GABA / metabolism Male Mice, Transgenic Connectome / methods Female
Alzheimer’s disease Brain connectivity Dementia Microglia Microglia desynchronization Microglia synchronicity Neuroinflammation PET TSPO

Journal

Molecular neurodegeneration
ISSN: 1750-1326
Titre abrégé: Mol Neurodegener
Pays: England
ID NLM: 101266600

Informations de publication

Date de publication:
05 Sep 2024
Historique:
received: 20 02 2024
accepted: 20 08 2024
medline: 6 9 2024
pubmed: 6 9 2024
entrez: 5 9 2024
Statut: epublish

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND 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 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 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 CONCLUSIONS
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.

Identifiants

DOI: 10.1186/s13024-024-00752-6 PMID: 39238030
pubmed: 39238030
doi: 10.1186/s13024-024-00752-6
pii: 10.1186/s13024-024-00752-6
doi:

Substances chimiques

Receptors, GABA 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

64

Informations de copyright

© 2024. The Author(s).

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Auteurs

Artem 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.
ORCID: 0000-0002-0224-088X

Johannes Gnörich (J)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Boris-Stephan Rauchmann (BS)

Institute of Neuroradiology, University Hospital LMU, Munich, Germany.
Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.

Laura M Bartos (LM)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Stephan Wagner (S)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Nicolai 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.

Maura Malpetti (M)

Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, UK.

Xianyuan 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.

Yuan Shi (Y)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Samira Parhizkar (S)

Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.

Maximilian Grosch (M)

German Center for Vertigo and Balance Disorders, University Hospital of Munich, LMU Munich, Munich, Germany.

Karin Wind-Mark (K)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Sebastian T Kunte (ST)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Leonie Beyer (L)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Carolin Meyer (C)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Desirée 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.

Ann-Christin 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.

Collins 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.

Steffanie Heindl (S)

Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany.

Arthur Liesz (A)

Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

Sophia Stoecklein (S)

Department of Radiology, University Hospital, LMU Munich, Munich, Germany.

Gloria Biechele (G)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.
Department of Radiology, University Hospital, LMU Munich, Munich, Germany.

Anika Finze (A)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Florian Eckenweber (F)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Simon Lindner (S)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Axel Rominger (A)

Department of Nuclear Medicine, Inselpital, Bern University Hospital, University of Bern, Bern, Switzerland.

Peter Bartenstein (P)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Michael Willem (M)

Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, LMU Munich, Munich, Germany.

Sabina Tahirovic (S)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Jochen 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.

Katharina Buerger (K)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany.

Mikael 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.

Christian 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.

Rainer Rupprecht (R)

Department of Psychiatry and Psychotherapy, University of Regensburg, Molecular Neurosciences, Regensburg, Germany.

Markus J Riemenschneider (MJ)

Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany.

Nathalie L 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.

Marc 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.

Jonas J 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.

Lars Paeger (L)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Johannes 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.

Günter U 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.

Robert 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.

Sibylle I Ziegler (SI)

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Matthias 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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Regional desynchronization of microglial...
questionsmedicales.fr › Cellules › Névroglie › Microglie › Regional desynchronization of microglial...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Regional desynchronization of microglial...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Regional desynchronization of microglial...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Troubles de la cognition › Dysfonctionnement cognitif › Regional desynchronization of microglial...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Regional desynchronization of microglial...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Regional desynchronization of microglial...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Regional desynchronization of microglial...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Techniques de diagnostic radioisotopique › Scintigraphie › Tomoscintigraphie › Tomographie par émission de positons › Regional desynchronization of microglial...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs GABA › Regional desynchronization of microglial...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Regional desynchronization of microglial...
questionsmedicales.fr › Techniques d'investigation › Neuroimagerie › Neuroimagerie fonctionnelle › Cartographie cérébrale › Connectome › Regional desynchronization of microglial...