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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 \u201cmixed\u201d, 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.<\/jats:p>","DOI":"10.1186\/s40478-025-02045-5","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T08:48:57Z","timestamp":1748681337000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Oedematic-atrophic astrocytes in hepatic encephalopathy"],"prefix":"10.1186","volume":"13","author":[{"given":"Mariusz","family":"Popek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Obara-Michlewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0141ukasz Mateusz","family":"Szewczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Ko\u0142odziej","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karol","family":"Perlejewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei","family":"Verkhratsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Albrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Zieli\u0144ska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"key":"2045_CR1","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1023\/A:1021989230535","volume":"17","author":"RF Butterworth","year":"2002","unstructured":"Butterworth RF (2002) Pathophysiology of hepatic encephalopathy: a new look at ammonia. 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Astrocyte remodelling was linked to a decrease of plasmalemma-cytoskeleton linker phosphorylated ezrin (Phos-ERM), actin modulator profilin-1 (PFN1), and water channel aquaporin 4 (AQP4).","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Abbreviated summary"}},{"value":"Additional materials are available at Acta Neuropathologica Communications online.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Additional materials"}}],"article-number":"122"}}