Acta Neuropathologica Communications最新文献

{"title":"Frontotemporal Lobar degeneration with TDP-43 presenting as progressive supranuclear palsy syndrome.","authors":"Aya Murakami, Shunsuke Koga, Hiroaki Sekiya, Masataka Nakamura, Yusuke Yakushiji, Dennis W Dickson","doi":"10.1186/s40478-025-02058-0","DOIUrl":"10.1186/s40478-025-02058-0","url":null,"abstract":"<p><strong>Objective: </strong>Frontotemporal lobar degeneration with TDP-43 pathology (FTLD) usually presents with frontotemporal dementia, semantic aphasia or progressive nonfluent aphasia. Corticobasal syndrome and atypical parkinsonism have been occasionally reported, but progressive supranuclear palsy (PSP) syndrome (also known as Richardson syndrome (RS)) has not been reported in patients with FTLD-TDP. In this study we report clinical and pathologic characteristics of FTLD-TDP, clinically diagnosed as PSP syndrome (FTLD-TDP-PSP).</p><p><strong>Methods: </strong>We reviewed clinical information of 270 patients with FTLD-TDP from the Mayo Clinic brain bank and identified 5 patients with FTLD-TDP-PSP. As a control group, we selected ten consecutive patients of pathologically confirmed PSP with clinical presentations of PSP syndrome (PSP-RS). We compared the clinical and pathological features of FTLD-TDP-PSP and PSP-RS.</p><p><strong>Results: </strong>The most common clinical symptoms in FTLD-TDP-PSP were memory loss (100%) followed by parkinsonism (80%), early falls (60%), and behavioral variant FTD (60%). All patients with PSP-RS met the Movement Disorder Society's criteria for probable PSP, while only one FTLD-TDP-PSP met the probable PSP. Two of the five patients with FTLD-TDP-PSP had moderate or severe neuronal loss in the substantia nigra and one had moderate or severe neuronal loss in the putamen and globus pallidus.</p><p><strong>Conclusion: </strong>A small subset of patients with FTLD-TDP can, in rare instances, present with symptoms associated with PSP. Therefore, FTLD-TDP may be considered in differential diagnosis, especially in patients who do not meet the diagnostic criteria. Our findings emphasize the need for further clinical and biomarker studies of FTLD-TDP.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"151"},"PeriodicalIF":6.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599070","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":"Immunoelectron microscopy and biochemical studies using three anti-tau antibodies in human brains: associations between pTau and ribosomes.","authors":"Douglas Price, Jillian Cramer, Colin B Rogers, Paresh Prajapati, Yamaan Shakhashiro, Peter T Nelson, Wang-Xia Wang","doi":"10.1186/s40478-025-02072-2","DOIUrl":"10.1186/s40478-025-02072-2","url":null,"abstract":"<p><p>The hallmark neuropathological lesions of Alzheimer's disease (AD) are extracellular amyloid-beta (Aβ) plaque deposits and intracellular Tau neurofibrillary tangles (NFTs). Identifying the intracellular localization of early pathologic changes can enhance our understanding of disease mechanisms and stimulate new approaches in diagnosis and treatment. Despite extensive biochemical studies of AD-related protein aggregates, there have been relatively few studies recently in terms of transmission electron microscopy of proteinaceous lesions in human brains across a range of disease severity. Here we performed immunoelectron microscope studies used three anti-Tau antibodies (MC-1, AT8, and PHF-1) on short post-mortem interval (PMI) human brain tissues obtained from the University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) autopsy cohort, along with corresponding biochemical and immunofluorescent studies. Although these three antibodies have been reported to label different phases of NFT formation, in our hands they all tended to stain pathologic structures along a continuum that included pretangles and mature NFTs. Immunoelectron microscopy studies, augmented by serial sectioning, revealed that all three Tau antibodies recognize both granular and fibrillary structures in pretangles and early-stage NFTs. Phosphorylated Tau (pTau) immunoreactivity often exhibited a peri-nuclear distribution. The pTau was frequently found localized to ribosomes, either free within the cytoplasm or attached to the endoplasmic reticulum (ER). This observation aligns with previous descriptions, but the enhanced ultrastructural preservation provided improved resolution. Subcellular fractionation and Western blot analyses confirmed the enrichment of pTau in the ER fractions in AD brains. Interestingly, total Tau (including non-phosphorylated Tau) did not preferentially co-purify with the ER in non-AD brains. Immunofluorescent staining revealed that pTau immunoreactivity evolved from cytoplasmic granules in pretangles, with an intracytoplasmic distribution that overlapped complementarily with ribosome and ER markers. Our results suggest that biochemical associations between pTau with ribosomes and ER are a common phenomenon in human aged brains.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"150"},"PeriodicalIF":6.2,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582789","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":"Spatial transcriptome analysis of myenteric plexus and intestinal epithelium of colon in patients with Parkinson's disease.","authors":"Chaewon Shin, Karoliina Eliisa Ruhno, Jung Hwan Shin, Sanha Hwang, Jasper Roldan Go, Minji Kang, Hyun Je Kim, Ji Hwan Moon, Han-Joon Kim","doi":"10.1186/s40478-025-02047-3","DOIUrl":"10.1186/s40478-025-02047-3","url":null,"abstract":"<p><p>Alpha-synuclein (AS) accumulation is found in the nerve plexuses of the gastrointestinal tract in patients with Parknison's disease (PD). Moreover, alterations in microbiome composition and its metabolites were confirmed in the colon of patients with PD. However, there has been no study that evaluates transcriptomic alterations of the nerve plexus and intestinal epithelium simultaneously using in vivo tissue of patients with PD. Therefore, we aimed to investigate the gene expression profiles of the myenteric plexus and intestinal epithelium of the colon of patients with PD. Ten full-depth slides of paraffin-embedded surgical specimens of the colon or rectum from five patients with PD and five controls were included. AS accumulation was found in the myenteric plexus in all patients with PD. We performed spatial-specific transcriptomic profiling of the myenteric plexus and epithelium using the GeoMX Digital Spatial Profiler. Forty-one differentially expressed genes (DEGs) (36 up-regulated and 5 down-regulated) were identified in the myenteric plexus of patients with PD compared to controls. In the intestinal epithelium, 240 DEGs (81 up-regulated and 159 down-regulated) were identified. Pathway analysis showed upregulated response to type II interferon and lymphocyte activation, while downregulated cellular response to zinc and copper ions in the intestinal epithelium of patients with PD. In the myenteric plexus, neuroepithelial cell differentiation and axon development were upregulated. Network analysis showed the following key genes: and HLA-DRA, SERPINA1, and metallothioneins in the intestinal epithelium, and LAMP1, TUBB2A, and S100B in the myenteric plexus. This study suggests that inflammatory processes may occur in the intestinal epithelium, while neuronal regeneration mechanisms may be active in the myenteric plexus in patients with overtly developed PD. A spatial transcriptomic analysis of the brain and the gastrointestinal tract will enable a better understanding of the gut-brain axis in PD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"146"},"PeriodicalIF":6.2,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566962","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":"DNA methylation as a contributor to dysregulation of STX6 and other frontotemporal Lobar degeneration genetic risk-associated loci.","authors":"Naiomi Rambarack, Katherine Fodder, Megha Murthy, Christina Toomey, Rohan de Silva, Peter Heutink, Jack Humphrey, Towfique Raj, Tammaryn Lashley, Conceição Bettencourt","doi":"10.1186/s40478-025-02071-3","DOIUrl":"10.1186/s40478-025-02071-3","url":null,"abstract":"<p><p>Frontotemporal lobar degeneration (FTLD) represents a spectrum of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders. The two major FTLD pathological subgroups are FTLD-TDP and FTLD-tau. While the majority of FTLD cases are sporadic, heterogeneity also exists within the familial cases, typically involving mutations in MAPT, GRN or C9orf72, which is not fully explained by known genetic mechanisms. We sought to address this gap by investigating the effect of epigenetic modifications, specifically DNA methylation variation, on genes associated with FTLD genetic risk in different FTLD subtypes. We used frontal cortex DNA methylation profiles from three FTLD datasets containing different subtypes of FTLD-TDP and FTLD-tau: FTLD1m (N = 23) containing FTLD-TDP C9orf72 mutation carriers and sporadic cases, FTLD2m (N = 48) containing FTLD-Tau MAPT mutation carriers, FTLD-TDP GRN and C9orf72 mutation carriers, and FTLD3m (N = 163) sporadic FTLD-Tau (progressive supranuclear palsy - PSP) cases, and corresponding controls. We then leveraged FTLD transcriptomic and proteomic datasets to investigate possible downstream effects of DNA methylation changes. Our analysis revealed shared promoter region hypomethylation in STX6 across FTLD-TDP and FTLD-tau subtypes, though the largest effect size was observed in PSP cases compared to controls (delta-beta = -32%, FDR adjusted-p value = 0.002). We also observed dysregulation of the STX6 gene and protein expression in some FTLD subtypes. Additionally, we performed a detailed examination of MAPT, GRN and C9orf72 across subtypes and observed nominally significant differentially methylated CpGs in variable positions across the genes, often with unique patterns and downstream changes in gene/protein expression in mutation carriers. We highlight aberrant DNA methylation at different CpG sites mapping to genes previously associated with genetic risk of FTLD, including STX6. Our findings support convergence of genetic and epigenetic factors towards disruption of risk loci, bringing new insights into the contribution of these mechanisms to FTLD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"148"},"PeriodicalIF":6.2,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566959","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":"Early transcriptional responses reveal cell type-specific vulnerability and neuroprotective mechanisms in the neonatal ischemic hippocampus.","authors":"Aleksandr Ianevski, María Cámara-Quílez, Wei Wang, Rajikala Suganthan, Gunn Hildrestrand, Jonas Viken Grini, Dagny Sanden Døskeland, Jing Ye, Magnar Bjørås","doi":"10.1186/s40478-025-02062-4","DOIUrl":"10.1186/s40478-025-02062-4","url":null,"abstract":"<p><p>Neonatal hypoxic-ischemic (H-I) brain injury, a leading cause of neurodevelopmental disabilities, severely affects the metabolically active and neurogenic hippocampus. To investigate its acute effects and identify drug targets for early therapeutic windows, we applied single-nucleus RNA sequencing on postnatal day 8 (P8) mouse hippocampi under sham, hypoxic, and hypoxic-ischemic conditions. We constructed a comprehensive hippocampal cell atlas and developed a machine-learning classifier for precise cell type identification. Our analysis reveals early vulnerabilities in mature neurons and notable resilience in immature DG, GABAergic, and Cajal-Retzius cells following H-I. Gene regulatory network analysis identified key transcription factors associated with neuronal vulnerability, along with upregulated ribosome biogenesis and dysregulated calcium homeostasis pathways. We observed rapid activation of astrocytes and microglia, with Runx1 identified as a potential key transcription factor associated with early microglia immune responses. Endothelial cells displayed complex transcriptional changes and predicted intercellular signaling patterns that may influence vascular repair and recovery. Our study advances the understanding of immediate cellular and transcriptional responses to neonatal H-I injury, providing new insights into hippocampal cell heterogeneity and pathophysiology. The integrated hippocampal atlas, post-H-I atlas, and machine learning classifier are available at https://hippo-seq.org .</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"147"},"PeriodicalIF":6.2,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566960","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":"Orthotopic pituitary tumors generated by stereotaxic GC cell injection in immunocompetent rats.","authors":"Etienne Lefevre, Fanny Chasseloup, Nataly Ladurelle, Clément Janot, Jean Laurent Thibaud, Isabelle Beau, Clovis Adam, Céline des Courtils, Philippe Zizzari, Alexandre Carpentier, Peter Kamenický","doi":"10.1186/s40478-025-02052-6","DOIUrl":"10.1186/s40478-025-02052-6","url":null,"abstract":"<p><p>Innovative treatment strategies for pituitary tumors are necessary to limit the disease burden and to improve survival in cases of carcinomas. The paucity and inaccuracy of available preclinical models substantially hamper pituitary research and drug discovery. Hence, we describe a novel method to generate orthotopic pituitary tumors via stereotaxic injection of somatotroph GC cells into the pituitaries of immunocompetent Wistar Furth rats. Tumor growth was monitored by repeated 7 Tesla magnetic resonance imaging. The procedure consistently led to rapidly expanding intra- and suprasellar growth hormone-secreting tumors within their native anatomical environment. The generated tumors faithfully reproduced the microarchitecture of human somatotroph pituitary adenomas, including the immune infiltrates and other typical components of their microenvironment, which is a prerequisite for testing immunomodulating agents. This orthotopic model of proliferative pituitary tumors developed in immunocompetent hosts therefore unlocks new opportunities for preclinical studies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"149"},"PeriodicalIF":6.2,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566961","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":"Brain macrophages and pial fibroblasts promote inflammation in a hypomyelination model.","authors":"Noriko Okuno, Seiji Yamamoto, Takeru Hamashima, Tung Son Dang, Naruho Okita, Miwa Fujikawa, Tomomi Kunisawa, Nobuyuki Takakura, Toshihiko Fujimori, Hisashi Mori, Christer Betsholtz, Katsuyoshi Takata, Masakiyo Sasahara","doi":"10.1186/s40478-025-02063-3","DOIUrl":"10.1186/s40478-025-02063-3","url":null,"abstract":"<p><p>Many neurological diseases remain difficult to treat, necessitating further elucidation of their pathogenesis. Conditional inactivation of Pdgfra in Nestin-expressing cells leads to the depletion of platelet-derived growth factor receptor-alpha⁺ (PDGFRα⁺) oligodendroglial lineage cells responsible for myelination, resulting in forebrain hypomyelination and severe, progressive neurological deficits in neonatal mice. The present study examined the cerebral cortex of these mice to better understand the mechanisms underlying such progressive neurological deficits, that are often observed in refractory neurological diseases. Histological and single-cell RNA sequencing analyses showed that, following activation of meningeal border-associated macrophages (BAMs), PDGFRα⁺ fibroblasts that escaped gene inactivation were extensively recruited from the meninges into the hypomyelinated subpial cerebral cortex. Transcriptional reprogramming suggested that these fibroblasts originated from the pial fibroblast lineage and adopted a myofibroblast-like transcriptional phenotype. The recruited fibroblasts established stable cell-cell interactions with activated brain macrophages, including BAMs and microglia, accompanied by signaling pathways associated with chronic, tissue-damaging inflammation. Subsequently, inflammatory cortical lesions emerged, characterized by glial activation, angiogenesis, and neuronal oxidative stress. Treatment with a PDGFRα-neutralizing antibody significantly reduced fibroblast recruitment and mitigated glial activation and angiogenesis. These findings suggest that meningeal BAMs and pial fibroblasts are key contributors to the formation of tissue-damaging subpial cortical lesions. The interactions between brain macrophages and pial fibroblasts may contribute to the mechanisms underlying chronic and progressive neurological deficits and represent potential therapeutic targets for refractory neurological diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"145"},"PeriodicalIF":6.2,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564286","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":"Comparison of plasma ALZpath p-Tau217 with Lilly p-Tau217 and p-Tau181 in a neuropathological cohort.","authors":"Divya Bali, Gemma Salvadó, Thomas G Beach, Geidy E Serrano, Alireza Atri, Eric M Reiman, Andreas Jeromin, Oskar Hansson, Shorena Janelidze","doi":"10.1186/s40478-025-02064-2","DOIUrl":"10.1186/s40478-025-02064-2","url":null,"abstract":"<p><p>There is an urgent need for accurate and validated methods to measure plasma phosphorylated tau (p-Tau) biomarkers in Alzheimer's disease (AD). In this study, we compared the performance of new commercially available plasma p-Tau217 assay developed by ALZpath to other established p-Tau assays in an autopsy-confirmed sample. We included 72 participants from the Arizona Study of Aging and Neurodegenerative Disorders cohort, with antemortem plasma assessments and postmortem neuropathological examination. Plasma p-Tau217 was measured using the single molecule arrays (SIMOA)-based ALZpath immunoassay and plasma p-Tau217 and p-Tau181 were analyzed with mesoscale discovery (MSD)-based immunoassays developed by Lilly Research Laboratories. Plasma biomarkers were compared with densities of post-mortem-assessed amyloid plaques and neurofibrillary changes. Levels of p-Tau217_ALZpath, p-Tau217_Lilly and p-Tau181_Lilly were significantly associated with plaque (partial Spearman ρ = 0.58, ρ = 0.78, ρ = 0.65; p < 0.001) and neurofibrillary (ρ = 0.26, ρ = 0.51, ρ = 0.37; p < 0.05) density scores, adjusting for age, sex, and time of interval between blood sampling and death. All three biomarkers were also significantly associated with plaque density scores (p-Tau217_ALZpath, ρ = 0.53; p-Tau217_Lilly, ρ = 0.73; p-Tau181_Lilly, ρ = 0.59; p < 0.001), when additionally adjusting for neurofibrillary density scores. However, only p-Tau217_Lilly was significantly associated with neurofibrillary density scores (ρ = 0.32, p = 0.022), when adjusting for plaque density scores. The correlations of p-Tau217_ALZpath and p-Tau181_Lilly with plaque density scores were comparable, whereas p-Tau217_Lilly exhibited significantly higher correlations with plaques (p_diff≤0.015) and neurofibrillary changes (p_diff≤0.004) than p-Tau217_ALZpath. While p-Tau217_ALZpath and p-Tau181_Lilly predicted the presence of Alzheimer's disease neuropathological change (ADNC), Braak staging (Braak 0-IV vs. Braak V-VI) and CERAD neuritic plaque classification (low/sparse vs. moderate/frequent) with similar accuracies (area under the curve [AUC]_range, 0.74-0.79), p-Tau217_Lilly AUCs were significantly higher (AUC_range,0.82-0.89, p_diff≤0.024) than the AUCs of p-Tau217_ALZpath. In conclusion, p-Tau217_ALZpath exhibited similar performance as p-Tau181_Lilly but its correlations with core measures of AD pathology were significantly lower in comparison with p-Tau217_Lilly. Future studies are warranted to replicate these findings in larger independent cohorts.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"144"},"PeriodicalIF":6.2,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12207803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525832","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":"Xenoline-polarized macrophages as an alternative in vitro model of tumor-associated macrophages in glioblastoma.","authors":"Hasan Alrefai, Benjamin Lin, Amr Elkholy, Manoj Kumar, Taylor L Schanel, Kevin J Lee, Patricia H Hicks, Joshua C Anderson, Gao Guo, Eun-Young Erin Ahn, C Ryan Miller, Christopher D Willey","doi":"10.1186/s40478-025-02057-1","DOIUrl":"10.1186/s40478-025-02057-1","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are the most abundant non-cancerous cell type in glioblastoma (GBM) and heavily influence GBM biology, contributing to tumor progression, therapeutic resistance, immune evasion, and neovascularization. Current in vitro models that utilize IL-4/IL-13 stimulation fail to capture the transcriptional and functional heterogeneity of TAMs observed in vivo. In this study, we utilize a serum-free indirect co-culture model with patient-derived xenolines to polarize primary human macrophages and characterize their molecular and functional phenotypes. We demonstrate that xenoline-polarized macrophages diverge from classical M1/M2 states and instead adopt transcriptional signatures reflective of TAM subsets identified from patients. Notably, macrophages polarized with the radiation-therapy selected xenoline, JX14P-RT, exhibited gene expression patterns enriched for interferon response and hypoxia, mirroring recurrent GBM samples. In contrast, JX14P TAMs showed enrichment in phagocytic gene sets. Functional validation of these phenotypes revealed discrepancies between the transcriptionally predicted and observed phenotypes, emphasizing the importance of integrating phenotypic validation in sequencing studies. Altogether, our findings establish xenoline-polarized macrophages as a useful alternative to traditional models that can be used to study immune-interactions in vitro.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"137"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525934","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":"Glial and immune dysregulation in glaucoma independent of retinal ganglion cell loss: a human post-mortem histopathology study.","authors":"Akanksha Salkar, Viswanthram Palanivel, Devaraj Basavarajappa, Mehdi Mirzaei, Angela Schulz, Peng Yan, Vivek Gupta, Stuart Graham, Yuyi You","doi":"10.1186/s40478-025-02066-0","DOIUrl":"10.1186/s40478-025-02066-0","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"141"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525930","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}