Neuropathology and Applied Neurobiology最新文献

{"title":"Role of Astrocytic and Microglial Phenotype in the Biology of Hippocampal Sclerosis.","authors":"Aditi Goyal, Shilpa Rao, Amit Kumar Saha, Harsha Sugur, Roshni Poulose, Omkar Shirke, Nivedha Mohanraj, Bhupesh Mehta, Mariamma Philip, A Arivazhagan, Jitender Saini, L G Vishwanathan, Ajay Asranna, K Raghavendra, R C Mundlamuri, Nishanth Sadashiva, R D Bharath, K Karthik, M Sandhya, Malla Bhaskara Rao, Sanjib Sinha, Anita Mahadevan","doi":"10.1111/nan.70044","DOIUrl":"https://doi.org/10.1111/nan.70044","url":null,"abstract":"<p><strong>Aims: </strong>Astrocytic and microglial phenotypes (A1/A2 and M1/M2, respectively) with neuro-inflammatory and neuroprotective roles are key players in the pathogenesis of several neurological diseases. However, their role in epilepsy is underexplored. We investigated astrocytic and microglial phenotypes in the pathogenesis of epileptogenesis in hippocampal sclerosis (HS), causing drug-resistant temporal lobe epilepsy.</p><p><strong>Methods: </strong>Astrocytic and microglial phenotypes were assessed in 10 histologically confirmed cases of surgically resected HS and four age-matched post-mortem controls by immunohistochemistry, using C3 and GBP2 (A1-astrocyte), pSTAT3 (A2-astrocyte), CD14 (M1-microglia) and CD163 and CD206 (M2-microglia), as well as Caspase 3 (apoptosis) and phosphorylated-tau and phosphorylated-neurofilament (pNF) (neuronal degeneration). These were semiquantitatively assessed for their expression in sclerotic hippocampus. Validation was carried out by immunoblotting and quantitative real-time polymerase chain reaction (RT-PCR). Results of the glial phenotypes were correlated with clinical parameters.</p><p><strong>Results: </strong>Compared to the control group, a significant increase in pSTAT3+ A2-astrocytes was detected (range: 26.7-230.5 cells/mm²) compared to a mild increase in GBP2+ A1-astrocytes (0.4-11.4 cells/mm²). pSTAT3 expression was localised to subpial astrocytes and vascular endothelial cells, aligning with subpial gliosis and vascular sclerosis observed in HS. The findings were confirmed by RT-PCR, reflecting a predominantly reparative and neuroprotective A2 response to chronic seizure activity in HS. Among microglial phenotypes, perivascular staining with CD14+ M1 (6-23.7 vessels/mm²) and CD163+ M2-microglia (7.4-16 vessels/mm²) was significantly higher in hippocampal subfields showing neuronal loss and gliosis. Predominant inflammatory M1-microglia, along with an increase in M2-microglia, indicate an ongoing reparative response to chronic epilepsy. Surviving neurons in sclerotic Ammon's horn (AH) were labelled by pNF, indicating dysmorphic change. Several astrocytes and oligodendroglia in hippocampal AH and temporal white matter were labelled by caspase 3, probably promoting gliosis rather than apoptosis.</p><p><strong>Conclusions: </strong>This is the first study providing a comprehensive assessment of astrocytic and microglial phenotypes in HS. These identified phenotypes can be targeted in multiple stages, offering potential modulation of epileptogenesis and contributing to the treatment of epilepsy, especially in cases marked by drug resistance.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 5","pages":"e70044"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Specific Methylation Class Identifies BAP1-Deficient Meningiomas, Including Meningeal Tumours With Poorly Differentiated Nonrhabdoid Histology.","authors":"Philippe Drabent, Mehdi Touat, Patrick R Benusiglio, Philipp Euskirchen, Florence Coulet, Badreddine Mohand Oumoussa, Arnaud de la Fouchardière, Vincent Thomas de Montpreville, Julian Jacob, Daniele Bernardeschi, Pierre Laurent-Puig, Marc Sanson, Michel Kalamarides, Franck Bielle","doi":"10.1111/nan.70042","DOIUrl":"10.1111/nan.70042","url":null,"abstract":"<p><p>BAP1-deficient meningiomas have a preferential infratentorial or spinal localization and may present with an undifferentiated histology of small or epithelioid cells rather than the meningothelial, rhabdoid or papillary variants. Frequent expression of cytokeratins may be misleading for a metastatic carcinoma but loss of BAP1 immunostaining in tumor cells and a specific methylation class enable the diagnosis. The clinical impact of the histomolecular diagnosis of BAP1-deficient meningioma is the high risk of relapse and a possible underlying BAP1 tumour predisposition syndrome.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 5","pages":"e70042"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192189","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":"Use of DNA Methylation Profiling as a Molecular Classification Tool for Paediatric Central Nervous System Tumours: A Middle-Income Country Population-Based Study.","authors":"Mayara F Euzébio, Felipe L T Silva, Iva L Hoffmann, Juliana S Ruas, Larissa Akemi Kido, Dieila G de Lima, Luciano Queiroz, Izilda A Cardinalli, Ana Luiza Seidinger, Suelen Nascimento, Helder Tedeschi, Renato D Puga, Priscila Pini Zenatti Sales, Patricia Y Jotta, Mariana Maschietto","doi":"10.1111/nan.70041","DOIUrl":"10.1111/nan.70041","url":null,"abstract":"<p><p>Paediatric central nervous system (CNS) tumours are the second most common childhood malignancy and the leading cause of cancer-related mortality in this age group. Histopathological diagnosis can be challenging, particularly for rare or ambiguous tumours, and may result in misclassification. To evaluate the utility of DNA methylation profiling in a middle-income country, we performed the Infinium MethylationEPIC BeadChip (Illumina) on tumours from 182 paediatric patients treated at a reference centre for paediatric oncology in Campinas, state of São Paulo, Brazil. Data were analysed using the DKFZ/Heidelberg CNS tumour classifier (v12.8). After excluding control tissue, 163 samples (89.6%) were suitable for classification; 135 (74.2%) achieved a calibrated score ≥ 0.9 and were assigned to a methylation class family. Methylation profiling resulted in a tumour subtype for 88 cases (65.7%) and changed the diagnosis in 28 cases (20.9%), identifying several rare tumour subtypes that were identified solely through methylation analysis, confirming the value of this method in improving diagnostic accuracy. This study highlights the utility of DNA methylation profiling for paediatric CNS tumours in a resource-limited setting and provides a cohort from an underrepresented middle-income population to international molecular databases.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 5","pages":"e70041"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207076","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":"Protein Coaggregation in Caribbean Atypical Parkinsonism: The Contribution of Annonacin.","authors":"Florencia González-Lizárraga, Susana Boluda, José Ruiz Hidalgo, Cesar L Avila, Camille Dos Santos, Benjamin Socias, Luciana Medina, Hugo Chaumont, David Akbar, Emmanuel Roze, Rosana Chehin, Rita Raisman-Vozari, Patrick Pierre Michel, Annie Lannuzel","doi":"10.1111/nan.70026","DOIUrl":"10.1111/nan.70026","url":null,"abstract":"<p><strong>Aims: </strong>There is an unexpectedly high proportion of atypical forms of degenerative parkinsonism in the French Caribbean islands. Residents of these islands are thought to be susceptible to Caribbean atypical parkinsonism (CAP) owing to their consumption of Annonaceae plant products containing the mitochondrial toxin annonacin. Here, we aimed to better correlate the clinical diagnosis of CAP with the misfolded protein pathology observed in affected individuals and to further investigate how annonacin could contribute to CAP pathogenesis.</p><p><strong>Methods: </strong>We conducted postmortem histopathological analysis of brain samples from eight patients; more specifically, we assessed the distribution and burden of α-synuclein (αS) and tau pathologies. Additionally, we studied how annonacin influences αS and tau aggregation using biophysical assays, with the corresponding recombinant human proteins serving as substrates.</p><p><strong>Results: </strong>CAP was associated with heterogeneous clinical and histopathological features. Tau/αS copathology with a predominance of either αS or tau aggregates was observed in the majority (5/8) of patients. Tau and αS aggregates were sometimes colocalised in the same brain regions or cells. In biophysical assays, we showed that annonacin leads to an increase in αS aggregation and the formation of αS fibrils that could cross-seed tau aggregation.</p><p><strong>Conclusions: </strong>Annonacin may contribute to degenerative CAP by modulating the production of tau and αS pathogenic protein assemblies.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 4","pages":"e70026"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699117","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":"Clinicopathological Characteristics and Immune Microenvironment of Posterior Pituitary Tumours.","authors":"Yu-Jie Li, Wei Wang, An-Li Zhang, Heng Li, Hai-Bo Wu","doi":"10.1111/nan.70029","DOIUrl":"10.1111/nan.70029","url":null,"abstract":"<p><strong>Aims: </strong>Posterior pituitary tumours (PPTs) represent a distinct group of low-grade neoplasms characterised by unique pathological features and immunohistochemical phenotypes. However, their precise immunological environment remains poorly understood, posing challenges to a deeper understanding of their biological behaviour and potential treatment implications. This study aimed to characterise the clinicopathological features and immune landscape of PPTs, focusing on the infiltration patterns of T cells and macrophages.</p><p><strong>Methods: </strong>Sixteen PPTs were retrospectively analysed, including 10 pituicytomas (PC) and six spindle cell oncocytomas (SCO), using clinicopathological evaluation, immunohistochemical staining and multiplex immunofluorescence.</p><p><strong>Results: </strong>Histopathological examination identified both classical and uncommon morphological characteristics, such as multinucleated giant cells, hemangiopericytoma-like vascular patterns, calcification and haemosiderosis. Immunohistochemical expression of programmed cell death ligand 1 (PD-L1) was rare, with only two cases showing focal positivity. Multiplex immunofluorescence for the analysis of the tumour immune microenvironment revealed distinct immune landscapes between PC and SCO. SCO exhibited a higher proportion of cytotoxic T lymphocytes (CTLs) and closer spatial interactions between macrophages and interferon (IFN)-γ-producing cells, reflecting a more robust antitumour immune response. In contrast, PC showed an increased proportion of exhausted CD8+ T cells, suggesting a more pronounced immunosuppressive microenvironment.</p><p><strong>Conclusions: </strong>This study reveals distinct immune microenvironmental profiles between PC and SCO, with SCO exhibiting an immune-active phenotype, whereas PC is characterised by features of immune exhaustion. These differences underscore the potential for differential immunotherapeutic approaches, such as targeting immune exhaustion pathways in PC or enhancing CTLs activity in SCO.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 4","pages":"e70029"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of Human Prion Seeding Activity in Formalin-Fixed Paraffin-Embedded Archival Tissues.","authors":"Soňa Baranová, Radoslav Matěj, Jiri G Safar, Karel Holada","doi":"10.1111/nan.70028","DOIUrl":"10.1111/nan.70028","url":null,"abstract":"<p><strong>Aims: </strong>Formalin-fixed paraffin-embedded (FFPE) samples, routinely used in neuropathology, represent an invaluable resource for studying rare diseases like transmissible spongiform encephalopathies (TSE). Despite fixation-induced protein cross-linking, prion seeding activity can be effectively detected using the seeding amplification assays. In this study, we employed the second-generation real-time quaking-induced conversion (RT-QuIC) assay to analyse and quantify human prion seeding activity in FFPE brain tissues.</p><p><strong>Methods: </strong>FFPE frontal brain tissues were deparaffinised in xylene, followed by rehydration through descending concentrations of ethanol. The prion seeding activity in tissue homogenates was assessed by RT-QuIC assay utilising short recombinant hamster prion protein (rHaPrP90-231) as a substrate.</p><p><strong>Results: </strong>A total of 60 samples, including 30 cases of confirmed TSE, comprising both sporadic and genetic forms, as well as 30 non-TSE controls, were analysed. Prion seeding activity has been detected in all TSE samples except one sCJD (VV2) and one GSS (P102L) case, corresponding to an assay sensitivity of 93.3%. Conversely, we did not detect any RT-QuIC positivity in the control group, resulting in 100% specificity. The mean 50% prion seeding dose of FFPE sporadic TSE samples was 10^7.8/g of brain tissue.</p><p><strong>Conclusion: </strong>Our study emphasises high sensitivity and specificity of RT-QuIC assay for prion detection in archival human FFPE brain tissues and demonstrates its diagnostic reliability comparable to other tissue types even after years of storage. The applicability of FFPE samples in RT-QuIC assays facilitates retrospective diagnostics and provides logistical advantages for sample preservation and transportation.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 4","pages":"e70028"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591798","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":"Standardised TruAI Automated Quantification of Intracellular Neuromelanin Granules in Human Brain Tissue Sections.","authors":"Anastasia Filimontseva, Thais Cuadros, Zac Chatterton, Amy Burke, Anahid Ansari Mahabadian, Joan Compte, YuHong Fu, Miquel Vila, Glenda M Halliday","doi":"10.1111/nan.70033","DOIUrl":"10.1111/nan.70033","url":null,"abstract":"<p><strong>Aims: </strong>To standardise and automate the quantitation of human-unique neuromelanin granules in catecholamine neurons in post-mortem tissue sections from healthy individuals at different ages to understand any changes in these granules with age.</p><p><strong>Methods: </strong>Five- to 6-μm-thick fixed and paraffin-embedded transverse midbrain tissue sections were supplied from 47 cases from three brain banks following ethical approvals. Sections were prepared and automated digital images acquired. Standardisation and automation of the quantification of neuromelanin granules was performed using the TruAI feature of the Olympus VS200 desktop platform. Comparisons between stained and unstained sections as well as correlations with age were performed.</p><p><strong>Results: </strong>The automated platform reliably identified both stained and unstained intracellular neuromelanin granules and extracellular pigments, showing high reproducibility in measurements across laboratories using different tissue processing methods. Extraneuronal pigments were significantly smaller than intracellular neuromelanin granules. Sections processed for haematoxylin and eosin staining impacted the size and colour of both neuromelanin and the neurons containing neuromelanin. Haematoxylin made neuromelanin bluer, and the increased tissue processing made the intracellular area occupied by neuromelanin smaller in younger people. There was an increase in neuromelanin optical density and colour change (browner) with age.</p><p><strong>Conclusions: </strong>The TruAI automated platform reliably quantifies individual neuromelanin granules in catecholamine neurons. Extraneuronal pigments are considerably smaller in size than intracellular neuromelanin, and intracellular neuromelanin changes its properties with age. The darkening and colour change of intracellular neuromelanin suggest an increase in eumelanin over time in healthy individuals. These changes can be reliably identified using the automated platform.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 4","pages":"e70033"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822131","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":"Three-Dimensional Visualisation of Blood Vessels in Human Gliomas Using Tissue Clearing and Deep Learning.","authors":"Xiaodu Yang, Xinyue Wang, Dian He, Feiyang Luo, Chenyang Li, Yunhao Luo, Ting Li, Zhaoyu Ye, Chun Ye, Minglin Zhang, Hei Ming Lai, Yingying Xu, Haitao Sun","doi":"10.1111/nan.70027","DOIUrl":"10.1111/nan.70027","url":null,"abstract":"<p><p>Gliomas, with their intricate and aggressive nature, call for a detailed visualisation of their vasculature. Traditional 2D imaging often overlooks the spatial heterogeneity of tumours. Our study overcomes this by combining tissue clearing, 3D-confocal microscopy imaging and deep learning-aided vessel extraction, achieving comprehensive 3D visualisation of glioma vasculature in intact human tissue. Specifically, we treated formalin-fixed thick human glioma tissue sections (500 μm) with OPTIClear for transparency and performed immunofluorescent labelling. Using confocal microscopy, we obtained 3D images of glioma vasculature. For vessel extraction, we employed a specialised 3D U-Net, enriched with image preprocessing and post-processing methods. In addition, we obtained 3D images of astrocytes or glioma cells, cell nuclei and vasculature with vascular basement membrane staining. Our findings indicated that OPTIClear-enabled tissue clearing yielded a holistic 3D representation of immunolabelled vessels and surrounding cells in human glioma samples. Our deep learning technique outperformed the traditional Imaris approach in terms of accuracy and efficiency in vessel extraction. Furthermore, discernible variations in vascular morphological metrics were observed between low- and high-grade gliomas, revealing the spatial heterogeneity of human glioma vessels. Analysis of other markers demonstrated differences in glioma cell morphology and vessel wall disruption across grades. In essence, our innovative blend of tissue clearing and deep learning not only enhances 3D visualisation of human glioma vasculature but also underscores morphological disparities across glioma grades, potentially influencing pathological grading, therapeutic strategies and prognostic evaluations.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 4","pages":"e70027"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased Incidence of Epilepsy in a Brain Bank Alzheimer's Disease Cohort and Its Association With TDP-43 Pathology.","authors":"Federica Rocca, Jaimee Kennedy, Shamis Osman, Zita Reisz, Andrew King, Istvan Bodi, Safa Al-Sarraj, Claire Troakes","doi":"10.1111/nan.70034","DOIUrl":"10.1111/nan.70034","url":null,"abstract":"<p><strong>Aims: </strong>Evidence suggests Alzheimer's disease (AD) patients are at increased risk of epilepsy and that seizure incidence is associated with faster cognitive decline. Previous studies indicate hyperphosphorylated tau may play a role in this disease association; however, abnormal TDP-43 and α-synuclein deposition have not been extensively examined.</p><p><strong>Methods: </strong>Clinical and neuropathological records of AD cases over a 5-year period were retrieved from the London Neurodegenerative Diseases Brain Bank. The 114 cases were categorised into three groups: AD plus epilepsy, AD plus hippocampal sclerosis (HS) and AD only. Semi-quantitative scores for tau, TDP-43 and α-synuclein pathology within the middle temporal gyrus, hippocampus and amygdala were compared between groups.</p><p><strong>Results: </strong>A 12% incidence of epilepsy and/or epileptic symptomology was found among the cohort. Twelve cases (11%) showed HS. No significant difference in tau pathology scores was seen between groups. However, a significantly higher score for TDP-43 was seen in AD plus epilepsy compared with AD only in the middle temporal gyrus (p = 0.004). The burden of α-synuclein pathology was increased in the amygdala of AD plus epilepsy and AD plus HS.</p><p><strong>Conclusions: </strong>The incidence of epilepsy within this AD cohort is higher than expected within the general population (even when matched for age), and this may be associated with increased TDP-43 burden. Understanding the relationship between AD and epilepsy may highlight mechanisms of cellular damage and tissue vulnerability.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 4","pages":"e70034"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962598","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":"An Intracerebrally-Infected Mouse Model of Enterovirus A71 Demonstrates Restricted Inter-Neuronal Spread Within the Brain Parenchyma Despite Strong SCARB2 Expression.","authors":"Munira Hamidi, Kien Chai Ong, Soon Hao Tan, Kum Thong Wong","doi":"10.1111/nan.70031","DOIUrl":"10.1111/nan.70031","url":null,"abstract":"<p><strong>Aims: </strong>Enterovirus A71 (EV-A71) can cause fatal encephalomyelitis, but the mechanisms of its spread within the central nervous system (CNS) remain unclear. This study aimed to investigate the pathways of EV-A71 dissemination after direct intracerebral inoculation and to assess the role of the murine Scavenger Receptor Class B Member 2 (mSCARB2) receptor in this process.</p><p><strong>Methods: </strong>A mouse-adapted EV-A71 strain (MAVS) was intracerebrally inoculated into the thalamus/hypothalamus or pons/medulla of 2-week-old ICR mice. Tissues were harvested and analysed by histopathology and viral titration at 24, 48 and 72 h post-infection (hpi). The infectivity of MAVS was also tested on N1E115 mouse neuroblastoma cells.</p><p><strong>Results: </strong>Viral antigens at the injection sites diminished over time, with restricted centrifugal inter-neuronal spread. From 48 hpi, viral antigens increased in distant motor-related neurons of the brainstem and spinal cord. There was a poor correlation between mSCARB2 expression and sites of infection; despite high mSCARB2 expression in the brain, spread was limited, while skeletal muscle, which lacks mSCARB2, showed severe infection. Direct infection of N1E115 cells was inefficient, but viral RNA transfection resulted in robust replication.</p><p><strong>Conclusions: </strong>The findings suggest a circuitous dissemination route: viral leakage from the CNS leads to viraemia and peripheral muscle infection, followed by retrograde axonal transport back into the brainstem and spinal cord. This pathway appears to be the dominant mode of CNS invasion, independent of mSCARB2 distribution. Alternative receptor pathways likely play a critical role in EV-A71 neuropathogenesis.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 4","pages":"e70031"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}