Oedematic-atrophic astrocytes in hepatic encephalopathy
Abstract Hepatic encephalopathy (HE) following acute liver failure (ALF) is considered as a primary toxic astrocytopathy, but in-depth characterisation of astrocytic contribution to the pathogenesis of this disease is far from complete. Using transmission electron microscopy, confocal fluorescent mi...
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BMC
2025-05-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-02045-5 |
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| author | Mariusz Popek Marta Obara-Michlewska Łukasz Mateusz Szewczyk Marcin Kołodziej Karol Perlejewski Alexei Verkhratsky Jan Albrecht Magdalena Zielińska |
| author_facet | Mariusz Popek Marta Obara-Michlewska Łukasz Mateusz Szewczyk Marcin Kołodziej Karol Perlejewski Alexei Verkhratsky Jan Albrecht Magdalena Zielińska |
| author_sort | Mariusz Popek |
| collection | DOAJ |
| description | Abstract Hepatic encephalopathy (HE) following acute liver failure (ALF) is considered as a primary toxic astrocytopathy, but in-depth characterisation of astrocytic contribution to the pathogenesis of this disease is far from complete. Using transmission electron microscopy, confocal fluorescent microscopy, and 3D reconstruction, we found complex morphological alterations of cortical astrocytes in mice with azoxymethane-induced ALF and post-mortem cortical tissue of patients at grade IV of HE. In both mice and post-mortem human tissues astrocytic primary branches demonstrated the territory occupied by astrocytes was increased, confirming astrocytic oedema. Astrocytic primary branches demonstrated swelling, while terminal leaflets showed atrophy quantified by the reduced area occupied by astrocytes, decreased number and the length of leaflets, decreased leaflets volume fraction, and altered astrocyte-to-neurone landscape. In mice these morphological changes develop in parallel with decreased expression of proteins critical for astrocytic modelling and function: the water channel aquaporin 4 (AQP4), the phosphorylated leaflet-associated ezrin, and the actin dynamics regulator, profilin 1 (PFN1). Pathological changes in astrocytes develop in parallel, and are likely causally linked to, the HE-linked neurological decline, manifested by a reduction in EEG power and by excessive glutamate in the brain microdialysates. We propose that HE evokes disease-specific remodelling of astrocytes to a “mixed”, oedematic/atrophic phenotype. Concurrence of HE-specific phenotype with alterations in the expression of astrocytic proteins are a likely cause of aberrant astrocyte synaptic support resulting in severe, often fatal brain malfunction in HE. |
| format | Article |
| id | doaj-art-94a70fd7c9514bcb9aee7de3f7c6492d |
| institution | OA Journals |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Acta Neuropathologica Communications |
| spelling | doaj-art-94a70fd7c9514bcb9aee7de3f7c6492d2025-08-20T02:38:32ZengBMCActa Neuropathologica Communications2051-59602025-05-0113111610.1186/s40478-025-02045-5Oedematic-atrophic astrocytes in hepatic encephalopathyMariusz Popek0Marta Obara-Michlewska1Łukasz Mateusz Szewczyk2Marcin Kołodziej3Karol Perlejewski4Alexei Verkhratsky5Jan Albrecht6Magdalena Zielińska7Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of SciencesDepartment of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of SciencesLaboratory of Molecular Neurobiology, Centre of New Technologies, The University of WarsawInstitute of Theory of Electrical Engineering, Measurement and Information Systems, Warsaw University of TechnologyDepartment of Immunopathology of Infectious and Parasitic Diseases, Medical University of WarsawFaculty of Biology, Medicine and Health, The University of ManchesterDepartment of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of SciencesDepartment of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of SciencesAbstract Hepatic encephalopathy (HE) following acute liver failure (ALF) is considered as a primary toxic astrocytopathy, but in-depth characterisation of astrocytic contribution to the pathogenesis of this disease is far from complete. Using transmission electron microscopy, confocal fluorescent microscopy, and 3D reconstruction, we found complex morphological alterations of cortical astrocytes in mice with azoxymethane-induced ALF and post-mortem cortical tissue of patients at grade IV of HE. In both mice and post-mortem human tissues astrocytic primary branches demonstrated the territory occupied by astrocytes was increased, confirming astrocytic oedema. Astrocytic primary branches demonstrated swelling, while terminal leaflets showed atrophy quantified by the reduced area occupied by astrocytes, decreased number and the length of leaflets, decreased leaflets volume fraction, and altered astrocyte-to-neurone landscape. In mice these morphological changes develop in parallel with decreased expression of proteins critical for astrocytic modelling and function: the water channel aquaporin 4 (AQP4), the phosphorylated leaflet-associated ezrin, and the actin dynamics regulator, profilin 1 (PFN1). Pathological changes in astrocytes develop in parallel, and are likely causally linked to, the HE-linked neurological decline, manifested by a reduction in EEG power and by excessive glutamate in the brain microdialysates. We propose that HE evokes disease-specific remodelling of astrocytes to a “mixed”, oedematic/atrophic phenotype. Concurrence of HE-specific phenotype with alterations in the expression of astrocytic proteins are a likely cause of aberrant astrocyte synaptic support resulting in severe, often fatal brain malfunction in HE.https://doi.org/10.1186/s40478-025-02045-5AstrocyteAcute liver failureAquaporin 4EzrinProfilin-1 |
| spellingShingle | Mariusz Popek Marta Obara-Michlewska Łukasz Mateusz Szewczyk Marcin Kołodziej Karol Perlejewski Alexei Verkhratsky Jan Albrecht Magdalena Zielińska Oedematic-atrophic astrocytes in hepatic encephalopathy Acta Neuropathologica Communications Astrocyte Acute liver failure Aquaporin 4 Ezrin Profilin-1 |
| title | Oedematic-atrophic astrocytes in hepatic encephalopathy |
| title_full | Oedematic-atrophic astrocytes in hepatic encephalopathy |
| title_fullStr | Oedematic-atrophic astrocytes in hepatic encephalopathy |
| title_full_unstemmed | Oedematic-atrophic astrocytes in hepatic encephalopathy |
| title_short | Oedematic-atrophic astrocytes in hepatic encephalopathy |
| title_sort | oedematic atrophic astrocytes in hepatic encephalopathy |
| topic | Astrocyte Acute liver failure Aquaporin 4 Ezrin Profilin-1 |
| url | https://doi.org/10.1186/s40478-025-02045-5 |
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