| Autor: |
Ha-Yeun Chung, Jonathan Wickel, Nina Hahn, Nils Mein, Meike Schwarzbrunn, Philipp Koch, Mihai Ceanga, Holger Haselmann, Carolin Baade-Büttner, Nikolai von Stackelberg, Nina Hempel, Lars Schmidl, Marco Groth, Nico Andreas, Juliane Götze, Sina M. Coldewey, Michael Bauer, Christian Mawrin, Justina Dargvainiene, Frank Leypoldt, Stephan Steinke, Zhao-Qi Wang, Michael Hust, Christian Geis |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Science Advances. 9 |
| ISSN: |
2375-2548 |
| DOI: |
10.1126/sciadv.abq7806 |
| Popis: |
Sepsis-associated encephalopathy (SAE) is a severe and frequent complication of sepsis causing delirium, coma, and long-term cognitive dysfunction. We identified microglia and C1q complement activation in hippocampal autopsy tissue of patients with sepsis and increased C1q-mediated synaptic pruning in a murine polymicrobial sepsis model. Unbiased transcriptomics of hippocampal tissue and isolated microglia derived from septic mice revealed an involvement of the innate immune system, complement activation, and up-regulation of lysosomal pathways during SAE in parallel to neuronal and synaptic damage. Microglial engulfment of C1q-tagged synapses could be prevented by stereotactic intrahippocampal injection of a specific C1q-blocking antibody. Pharmacologically targeting microglia by PLX5622, a CSF1-R inhibitor, reduced C1q levels and the number of C1q-tagged synapses, protected from neuronal damage and synapse loss, and improved neurocognitive outcome. Thus, we identified complement-dependent synaptic pruning by microglia as a crucial pathomechanism for the development of neuronal defects during SAE. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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