Academic Journal
Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease
| Title: | Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease |
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| Authors: | Zatcepin, Artem, Gnörich, Johannes, Rauchmann, Boris-Stephan, Bartos, Laura M, Wagner, Stephan, Franzmeier, Nicolai, Malpetti, Maura, Xiang, Xianyuan, Shi, Yuan, Parhizkar, Samira, Grosch, Maximilian, Wind-Mark, Karin, Kunte, Sebastian T, Beyer, Leonie, Meyer, Carolin, Brösamle, Desirée, Wendeln, Ann-Christin, Osei-Sarpong, Collins, Heindl, Steffanie, Liesz, Arthur, Stoecklein, Sophia, Biechele, Gloria, Finze, Anika, Eckenweber, Florian, Lindner, Simon, Rominger, Axel, Bartenstein, Peter, Willem, Michael, Tahirovic, Sabina, Herms, Jochen, Buerger, Katharina, Simons, Mikael, Haass, Christian, Rupprecht, Rainer, Riemenschneider, Markus J, Albert, Nathalie L, Beyer, Marc, Neher, Jonas J, Paeger, Lars, Levin, Johannes, Höglinger, Günter U, Perneczky, Robert, Ziegler, Sibylle I, Brendel, Matthias |
| Contributors: | Zatcepin, Artem, Gnörich, Johannes, Rauchmann, Boris-Stephan, Bartos, Laura M., Wagner, Stephan, Franzmeier, Nicolai, Malpetti, Maura, Xiang, Xianyuan, Shi, Yuan, Parhizkar, Samira, Brendel, Matthias, DSpace at Cambridge pro (8.1) |
| Source: | Mol Neurodegener Molecular Neurodegeneration, Vol 19, Iss 1, Pp 1-25 (2024) Molecular neurodegeneration 19(1), 64 (2024). doi:10.1186/s13024-024-00752-6 |
| Publisher Information: | Springer Science and Business Media LLC, 2024. |
| Publication Year: | 2024 |
| Subject Terms: | Male, Cognitive Dysfunction/metabolism [MeSH], Neuroinflammation, Microglia desynchronization, PET, Alzheimer's disease, Mice, Transgenic [MeSH], Microglia/metabolism [MeSH], Male [MeSH], Positron-Emission Tomography [MeSH], Alzheimer Disease/metabolism [MeSH], Disease Models, Animal [MeSH], Research Article, Dementia, Female [MeSH], Brain/pathology [MeSH], Humans [MeSH], Microglia, TSPO, Connectome/methods [MeSH], Microglia synchronicity, Animals [MeSH], Brain connectivity, Mice [MeSH], Brain/metabolism [MeSH], Receptors, GABA/metabolism [MeSH], Alzheimer Disease/pathology [MeSH], Mice, Transgenic, metabolism [Microglia], pathology [Alzheimer Disease], metabolism [Cognitive Dysfunction], Mice, methods [Connectome], Receptors, GABA, pathology [Brain], Alzheimer Disease, ddc:570, Connectome, Animals, Humans, Cognitive Dysfunction, RC346-429, RC952-954.6, Brain, ddc, metabolism [Receptors, GABA], Disease Models, Animal, metabolism [Brain], Geriatrics, Positron-Emission Tomography, Female, Neurology. Diseases of the nervous system, metabolism [Alzheimer Disease] |
| Description: | 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. |
| Document Type: | Article Other literature type |
| File Description: | application/pdf; text/xml |
| Language: | English |
| ISSN: | 1750-1326 |
| DOI: | 10.1186/s13024-024-00752-6 |
| DOI: | 10.48620/36430 |
| DOI: | 10.15496/publikation-101658 |
| Access URL: | https://pubmed.ncbi.nlm.nih.gov/39238030 https://doaj.org/article/a5bbc5a0c7914c46ad9ff511752e6937 https://resolver.sub.uni-goettingen.de/purl?gro-2/145782 https://repository.publisso.de/resource/frl:6519401 https://epub.ub.uni-muenchen.de/123137/ https://mediatum.ub.tum.de/doc/1770432/document.pdf |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (http://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Accession Number: | edsair.doi.dedup.....a6b3abd6b1d147a0fac4b8015e1e712b |
| Database: | OpenAIRE |
| ISSN: | 17501326 |
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| DOI: | 10.1186/s13024-024-00752-6 |