Acta Neuropathologica Communications最新文献

{"title":"Hippocampal mitophagy alterations in MAPT-associated frontotemporal dementia with parkinsonism.","authors":"Tyrique Richardson, Xu Hou, Fabienne C Fiesel, Zbigniew K Wszolek, Dennis W Dickson, Wolfdieter Springer","doi":"10.1186/s40478-025-01955-8","DOIUrl":"https://doi.org/10.1186/s40478-025-01955-8","url":null,"abstract":"<p><p>The enzyme pair PINK1 and PRKN together orchestrates a cytoprotective mitophagy pathway that selectively tags damaged mitochondria with phospho-serine 65 ubiquitin (pS65-Ub) and directs them for autophagic-lysosomal degradation (mitophagy). We previously demonstrated a significant accumulation of pS65-Ub signals in autopsy brains of sporadic Lewy body disease and Alzheimer's disease cases, which strongly correlated with early tau pathology. In this study, we extended our analysis to a series of pathologically confirmed cases of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) harboring different pathogenic mutations in MAPT, the gene encoding tau. We assessed the morphology, levels, and distribution of the mitophagy tag pS65-Ub in several affected brain regions and hippocampal subregions of these cases. While tau pathological burden was similarly increased across all FTDP-17 cases, pS65-Ub immunopositive signals were strongly accumulated in P301L cases and only weakly present in N279K cases. In the hippocampus of both mutation groups, the density of pS65-Ub positive cells was overall the greatest in the dentate gyrus followed by the subiculum, CA1, and CA2/3, with the CA4 showing only minimal presence. Notably, positive cells in the subiculum carried greater numbers and particularly vacuolar pS65-Ub structures, while cells in the dentate gyrus mostly contained fewer and rather granular pS65-Ub inclusions. Single cell analyses revealed differential co-localization of pS65-Ub with mitochondria, autophagosomes, and lysosomes in these two regions. Together, our study demonstrates distinct mitophagy alteration in different FTDP-17 MAPT cases and hint at selective organelle failure in the hippocampal subregions that was associated with the P301L mutation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"41"},"PeriodicalIF":6.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490356","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":"Bridging the gap: investigating the role of phosphorylation at the serine 129 site of α-synuclein in VAPB-PTPIP51 interactions.","authors":"Weijin Liu, Yongquan Lu, Jia Liu, Yan Yu, Hui Yang","doi":"10.1186/s40478-025-01949-6","DOIUrl":"https://doi.org/10.1186/s40478-025-01949-6","url":null,"abstract":"<p><p>Parkinson's Disease (PD) is characterized by the aggregation and accumulation of α-synuclein (α-syn), along with abnormally high levels of α-syn phosphorylation at the serine 129 site (pSer 129 α-syn, p-α-syn). However, the mechanisms underlying the extensive phosphorylation at the serine 129 site in the pathogenesis of PD, as well as the role of p-α-syn in the process, remain unclear. Furthermore, though α-syn could bind to VAPB and loosen Endoplasmic Reticulum (ER)-mitochondria associations by disrupting VAPB-PTPIP51 tethers, whether and how the phosphorylation of α-syn at the serine 129 site regulates VAPB-PTPIP51 interactions, remains unclear. Herein, Co-Immunoprecipitation and Mass Spectrometry (CO-IP/MS) studies were preformed to identify and compare the Protein-Protein Interactions (PPIs) of phosphorylated and total α-syn in the midbrains of Thy1-SNCA transgenic mice. We further performed CO-IP and Molecular Dynamics (MD) simulation assays to confirm the influence of α-syn phosphorylation on the aforementioned interactions. Additionally, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to annotate the functional features of the common interacting proteins of p-α-syn and VAPB. The potential downstream proteins were further verified via CO-IP. According to the CO-IP and MD results, phosphorylation at the serine 129 site of α-syn increased VAPB-PTPIP51 interactions, and α-syn interacted directly with PTPIP51. Furthermore, functional and pathway enrichment analyses revealed that the common interacting proteins of p-α-syn and VAPB were significantly involved in protein binding, metal ion binding, structural constituent of the cytoskeleton, the intermediate filament cytoskeleton, and microtubule organization processes. Moreover, our findings confirmed the interactions of potential downstream target proteins (CLTC, CAMK2A, ATP1A3, and TUBB4B) with p-α-syn and VAPB. These findings collectively elucidate the structural underpinnings of serine 129 phosphorylation regulates the interaction between α-syn and both VAPB and PTPIP51. We hope that these findings will provide valuable insights into the role and regulatory mechanisms of serine 129 phosphorylation in the pathogenesis of pertinent diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"40"},"PeriodicalIF":6.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490355","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":"TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-ΔNLS model of Amyotrophic Lateral Sclerosis.","authors":"Svetlana Djukic, Zhenxiang Zhao, Lasse Mathias Holmsted Jørgensen, Anna Normann Bak, Dennis Bo Jensen, Claire Francesca Meehan","doi":"10.1186/s40478-025-01934-z","DOIUrl":"https://doi.org/10.1186/s40478-025-01934-z","url":null,"abstract":"<p><p>A hyperexcitability of the motor system is consistently observed in Amyotrophic Lateral Sclerosis (ALS) and has been implicated in the disease pathogenesis. What drives this hyperexcitability in the vast majority of patients is unknown. This is important to know as existing treatments simply reduce all neuronal excitability and fail to distinguish between pathological changes and important homeostatic changes. Understanding what drives the initial pathological changes could therefore provide better treatments. One challenge is that patients represent a heterogeneous population and the vast majority of cases are sporadic. One pathological feature that almost all (~97%) cases (familial and sporadic) have in common are cytoplasmic aggregates of the protein TDP-43 which is normally located in the nucleus. In our experiments we investigated whether this pathology was sufficient to increase neuronal excitability and the mechanisms by which this occurs. We used the TDP-43(ΔNLS) mouse model which successfully recapitulates this pathology in a controllable way. We used in vivo intracellular recordings in this model to demonstrate that TDP-43 pathology is sufficient to drive a severe hyper-excitability of spinal motoneurones. Reductions in soma size and a lengthening and constriction of axon initial segments were observed, which would contribute to enhanced excitability. Resuppression of the transgene resulted in a return to normal excitability parameters by 6-8 weeks. We therefore conclude that TDP-43 pathology itself is sufficient to drive a severe but reversible hyperexcitability of spinal motoneurones.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"42"},"PeriodicalIF":6.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490357","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":"Neuronal TDP-43 aggregation drives changes in microglial morphology prior to immunophenotype in amyotrophic lateral sclerosis.","authors":"Molly E V Swanson, Miran Mrkela, Clinton Turner, Maurice A Curtis, Richard L M Faull, Adam K Walker, Emma L Scotter","doi":"10.1186/s40478-025-01941-0","DOIUrl":"10.1186/s40478-025-01941-0","url":null,"abstract":"<p><p>Microglia are the innate immune cells of the brain with the capacity to react to damage or disease. Microglial reactions can be characterised in post-mortem tissues by assessing their pattern of protein expression, or immunophenotypes, and cell morphologies. We recently demonstrated that microglia have a phagocytic immunophenotype in early-stage ALS but transition to a dysfunctional immunophenotype by end stage, and that these states are driven by TAR DNA-binding protein 43 (TDP-43) aggregation in the human brain. However, it remains unclear how microglial morphologies are changed in ALS. Here we examine the relationship between microglial immunophenotypes and morphologies, and TDP-43 pathology in motor cortex tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from 10 control and 10 ALS cases was analysed alongside brain tissue from the bigenic NEFH-tTA/tetO-hTDP-43∆NLS (rNLS) mouse model of ALS at distinct disease stages. Sections were immunohistochemically labelled for microglial markers (HLA-DR, CD68, and Iba1) and phosphorylated TDP-43 (pTDP-43). Single-cell microglial HLA-DR, CD68, and Iba1 average intensities, and morphological features (cell body area, process number, total outgrowth, and branch number) were measured using custom image analysis pipelines. In human ALS motor cortex, we identified a significant change in microglial morphologies from ramified to hypertrophic, which was associated with increased Iba1 and CD68 levels. In the rNLS mouse motor cortex, the microglial morphologies changed from ramified to hypertrophic and increased Iba1 levels occurred in parallel with pTDP-43 aggregation, prior to increases in CD68 levels. Overall, the evidence presented in this study demonstrates that microglia change their morphologies prior to immunophenotype changes. These morphological changes may prime microglia near neurons with pTDP-43 aggregation for phagocytosis, in turn triggering immunophenotype changes; first, to a phagocytic state then to a dysfunctional one.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"39"},"PeriodicalIF":6.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476124","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":"Human induced pluripotent stem cell-derived myotubes to model inclusion body myositis.","authors":"Judith Cantó-Santos, Laura Valls-Roca, Ester Tobías, Francesc Josep García-García, Mariona Guitart-Mampel, Félix Andújar-Sánchez, Adrià Vilaseca-Capel, Anna Esteve-Codina, Beatriz Martín-Mur, Joan Padrosa, Emma Peruga, Irene Madrigal, Paula Segalés, Carmen García-Ruiz, José Carlos Fernández-Checa, Pedro J Moreno-Lozano, Albert Selva O'Callaghan, Ana Sevilla, José César Milisenda, Glòria Garrabou","doi":"10.1186/s40478-025-01933-0","DOIUrl":"10.1186/s40478-025-01933-0","url":null,"abstract":"<p><p>Inclusion body myositis (IBM) is an inflammatory myopathy that displays proximal and distal muscle weakness. At the histopathological level, the muscles of IBM patients show inflammatory infiltrates, rimmed vacuoles and mitochondrial changes. The etiology of IBM remains unknown, and there is a lack of validated disease models, biomarkers and effective treatments. To contribute to unveil disease underpins we developed a cell model based on myotubes derived from induced pluripotent stem cells (iPSC-myotubes) from IBM patients and compared the molecular phenotype vs. age and sex-paired controls (n = 3 IBM and 4 CTL). We evaluated protein histological findings and the gene expression profile by mRNA-seq, alongside functional analysis of inflammation, degeneration and mitochondrial function. Briefly, IBM iPSC-myotubes replicated relevant muscle histopathology features of IBM, including aberrant expression of HLA, TDP-43 and COX markers. mRNA seq analysis identified 1007 differentially expressed genes (DEGs) (p-value adj < 0.01; 789 upregulated and 218 downregulated), associated with myopathy, muscle structure and developmental changes. Among these, 1 DEG was related to inflammation, 28 to autophagy and 28 to mitochondria. At the functional level, inflammation was similar between the IBM and CTL groups under basal conditions (mean cytokine expression in IBM 4.6 ± 1.4 vs. 6.7 ± 3.4 in CTL), but increased in IBM iPSC-myotubes after lipopolysaccharide treatment (72.5 ± 21.8 in IBM vs. 13.0 ± 6.7 in CTL). Additionally, autophagy was disturbed, with 40.14% reduction in autophagy mediators. Mitochondrial dysfunction was strongly manifested, showing a conserved respiratory profile and antioxidant capacity, but a 56.33% lower cytochrome c oxidase/citrate synthase ratio and a 66.59% increase in lactate secretion. Overall, these findings support patient-derived iPSC-myotubes as a relevant model for IBM, reflecting the main muscle hallmarks, including inflammation, autophagy dysfunction and mitochondrial alterations at transcriptomic, protein and functional levels.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"38"},"PeriodicalIF":6.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472085","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":"Distinctive autophagy/mitophagy biomarker profiles in frontotemporal lobar degeneration and Alzheimer's disease.","authors":"Kateřina Veverová, Alžběta Katonová, Hana Horáková, Jan Laczó, Francesco Angelucci, Jakub Hort, Sofie Lautrup, Evandro Fei Fang, Martin Vyhnálek","doi":"10.1186/s40478-025-01954-9","DOIUrl":"10.1186/s40478-025-01954-9","url":null,"abstract":"<p><p>Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer's disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"37"},"PeriodicalIF":6.2,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456564","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":"Correction: Gene-expression profiling of individuals resilient to Alzheimer's disease reveals higher expression of genes related to metallothionein and mitochondrial processes and no changes in the unfolded protein response.","authors":"Luuk E de Vries, Aldo Jongejan, Jennifer Monteiro Fortes, Rawien Balesar, Annemieke J M Rozemuller, Perry D Moerland, Inge Huitinga, Dick F Swaab, Joost Verhaagen","doi":"10.1186/s40478-025-01931-2","DOIUrl":"10.1186/s40478-025-01931-2","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"36"},"PeriodicalIF":6.2,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456557","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 analysis of a complete DIPG-infiltrated brainstem reveals novel ligand-receptor mediators of tumour-to-TME crosstalk.","authors":"Anja Kordowski, Onkar Mulay, Xiao Tan, Tuan Vo, Ulrich Baumgartner, Mellissa K Maybury, Timothy Hassall, Lachlan Harris, Quan Nguyen, Bryan W Day","doi":"10.1186/s40478-025-01952-x","DOIUrl":"10.1186/s40478-025-01952-x","url":null,"abstract":"<p><p>Previous studies have highlighted the capacity of brain cancer cells to functionally interact with the tumour microenvironment (TME). This TME-cancer crosstalk crucially contributes to tumour cell invasion and disease progression. In this study, we performed spatial transcriptomic sequencing analysis of a complete annotated tumour-infiltrated brainstem from a single diffuse intrinsic pontine glioma (DIPG) patient. Gene signatures from ten sequential tumour regions were analysed to assess mechanisms of disease progression and oncogenic interactions with the TME. We identified four distinct tumour subpopulations and assessed respective ligand-receptor pairs that actively promote DIPG tumour progression via crosstalk with endothelial, neuronal and immune cell communities. Our analysis found potential targetable mediators of tumour-to-TME communication, including members of the complement component system and the neuropeptide/GPCR ligand-receptor pair ADCYAP1-ADCYAP1R1. These interactions could influence DIPG tumour progression and represent novel therapeutic targets.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"35"},"PeriodicalIF":6.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456566","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":"Density and entropy of immune cells within the tumor microenvironment of primary tumors and matched brain metastases.","authors":"Markus Kleinberger, Didem Çifçi, Christina Paiato, Erwin Tomasich, Maximilian J Mair, Ariane Steindl, Zoltán Spiró, Zunamys I Carrero, Luzia Berchtold, Johannes Hainfellner, Leonhard Müllauer, Gerwin Heller, Matthias Preusser, Jakob Niklas Kather, Anna Sophie Berghoff","doi":"10.1186/s40478-025-01939-8","DOIUrl":"10.1186/s40478-025-01939-8","url":null,"abstract":"<p><strong>Background: </strong>Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) have increasingly been reported to impact the brain metastatic process of solid tumors. However, data on intra-individual differences between primary tumor and brain metastasis (BM), as well as their correlation with clinical outcome parameters, is scarce.</p><p><strong>Methods: </strong>We retrospectively identified patients who received resection of the primary tumor and BM between 01/1990 and 10/2022. Density quantification of TAMs (CD68⁺, CD163⁺) and TILs (CD3⁺, CD8⁺, CD45RO⁺, FOXP3⁺) was performed by immunohistochemical staining of matched tumor tissue samples. Images were processed with QuPath software and heterogeneity of generated heatmaps was measured by Shannon Entropy. Time-to-BM (TTBM) was defined as the time from diagnosis of the primary tumor until the first diagnosis of BM.</p><p><strong>Results: </strong>In total, 104 patients (46.2% female; median age 57.3 years at BM diagnosis) were included: 78/104 (75%) non-small cell lung cancer, 18/104 (17%) breast cancer, 8/104 (8%) renal cell carcinomas. Densities of CD3⁺ (p < 0.001) and CD8⁺-TILs (p < 0.001) were higher in primary tumor samples, while CD68⁺ (p = 0.035) and CD163⁺-TAM densities (p < 0.001) were higher in the matched BM. Higher CD3⁺, CD8⁺-TILs and CD163⁺-TAMs densities in primary tumors were associated with shorter TTBM (p = 0.005, p = 0.015 and p = 0.006, respectively). Higher entropies of CD3⁺ (p < 0.001) and FOXP3⁺ (p = 0.011) TILs were observed in primary tumors compared to BM. Longer TTBM was associated with higher entropy of FOXP3⁺ TILs (p = 0.024) and lower entropy in CD163⁺ TAMs (p = 0.039). No significant associations of immune cell densities or entropies with OS after BM diagnosis were found.</p><p><strong>Discussion: </strong>By utilizing a unique cohort of matched primary tumor and BM tissue samples, we could demonstrate higher TIL densities in primary tumors and higher TAM densities in BM, respectively. Higher cell densities of CD3⁺, CD8⁺-TILs and CD163⁺-TAMs in primary tumors were associated with shorter TTBM, while a larger difference between CD3⁺ and CD8⁺ densities between primary tumor and BM was associated with longer TTBM. These findings highlight the potential of targeting TAMs as a therapeutic strategy to mitigate the development of brain metastases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"34"},"PeriodicalIF":6.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456560","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":"Blocking peptidyl arginine deiminase 4 confers neuroprotective effect in the post-ischemic brain through both NETosis-dependent and -independent mechanisms.","authors":"Song-I Seol, Sang-A Oh, Dashdulam Davaanyam, Ja-Kyeong Lee","doi":"10.1186/s40478-025-01951-y","DOIUrl":"10.1186/s40478-025-01951-y","url":null,"abstract":"<p><p>Peptidylarginine deiminase 4 (PAD4) is an enzyme that modifies proteins by converting positively charged arginine residues to neutral citrulline residues. This process, termed citrullination, has been known to trigger NETosis, a neutrophil cell death pathway involving the release of neutrophil extracellular traps (NETs). Abnormal PAD4 activity and protein citrullination have been linked to various diseases, including those affecting the central nervous system. Herein we investigated the profile of PAD4 expression in an animal model of stroke induced by middle cerebral artery occlusion (MCAO). PAD4 levels were significantly elevated in the ischemic core and penumbra of the affected hemisphere at 3-6 and 6-48 h post-MCAO, respectively. Notably, NETosis induction, indicated by the upregulation of CitH3 (citrullinated histone H3, a NETosis marker), was observed between 48 and 96 h post-MCAO, peaking at 96 h. While PAD4 was present in most brain cell types of sham controls, strong PAD4 induction was primarily observed in neurons during the peak PAD4 induction period (12-24 h post-MCAO). Importantly, intranasal administration of the PAD4 inhibitor BB-Cl-amidine (BBCA) significantly reduced infarct volume and improved neurological and functional outcomes at 24 h post-MCAO, demonstrating a strong protective effect of PAD4 inhibition in ischemic stroke. Staining with an antibody that recognizing citrullinated proteins (F95) revealed an accumulation of these proteins, especially degenerating neurons, however, BBCA treatment significantly suppressed this accumulation in dying neurons. These findings indicate that PAD4-mediated protein citrullination in neurons plays a critical role in promoting ischemic brain damage. Furthermore, delayed administration of BBCA (at 48/72 h post-MCAO) suppresses the NETosis induction observed at 96 h post-MCAO, potentially ameliorating repair processes such as blood vessel regeneration. Collectively, these findings suggest a complex role of PAD4 in cerebral ischemia, with neuroprotective effects (NETosis-independent function) during the acute to subacute period and NETosis-suppressive effects at later time points.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"33"},"PeriodicalIF":6.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447568","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}