Acta Neuropathologica Communications最新文献

{"title":"ATRX loss in adult gliomas lacking H3 alterations or IDH mutations, an exceptional situation for exceptional diagnoses: the experience of Sainte-Anne hospital.","authors":"Arnault Tauziède-Espariat, Alexandre Roux, Joseph Benzakoun, Paul Kauv, Sanaa Tazi, Alice Métais, Abigail K Suwala, Felix Hinz, Lauren Hasty, Mathilde Filser, Julien Masliah-Planchon, Raphaël Saffroy, Margot Bucau, Johan Pallud, Pascale Varlet","doi":"10.1186/s40478-025-02044-6","DOIUrl":"10.1186/s40478-025-02044-6","url":null,"abstract":"<p><p>ATRX immunostaining constitutes a routinely used biomarker for the practice of neuropathology. The loss of ATRX expression correlating with ATRX gene alterations is implicated in a wide variety of pediatric and adult gliomas, and has been indexed as a desirable or essential diagnostic criterion for four tumor types featured in the latest world health organization classification of central nervous system Tumors. In adult-type diffuse glioma, the loss of ATRX expression is a hallmark of astrocytoma, IDH-mutant. Recently, novel tumor types and alterations have been referenced in the literature. These include the high-grade astrocytoma with piloid features (HGAP), for which no consistent clinicopathological features have been defined, and the presence of other alterations in the Krebs cycle genes (variants of the Fumarate hydratase -FH- gene) found in gliomas resembling astrocytomas, IDH-mutant. Because of this rapidly evolving classification and histomolecular landscape, we retrospectively analyzed adult gliomas diagnosed over a four consecutive year period to identify supratentorial gliomas, lacking H3 alterations or IDH mutations and harboring a loss of ATRX expression, in order to update their diagnoses in terms of histopathology, genetics and epigenetics. Four specimens (from 620 adult gliomas, 0.7%) were reclassified at the end of the molecular workup, as: 1/ one HGAP, 2/ one malignant transformation with a primitive neuronal component of an astrocytoma, IDH-mutant which lost the IDH2 mutation at recurrence, 3/ a glioma, FH-mutant for which the histopathological and epigenetic features were similar to an astrocytoma, IDH-mutant, and 4/ a glioblastoma, IDH-wildtype. To conclude, these exceptional cases extend the spectrum of ATRX loss in gliomas, beyond the astrocytoma, IDH-mutant and the diffuse hemispheric glioma, H3 G34-mutant.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"131"},"PeriodicalIF":6.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of immune subtypes associated with the prognosis in skull base chordoma.","authors":"Yujia Xiong, Mingxuan Li, Guangyi Niu, Tianyi Xu, Chuzhong Li, Tianshun Ma, Tianhao Zhang, Hela Koka, Lili Hao, Yazhuo Zhang, Jiwei Bai, Xiaohong R Yang","doi":"10.1186/s40478-025-02053-5","DOIUrl":"10.1186/s40478-025-02053-5","url":null,"abstract":"<p><p>Chordoma is a rare malignant bone tumor that is prone to local recurrence. Recent omics studies suggest that chordoma is a heterogenous disease and the tumor immune microenvironment (TIME) may be associated with chordoma recurrence and patient survival. The aim of this study was to explore the prognostic role of TIME in skull base chordoma. We conducted RNA sequencing of fresh frozen tumors from 77 Chinese skull base chordoma patients and performed unsupervised clustering using immune cell scores estimated by single sample gene set enrichment analysis (ssGSEA) to identify potential immune subtypes. Immunohistochemical (IHC) staining, ESTIMATE, CIBERSORT and xCell were used to validate differences in immune composition between the two immune subtypes. An independent cohort of 261 skull base chordoma patients with long follow-up data was further used to investigate the prognostic associations of immune cells. We identified two immune subtypes (A and B) of skull base chordoma. Compared to tumors in cluster A, tumors in cluster B had higher infiltration of most immune cell populations especially macrophages and T cells. The differences were confirmed by IHC staining of CD68, CD163, and CD3 in a subset of patients (n = 51) with fixed tumor blocks available. Moreover, higher proportions of macrophages (CD68 and CD163) were significantly correlated with shorter PFS (CD68: P < 0.001, CD163: P < 0.001) and OS (CD68: P = 0.04, CD163: P = 0.004) in an independent set of 261 patients with long follow-up data. Our study identified immune subtypes of chordoma that were associated with clinical outcomes and highlighted the potential prognostic value of macrophages. These findings may enhance our understanding of TIME and suggest the importance of macrophages in chordomas.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"130"},"PeriodicalIF":6.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement inhibition rapidly blocks lesion extension and facilitates remyelination in neuromyelitis optica.","authors":"Katherine S Given, Elizabeth G Acker, Wendy B Macklin, Dan Carlin, Gregory P Owens, Jeffrey L Bennett","doi":"10.1186/s40478-025-02019-7","DOIUrl":"10.1186/s40478-025-02019-7","url":null,"abstract":"<p><p>Cumulative disability in neuromyelitis optica spectrum disorder (NMOSD) results from incomplete recovery following inflammatory, demyelinating attacks. Retrospective case studies and current clinical practice indicate that rapid treatment of acute attacks with apheresis limits injury and improves recovery. We evaluated the effects of apheresis and complement inhibition on lesion progression and recovery in a murine ex vivo cerebellar explant model of NMOSD injury. While both strategies reduced lesion formation relative to vehicle treatment, we observed that anti-C5 complement inhibition with eculizumab rapidly halted astrocyte destruction and immediately curtailed lesion extension; whereas an experimental mimic of immunoadsorption (IA), allowed for continued low level astrocyte destruction. During lesion recovery, C5 complement inhibition resulted in a faster rate of oligodendrocyte repopulation and improved myelin repair compared to IA. Complement inhibition may offer multiple benefits for the treatment of acute NMOSD attacks.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"129"},"PeriodicalIF":6.2,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the brain: early autonomic dysfunction in Alzheimer's disease.","authors":"Carmen Nanclares, Inés Colmena, Alicia Muñoz-Montero, Andrés M Baraibar, Ricardo de Pascual, Aneta Wojnicz, Ana Ruiz-Nuño, Antonio G García, Adrián Gironda-Martínez, Luis Gandía","doi":"10.1186/s40478-025-02042-8","DOIUrl":"10.1186/s40478-025-02042-8","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is classically defined by central hallmarks such as amyloid-beta plaques, tau hyperphosphorylation, and synaptic failure. However, mounting evidence suggests that dysfunction outside the brain, particularly in the peripheral nervous system, may also play a significant role in disease progression. The adrenal medulla-a key regulator of systemic neurotransmission and stress response-has received little attention in this context. In this study, we investigated whether chromaffin cells (CCs) from the triple transgenic AD mouse model (3xTg) exhibit functional alterations that could contribute to peripheral neurochemical imbalance. Using electrophysiology, high-resolution amperometry, and neurotransmitter quantification, we identified early and progressive defects in CC function. Remarkably, even at two months of age-prior to cognitive decline-3xTg CCs showed impaired exocytosis, reduced vesicle release, and slower fusion pore kinetics. These changes were accompanied by diminished sodium (I_Na), calcium (I_Ca), and nicotinic (I_ACh) currents, compromising CC excitability. With age, a shift toward increased potassium (I_K) currents and enhanced catecholamine secretion may reflect compensatory adaptations aimed at preserving output. These functional deficits were paralleled by structural remodeling of the actin cytoskeleton and systemic neurotransmitter disturbances. Noradrenaline levels increased in both plasma and brain, while dopamine decreased peripherally but paradoxically increased in the prefrontal cortex and hippocampus. Serotonin levels consistently declined across compartments. These imbalances correlated with altered behavior: 3xTg mice displayed increased exploration of exposed areas and heightened behavioral despair, pointing to anxiety- and depression-like phenotypes. Together, our findings identify the adrenal medulla as a previously underrecognized site of early catecholaminergic dysregulation in AD. The observed associations between peripheral CC dysfunction, systemic neurotransmitter imbalance, and behavioral changes point to a potential link between peripheral neuroendocrine alterations and central disease features. These results broaden the current understanding of AD pathophysiology and support the adrenal medulla as a promising candidate for further investigation as a therapeutic target and source of peripheral biomarkers.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"128"},"PeriodicalIF":6.2,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptome sequencing reveals new epithelial-stromal associated mesenchymal-like subsets in recurrent gliomas.","authors":"Jinwei Li, Shengrong Long, Yang Zhang, Shuangqi Yu, Hongyu Xu, Rui Liang, Quan Liu, Jinnan Zhang, Xiang Li, Yixin Fu, Tao Xin, Yinyan Wang","doi":"10.1186/s40478-025-02036-6","DOIUrl":"10.1186/s40478-025-02036-6","url":null,"abstract":"<p><p>Gliomas, particularly glioblastomas, are highly malignant brain tumors with high recurrence rates and poor prognosis. Despite advances in treatment, recurrence remains a major challenge. Epithelial-mesenchymal transition (EMT) plays a key role in tumor invasion and recurrence. This study explores the transcriptional and regulatory mechanisms driving glioma recurrence, focusing on mesenchymal-like (MES-like) subpopulations. Single-nucleus RNA sequencing was performed on 52 IDH wild-type GBM specimens, including 26 primary and 26 recurrent tumors. Spatial transcriptomics data were also incorporated. Tumor subpopulations were identified through gene regulatory network analysis, copy number variation detection, and nonnegative matrix factorization. Functional validation was conducted using gene knockdown experiments, followed by xenograft studies. We discovered novel MES-like subpopulations in recurrent GBM enriched with EMT-related genes like EGR1 and SERPINE1. These subpopulations exhibited increased transcriptional activity and were associated with poor prognosis and invasiveness. Knockdown of SERPINE1 significantly reduced cell proliferation and migration. Spatial transcriptomics showed MES-like cells concentrated at the tumor margins, highlighting their role in invasion and recurrence. MES-like subpopulations, driven by EGR1 and SERPINE1, are critical in GBM. Targeting these regulators could offer new therapeutic strategies to reduce glioma recurrence and improve outcomes.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"127"},"PeriodicalIF":6.2,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights.","authors":"Hengzeng Li, Yahui Wu, Yue Chen, Jinquan Lv, Chengkang Qu, Tingjie Mei, Yunfan Zheng, Cheng Ye, Feifei Li, Shuo Ge, Anhui Yao, Liyun Jia","doi":"10.1186/s40478-025-02046-4","DOIUrl":"10.1186/s40478-025-02046-4","url":null,"abstract":"<p><p>Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O⁶-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective autophagy, an immunosuppressive tumor microenvironment (TME), altered signaling pathways, and active drug efflux transporters. Recent advancements to overcome these resistance mechanisms, including enhancing TMZ bioavailability through nanoparticle-based delivery systems and the inhibition of efflux transporters, have been explored. Novel therapeutic approaches that target DNA repair pathways and manipulate autophagy are highlighted. Immunotherapeutic interventions reversing immune suppression and metabolic strategies targeting tumor metabolism offer additional avenues. Emerging therapies such as CRISPR-based gene editing, phytochemical combinations, repurposed drugs, and novel TMZ analogs designed to bypass MGMT-mediated resistance are also discussed. This review highlights current developments and identifies emerging areas, with the goals of enhancing clinical outcomes and prolonging survival for glioma patients.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"126"},"PeriodicalIF":6.2,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid metabolism disorder promoting retinal structural and functional damage in ApoE^-/- mice with age superposition.","authors":"Rucui Yang, Shaolang Chen, Tsz Kin Ng, Jiajian Liang, Shaofen Huang, Minru Deng, Zhenggen Wu, Yaru Sun, Changzhen Fu, Chi Pui Pang, Qingping Liu, Mingzhi Zhang","doi":"10.1186/s40478-025-02043-7","DOIUrl":"10.1186/s40478-025-02043-7","url":null,"abstract":"<p><p>This study aimed to establish a model of abnormal lipid metabolism in Apolipoprotein E (ApoE) knockout mice by feeding them a high-fat diet (HFD) and to investigate the impact of this abnormal lipid metabolism on retinal blood perfusion, structure, and function, particularly the retinal ganglion cell (RGC). Both HFD and regular diet (RD) feeding were conducted in C57BL/6J mice and ApoE^-/- mice. Lipid metabolism was assessed using hematoxylin-eosin (HE) staining, oil red staining, and blood lipid detection. Retinal microcirculation was evaluated through fundus fluorescein angiography. The expression levels of inflammatory cytokines were determined using quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Intraocular pressure, retinal structure, and RGCs were assessed using tonometer, optical coherence tomography, HE staining, and immunofluorescence staining. Retinal function was measured by electroretinogram. Hyperlipidemia was induced in ApoE^-/- mice fed HFD. Retinal microcirculation was impaired in mice with abnormal lipid metabolism, while the expression of the inflammatory cytokine Tnf-α was significantly increased in atherosclerotic plaques, serum, and retina. Ultimately, compared with normal mice on a RD, ApoE^-/- mice fed HFD exhibited no significant changes in intraocular pressure but demonstrated decreased RGC density and impaired retinal structure and function of the inner and outer layers of the retina. The abnormal lipid metabolism in ApoE^-/- mice fed a HFD can exacerbate the disturbance of intraocular microcirculation and RGC loss caused by aging, as well as inflammation of the intraocular microenvironment and damage to retinal function.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"125"},"PeriodicalIF":6.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation alters myeloid cell and oligodendroglial iron-handling in multiple sclerosis.","authors":"Christian J Riedl, Daniel Bormann, Anja Steinmaurer, Anja Novak, Giulia Testa, Elena Poldlehner, Carmen Haider, Thomas Berger, Michael Mildner, Romana Höftberger, Ferdinand Schweser, Simon Hametner","doi":"10.1186/s40478-025-02020-0","DOIUrl":"10.1186/s40478-025-02020-0","url":null,"abstract":"<p><p>Changes in brain iron levels are a consistent feature of multiple sclerosis (MS) over its disease course. They encompass iron loss in oligodendrocytes in myelinated brain regions and iron accumulation in myeloid cells at so-called paramagnetic rims of chronic active lesions. Here, we explore the mechanisms behind this overall shift of iron from oligodendrocytes (OLs) to myeloid cells (MCs) and the loss of total brain-iron in MS. We investigated the expression of various iron importers and exporters, applying immunohistochemistry to a sample of control and MS autopsy cases. Additionally, we studied the transcriptional response of iron-related genes in primary rodent OL progenitor cells (OPCs) and microglia (MG) to various combinations of known MS-relevant pro-inflammatory stimuli together with iron loading. Histologically, we identified a correlation of OL-iron accumulation and the expression of the ferritin receptor TIM1 in myelinated white matter and observed an increase in the expression of iron-related proteins in myeloid cells at the lesion rims of MS plaques. qPCR revealed a marked increase of the heme scavenging and degradation machinery of MG under IFN-γ exposure, while OPCs changed to a more iron-inert phenotype with apparent decreased iron handling capabilities under MS-like inflammatory stimulation. Collectively, our data suggest that OL iron loss in MS is mainly due to a decrease in ferritin iron import. Iron accumulation in MCs at rims of chronic active lesions is in part driven by up-regulation of heme import and metabolism, while these cells also actively export ferritin.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"124"},"PeriodicalIF":6.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive, multi-center, immunogenomic analysis of melanoma brain metastases.","authors":"Lucy Boyce Kennedy, Amanda E D Van Swearingen, Marissa R Lee, Layne W Rogers, Alexander B Sibley, Jeff Sheng, Dadong Zhang, Xiaodi Qin, Eric S Lipp, Swaminathan Kumar, Aron Joon, Pixu Shi, Michael A Davies, Kouros Owzar, Carey K Anders, April K S Salama","doi":"10.1186/s40478-025-02035-7","DOIUrl":"10.1186/s40478-025-02035-7","url":null,"abstract":"<p><strong>Background: </strong>Melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biological features and clinical outcomes of MBM will facilitate the design of rational therapies.</p><p><strong>Methods: </strong>We examined the mutational landscape and gene expression profiles of MBM (74 patients) and ECM (34 patients) in paired patient samples from a previously published dataset with whole-exome sequencing (WES) and RNA sequencing (RNAseq) data from MD Anderson Cancer Center (MDACC). We also present findings from MBM from a new cohort of 14 patients from Duke University to strengthen investigation of somatic mutations and gene expression profiles. Gene Set Enrichment Analysis (GSEA) was used to compare paired MBM versus lymph node (LN) metastases and skin metastases. Relative immune cell abundance was inferred using deconvolution methods. Survival outcomes from craniotomy and associations with biological features, BRAF mutation status, and PTEN expression were assessed.</p><p><strong>Results: </strong>GSEA found that autophagy signaling pathways are enriched in MBM versus LN and skin metastases. BRAF was the most frequently mutated clinically relevant gene in MBM and ECM, with NRAS and PTEN also frequently altered in MBM. The most strongly upregulated genes in autophagy pathways were glial fibrillary acidic protein (GFAP) and hemoglobin beta (HBB). An increased proportion of immune-suppressive M2 compared to tumor-suppressive M1 macrophages in MBM and ECM was identified. There was not sufficient evidence for an association between BRAF V600 mutation status or expression and overall survival (OS) from craniotomy.</p><p><strong>Conclusions: </strong>The mutational landscape and gene expression of MBM from the Duke cohort resembled those previously reported in the MDACC cohort. Upregulation of autophagy pathways was observed in patient-matched MBM versus LN and skin metastases due to upregulation of two genes, GFAP and HBB. In MBM, higher M2:M1 ratio may contribute to a therapeutically relevant immune-suppressive tumor microenvironment (TME).</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"123"},"PeriodicalIF":6.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oedematic-atrophic astrocytes in hepatic encephalopathy.","authors":"Mariusz Popek, Marta Obara-Michlewska, Łukasz Mateusz Szewczyk, Marcin Kołodziej, Karol Perlejewski, Alexei Verkhratsky, Jan Albrecht, Magdalena Zielińska","doi":"10.1186/s40478-025-02045-5","DOIUrl":"10.1186/s40478-025-02045-5","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"122"},"PeriodicalIF":6.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}