Acta Neuropathologica Communications最新文献

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The malignant transformation of an atypical angiocentric glioma, MYB-altered. 非典型血管中心性胶质瘤的恶性转化,myb改变。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-23 DOI: 10.1186/s40478-025-02070-4
Oumaima Aboubakr, Annika K Wefers, Volodia Dangouloff-Ros, Alice Métais, Philipp Sievers, Lauren Hasty, Raphaël Saffroy, Gaelle Pierron, Delphine Guillemot, Thomas Samoyeau, Nathalie Boddaert, Jacques Grill, Kevin Beccaria, Thomas Blauwblomme, Pascale Varlet, Arnault Tauziède-Espariat
{"title":"The malignant transformation of an atypical angiocentric glioma, MYB-altered.","authors":"Oumaima Aboubakr, Annika K Wefers, Volodia Dangouloff-Ros, Alice Métais, Philipp Sievers, Lauren Hasty, Raphaël Saffroy, Gaelle Pierron, Delphine Guillemot, Thomas Samoyeau, Nathalie Boddaert, Jacques Grill, Kevin Beccaria, Thomas Blauwblomme, Pascale Varlet, Arnault Tauziède-Espariat","doi":"10.1186/s40478-025-02070-4","DOIUrl":"https://doi.org/10.1186/s40478-025-02070-4","url":null,"abstract":"<p><p>According to the current World Health Organization classification of central nervous system tumors, the angiocentric glioma (AG) assigned a grade 1, characterized by recurrent MYB fusions. However, it also mentions that increased proliferative activity and other anaplastic features have been reported, but the clinical significance of such findings is unclear as an increased proliferative activity alone does not necessarily alter the benign behavior of AGs. Most cases with \"anaplasia\" were mainly described before the molecular era. Herein, we report the case of a 3-year-old female with epilepsy symptomatic of a left temporo-parietal tumor. Histopathologically, the initial tumor displayed atypical AG morphology and a proliferation index of 1%, without mitoses, or necrosis. RNA sequencing identified a MYB::QKI fusion. After several tumor recurrences, the last tumor sample showed strong evidence of a histopathological transformation into a high-grade tumor with proliferation and mitotic indexes, necrosis and microvascular proliferation. The recurrent tumor still harbored the same MYB::QKI fusion but acquired an hTERT mutation. DNA-methylation analysis classified the initial tumor as an LGG, MYB/MYBL1-altered (AG, MYB/MYBL1-altered with a calibrated score of 0.58) while the progression clustered with glioblastoma, IDH-wildtype, RTK1 (with a calibrated score of 0.33). The copy number variation both at presentation and at last recurrence (CNV) exhibited a chromosome 6 chromothripsis. The patient died from tumor progression after an overall survival of 89 months. This novel observation raises the question of whether this case represents an aggressive form of MYB/MYBL1-altered LGGs driven by an oncogenic MYB fusion, or if they are actually high-grade gliomas that coincidentally exhibit alterations near the MYB locus. Further reports are needed to confirm the existence of malignant forms of LGG, MYB/MYBL1-altered, potentially correlated with a higher grade.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"161"},"PeriodicalIF":6.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697251","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}
引用次数: 0
Gene therapy ameliorates neuromuscular pathology in CLN3 disease. 基因治疗改善CLN3疾病的神经肌肉病理。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-23 DOI: 10.1186/s40478-025-02059-z
Ewa A Ziółkowska, Albina Jablonka-Shariff, Letitia L Williams, Matthew J Jansen, Sophie H Wang, Elizabeth M Eultgen, Matthew D Wood, Daniel A Hunter, Jaiprakash Sharma, Marco Sardiello, Robyn Reese, Alan Pestronk, Mark S Sands, Alison K Snyder-Warwick, Jonathan D Cooper
{"title":"Gene therapy ameliorates neuromuscular pathology in CLN3 disease.","authors":"Ewa A Ziółkowska, Albina Jablonka-Shariff, Letitia L Williams, Matthew J Jansen, Sophie H Wang, Elizabeth M Eultgen, Matthew D Wood, Daniel A Hunter, Jaiprakash Sharma, Marco Sardiello, Robyn Reese, Alan Pestronk, Mark S Sands, Alison K Snyder-Warwick, Jonathan D Cooper","doi":"10.1186/s40478-025-02059-z","DOIUrl":"https://doi.org/10.1186/s40478-025-02059-z","url":null,"abstract":"<p><p>CLN3 disease is a neuronopathic lysosomal storage disorder that severely impacts the central nervous system (CNS) while also inducing notable peripheral neuromuscular symptoms. Although considerable attention has been directed towards the neurodegenerative consequences within the CNS, the involvement of peripheral tissues, including skeletal muscles and their innervation, has been largely neglected. We hypothesized that, CLN3 deficiency could directly influence peripheral nerves and investigated the neuromuscular system in Cln3<sup>Δex7/8</sup> mice. Our study found no overt loss of sciatic nerve axons or demyelination in 18-month-old Cln3<sup>Δex7/8</sup> mice at disease endstage, but a marked reduction of terminal Schwann cells (tSCs) at lower limb neuromuscular junctions (NMJs), culminating in progressive denervation of these NMJs which appeared abnormal. This led us to investigate skeletal muscle where we found significant myofiber atrophy and decreased and misplaced myofibril nuclei. Similar myopathic alterations were present in a muscle biopsy from an 8-year-old human CLN3 patient shortly after diagnosis. To assess a potential therapeutic intervention, we administered intravenous gene therapy using AAV9.hCLN3 to neonatal Cln3<sup>Δex7/8</sup> mice, which at disease endstage, entirely prevented tSC loss and NMJ abnormalities, while also averting skeletal muscle atrophy. These findings underscore the underappreciated, yet substantial effects of CLN3 disease beyond the CNS, highlighting peripheral neuromuscular pathologies as novel features of this disorder. Our findings also indicate that these manifestations could be amenable to treatment via gene therapy, opening new therapeutic strategies in the management of CLN3 disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"160"},"PeriodicalIF":6.2,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697250","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}
引用次数: 0
Expression of LTR and LINE1 transposable elements defines atypical teratoid/rhabdoid tumor subtypes. LTR和LINE1转座因子的表达定义了非典型畸胎瘤/横纹肌样肿瘤亚型。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-22 DOI: 10.1186/s40478-025-02078-w
Martin V Hamann, Shweta Godbole, Maisha Adiba, Sabrina M Leddy, Jelena Navolić, Ghazaleh Tabatabai, Daniel J Merk, Ulrike C Lange, Julia E Neumann
{"title":"Expression of LTR and LINE1 transposable elements defines atypical teratoid/rhabdoid tumor subtypes.","authors":"Martin V Hamann, Shweta Godbole, Maisha Adiba, Sabrina M Leddy, Jelena Navolić, Ghazaleh Tabatabai, Daniel J Merk, Ulrike C Lange, Julia E Neumann","doi":"10.1186/s40478-025-02078-w","DOIUrl":"https://doi.org/10.1186/s40478-025-02078-w","url":null,"abstract":"<p><p>Atypical teratoid rhabdoid tumors (ATRTs) are aggressive central nervous system tumors mainly affecting young children. Extensive molecular characterization based on gene expression and DNA methylation patterns has solidly established three major ATRT subtypes (MYC, SHH and TYR), which show distinct clinical features, setting the basis for more effective, targeted treatment regimens. Transcriptional activity of transposable elements (TEs), like LINE1s and LTRs, is tightly linked with human cancers as a direct consequence of lifting epigenetic repression over TEs. The sole recurrent biallelic loss-of-function mutation in SMARCB1 in ATRTs, a core component of the SWI/SNF chromatin remodeling complex, raises the question of how TE transcription contributes to ATRT development. Here, we comprehensively investigate the transcriptional profiles of 1.9M LINE1 and LTR elements across ATRT subtypes in primary human samples. We find TE transcription profiles allow sample stratification into ATRT subtypes. The TE activity signature in the ATRT-MYC subtype is unique, setting these tumors apart from SHH and TYR ATRTs. More specifically, ATRT-MYC show broadly reduced transcript levels of LINE1 and ERVL-MaLR subfamilies. ATRT-MYC also displayed significantly less LTR and LINE1 loci with bidirectional promoter activity. Furthermore, we identify 849 differentially transcribed TEs in primary samples, which are predictive towards established ATRT-SHH and -MYC cell line models. In summary, including TE transcription profiles into the molecular characterization of ATRTs might reveal new tumor vulnerabilities leading to novel therapeutic interventions, such as immunotherapy.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"159"},"PeriodicalIF":6.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688568","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}
引用次数: 0
Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis. ATXN2中间CAG重复序列、9bp重复和选择性剪接对SCA3发病机制的影响。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-19 DOI: 10.1186/s40478-025-02074-0
Marilena Lauerer, Jennifer Faber, Nicolas Casadei, Magda M Santana, Georg Auburger, Michaela Pogoda, Jakob Admard, Lea Kaupp, Patricia Laura Kos, Mafalda Raposo, Manuela Lima, Luis Pereira de Almeida, Hector Garcia-Moreno, Paola Giunti, Jeroen de Vries, Bart P van de Warrenburg, Judith van Gaalen, Marcus Grobe-Einsler, Berkan Koyak, Kathrin Reetz, Friedrich Erdlenbruch, Heike Jacobi, Jon Infante, Holger Hengel, Ludger Schöls, Thomas Klockgether, Olaf Rieß, Jeannette Hübener-Schmid
{"title":"Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis.","authors":"Marilena Lauerer, Jennifer Faber, Nicolas Casadei, Magda M Santana, Georg Auburger, Michaela Pogoda, Jakob Admard, Lea Kaupp, Patricia Laura Kos, Mafalda Raposo, Manuela Lima, Luis Pereira de Almeida, Hector Garcia-Moreno, Paola Giunti, Jeroen de Vries, Bart P van de Warrenburg, Judith van Gaalen, Marcus Grobe-Einsler, Berkan Koyak, Kathrin Reetz, Friedrich Erdlenbruch, Heike Jacobi, Jon Infante, Holger Hengel, Ludger Schöls, Thomas Klockgether, Olaf Rieß, Jeannette Hübener-Schmid","doi":"10.1186/s40478-025-02074-0","DOIUrl":"10.1186/s40478-025-02074-0","url":null,"abstract":"<p><p>Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease whose exact disease pathogenesis is not yet fully understood. We performed a genetic in-depth analysis of ataxin-2 (ATXN2), a gene that has already been described as a modulator of neurodegenerative diseases. We focused on the influence of an intermediate CAG repeat, a 9bp duplication (9bp), and isoform expression of ATXN2 on the pathogenesis of SCA3.Clinical and genetic data from a large European SCA3 cohort (total 390 probands) were analyzed. Fragment analyses were performed to determine the cytosine-adenine-guanine (CAG) repeat length and the 9bp duplication in ATXN2. RNA sequencing was performed on blood and cerebellum to evaluate ATXN2 isoform profile. Cell culture and SCA3 mice were used to investigate the influence of intermediate ATXN2 length on ataxin-3 protein abundance, aggregation, and cell viability.SCA3 carriers with an intermediate ATXN2 repeat presented a significant increase in non-ataxic symptoms. A greater age at onset and faster disease progression were found in SCA3 carriers with a 9bp duplication. Co-expression of ATXN2 and ATXN3 in cell models revealed an influence of ATXN2 on ataxin-3 abundance and aggregation patterns. Determination of soluble ATXN2 abundance demonstrated a significant genotype-independent reduction in mouse brain. Aggregate analyses indicated that ataxin-2 is not co-localized with ataxin-3-containing aggregates.Our comprehensive genetic study confirmed ATXN2 as a modulator of SCA3 pathogenesis, including onset and presence of clinical symptoms. For the first time, the ATXN2 isoform profile was compared in blood and cerebellar tissue, revealing a unique profile depending on the genotype and tissue. Here, a significant higher expression of ATXN2 splice variant type I in blood and significantly lower expression in cerebellar tissue were found compared to ATXN2 splice variant type II. Molecular and biochemical analyses in SCA3 mice and cell culture provide further evidence on mechanistic aspects, including differences in protein abundance and co-aggregation propensity. In summary, our study provides new insights into the modulatory effects of ATXN2 on SCA3 pathogenesis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"157"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666773","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}
引用次数: 0
Unraveling the development of cutaneous neurofibromas in neurofibromatosis type 1. 揭示1型神经纤维瘤病皮肤神经纤维瘤的发展。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-19 DOI: 10.1186/s40478-025-02075-z
Pernelle Pulh, Fanny Coulpier, Audrey Onfroy, Layna Oubrou, Wanzhen Zhang, Léa Toledano, Elie Abou Zougheib, Laura Fertitta, Pierre Wolkenstein, Piotr Topilko
{"title":"Unraveling the development of cutaneous neurofibromas in neurofibromatosis type 1.","authors":"Pernelle Pulh, Fanny Coulpier, Audrey Onfroy, Layna Oubrou, Wanzhen Zhang, Léa Toledano, Elie Abou Zougheib, Laura Fertitta, Pierre Wolkenstein, Piotr Topilko","doi":"10.1186/s40478-025-02075-z","DOIUrl":"10.1186/s40478-025-02075-z","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1) is a genetic disorder that leads to the formation of cutaneous neurofibromas (cNFs), benign nerve sheath tumors that develop in the skin and significantly impact the quality of life of patients. cNF development begins with bi-allelic NF1 loss in the Schwann cell (SC) lineage, followed by the recruitment of a complex tumor microenvironment consisting of fibroblasts, immune cells, blood vessels, axons, and a dense extracellular matrix. Despite its high prevalence and clinical impact, the molecular mechanisms underlying cNF formation remain poorly understood. Here, we used an Nf1 knockout (Nf1-KO) mouse model combined with immunohistochemistry and single cell transcriptomics in order to investigate the mechanisms driving cNF development. Our results showed that mutant SCs accumulate in the skin of young mice weeks prior to the onset of cNF. However, these cells remain quiescent until triggered by skin trauma, which induces their proliferation and the rapid formation of cNFs. Using a trauma-induced Nf1-KO model with scRNAseq, we designed a transcriptomic atlas of growing and mature cNFs, as well as adjacent apparently healthy skin. This analysis identified a population of non-myelinating Aquaporin1<sup>high</sup>Nestin<sup>low</sup> SCs as the likely cells of origin for cNFs. These cells overexpress genes involved in axon growth and guidance, potentially driving the abnormal innervation observed in both mouse and patient cNFs. In addition, we found that tumor SCs, along with dermal and/or epineurial fibroblasts and pericytes, overexpress genes encoding collagen, contributing to the extensive fibrosis characteristic of cNFs. Notably, all of these cells exhibit high expression of periostin and tenascin C, key extracellular matrix components, highlighting them as novel therapeutic targets in view of cNF treatment.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"158"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666774","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}
引用次数: 0
Relationship between cerebral small vessel disease and proteinopathies in the medial temporal lobe. 内侧颞叶蛋白质病变与脑血管病的关系。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-16 DOI: 10.1186/s40478-025-02076-y
Valentina Perosa, Jan Oltmer, Francesco Bax, Maarten L van den Berg, Corinne A Auger, Johanna Rotta, Romain Perbet, Jean Augustinack, Matthew P Frosch, Theresa Connors, Steven M Greenberg, Bradley T Hyman, Susanne J van Veluw
{"title":"Relationship between cerebral small vessel disease and proteinopathies in the medial temporal lobe.","authors":"Valentina Perosa, Jan Oltmer, Francesco Bax, Maarten L van den Berg, Corinne A Auger, Johanna Rotta, Romain Perbet, Jean Augustinack, Matthew P Frosch, Theresa Connors, Steven M Greenberg, Bradley T Hyman, Susanne J van Veluw","doi":"10.1186/s40478-025-02076-y","DOIUrl":"10.1186/s40478-025-02076-y","url":null,"abstract":"<p><p>The medial temporal lobe (MTL) is strategically important for cognition and the pathogenesis of Alzheimer's Disease (AD). Cerebral small vessel disease (CSVD) independently contributes to cognitive impairment and is believed to play a role in AD. CSVD and proteinopathies related to AD often coexist in the MTL but neither the severity of CSVD, nor the associations between these pathologies have been quantitatively addressed in this brain region. We hypothesized that the severity of CSVD in the MTL is associated with the local burden of proteinopathies implicated in neurodegeneration (tau-tangles, amyloid-β-plaques, phospho-Tar-DNA-Binding-Protein-43 [pTDP-43]), regardless of disease stage. One potential mechanism linking CSVD and proteinopathies is a failure in perivascular brain clearance. Therefore, the relationship between CSVD and the enlargement of perivascular spaces (PVS) was investigated. AI-models and manual ratings were applied to digitized histological MTL-sections of 152 autopsy cases with and without Alzheimer's Disease Neuropathological Changes to quantify proteinopathies and the two common forms of CSVD, cerebral amyloid angiopathy (CAA) and arteriolosclerosis. The associations between CSVD and proteinopathies were assessed using linear-mixed-effects models. The relationship between CSVD and PVS enlargement was also investigated. Regional CAA-burden increased along Braak-stages and was positively associated with amyloid-β-plaques percentage area and tau-tangles density, irrespective of Braak-stage, but not with density of pTDP-43 inclusions. Local arteriolosclerosis severity was not associated with Braak-stages and had no direct effect on parenchymal proteinopathies. However, arteriolosclerosis severity and its interaction with CAA were positively associated with PVS enlargement. These results suggest that CAA, but not arteriolosclerosis, is more directly implicated in the pathophysiology of proteinopathies in the MTL. Moreover, arteriolosclerosis may contribute to perivascular clearance dysfunction.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"156"},"PeriodicalIF":6.2,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648222","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}
引用次数: 0
Associations of neurodegenerative and cerebrovascular neuropathology with frailty in a diverse sample. 神经退行性和脑血管神经病理与脆弱在不同样本的关联。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-14 DOI: 10.1186/s40478-025-02003-1
Felipe Bozi-Soares, Márlon Juliano Romero Aliberti, Alberto Fernando Oliveira Justo, Renata E P Leite, Lea T Grinberg, Vitor R Paes, Roberta D Rodriguez, Carlos A Pasqualucci, Eduardo Ferrioli, Claudia Kimie Suemoto
{"title":"Associations of neurodegenerative and cerebrovascular neuropathology with frailty in a diverse sample.","authors":"Felipe Bozi-Soares, Márlon Juliano Romero Aliberti, Alberto Fernando Oliveira Justo, Renata E P Leite, Lea T Grinberg, Vitor R Paes, Roberta D Rodriguez, Carlos A Pasqualucci, Eduardo Ferrioli, Claudia Kimie Suemoto","doi":"10.1186/s40478-025-02003-1","DOIUrl":"10.1186/s40478-025-02003-1","url":null,"abstract":"<p><p>Associations between neurodegenerative and cerebrovascular neuropathologies and frailty are not well understood, especially in diverse populations. This study investigated these associations in an admixed Brazilian cohort. This cross-sectional study included participants aged 60 + from the Brazilian Biobank for Aging Studies (2004-2024). Neuropathology data covered nine markers and a neuropathological comorbidity score (NPC). Frailty was measured using a frailty index from 33 health deficits, and cognitive impairment was defined as a Clinical Dementia Rating ≥ 0.5, both based on post-mortem informant reports with the next of kin. Linear regression models, adjusted for age, sex, education, race, and cognitive impairment, assessed associations between neuropathology and frailty. Effect modification by cognitive status was also explored. Among 1,370 participants (mean age = 78.4 ± 9.3 years; 53% women), 45% were frail, and 38% had cognitive impairment. Neurofibrillary tangles (NFT) (β = 0.005, 95%CI = 0.000-0.008, p = 0.036), Lewy body disease pathology (β = 0.008, 95%CI = 0.003-0.012, p = 0.001), lacunar infarcts (β = 0.032, 95%CI = 0.012-0.052, p = 0.002), siderocalcinosis (β = 0.015, 95%CI = 0.002-0.030, p = 0.023), and hyaline arteriolosclerosis (β = 0.034, 95%CI = 0.021-0.048, p < 0.001) were associated with frailty, independent of cognitive impairment. Higher NPC scores were linked to higher frailty with stronger associations observed among cognitively impaired participants (β = 0.007, 95%CI = 0.003-0.011, p = 0.001), as indicated by a p-value for interaction = 0.007. There was a more pronounced association between neuropathology and frailty among cognitively impaired participants for NFT (β = 0.007, 95%CI = 0.001-0.015, p = 0.020) and hyaline arteriolosclerosis (β = 0.052, 95%CI = 0.031-0.073, p < 0.001). Unlike other neuropathologies, hyaline arteriolosclerosis was associated with higher frailty levels in participants without cognitive impairment (β = 0.020, 95%CI = 0.002-0.038, p = 0.023). Our findings suggest that neuropathology affects frailty independently of cognitive status, although its impact is compounded by cognitive impairment. Moreover, cerebrovascular pathology's association with frailty in cognitively normal participants highlights the potential benefit of early cardiovascular risk management to reduce frailty risk, which is crucial in low- and middle-income countries considering the disproportionately high burden of cardiovascular and cerebrovascular conditions in these populations.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"155"},"PeriodicalIF":6.2,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635889","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}
引用次数: 0
Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis. Kv3通道激动剂改善肌萎缩侧索硬化症小鼠模型的表型。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-14 DOI: 10.1186/s40478-025-02067-z
Manuela Marabita, Caterina Marchioretti, Aishwarya Aravamudhan, Simona Zito, Antonella Falconieri, Emanuela Zuccaro, Roberta Andreotti, Lisa Gambarotto, Samuele Metti, Marika Tonellato, Valentina Adami, Kyung Ho Park, Martin J Gunthorpe, Charles H Large, Agostino Marasco, Sara Vianello, Jessica Rosati, Elisa Belluzzi, Assunta Pozzuoli, Carlo Biz, Pietro Ruggieri, Manuela Basso, Angelo Poletti, Giuseppe Alvaro, Gianni Sorarù, Paolo Bonaldo, Ornella Rossetto, Nadia Pilati, Maria Pennuto
{"title":"Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis.","authors":"Manuela Marabita, Caterina Marchioretti, Aishwarya Aravamudhan, Simona Zito, Antonella Falconieri, Emanuela Zuccaro, Roberta Andreotti, Lisa Gambarotto, Samuele Metti, Marika Tonellato, Valentina Adami, Kyung Ho Park, Martin J Gunthorpe, Charles H Large, Agostino Marasco, Sara Vianello, Jessica Rosati, Elisa Belluzzi, Assunta Pozzuoli, Carlo Biz, Pietro Ruggieri, Manuela Basso, Angelo Poletti, Giuseppe Alvaro, Gianni Sorarù, Paolo Bonaldo, Ornella Rossetto, Nadia Pilati, Maria Pennuto","doi":"10.1186/s40478-025-02067-z","DOIUrl":"10.1186/s40478-025-02067-z","url":null,"abstract":"<p><p>Voltage-gated potassium channels, Kv3.1, Kv3.2, Kv3.3, and Kv3.4, facilitate rapid repolarization and shape action potentials, which are crucial to maintaining high-frequency firing. Little is known about the expression and function of Kv3 channels in skeletal muscle. We show that these channels are expressed in type IIa/IIx fibers, and their transcript levels progressively increase from postnatal age to adulthood in physiological context. In mature myofibers, the Kv3.1 and Kv3.4 channels are enriched in the muscle triads. The expression of the Kv3 channel is lost upon acute motor unit damage, in mouse models of amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), and the skeletal muscle of patients with sporadic ALS. Early treatment of ALS and SBMA mice with AUT00201, a positive allosteric modulator of Kv3 channels, improved the phenotype of ALS mice specifically, suggesting that positive modulation of Kv3 channels is a novel therapeutic option for patients with ALS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"153"},"PeriodicalIF":6.2,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625245","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}
引用次数: 0
Reciprocal regulation of GPNMB/HIF-1α for Inhibition of neuronal ferroptosis in delayed encephalopathy after acute carbon monoxide poisoning. GPNMB/HIF-1α相互调控抑制急性一氧化碳中毒后迟发性脑病神经元铁下垂。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-14 DOI: 10.1186/s40478-025-02069-x
Zuolong Liu, Lanyue Sun, Nan Gao, Wei Li, Li Pang
{"title":"Reciprocal regulation of GPNMB/HIF-1α for Inhibition of neuronal ferroptosis in delayed encephalopathy after acute carbon monoxide poisoning.","authors":"Zuolong Liu, Lanyue Sun, Nan Gao, Wei Li, Li Pang","doi":"10.1186/s40478-025-02069-x","DOIUrl":"10.1186/s40478-025-02069-x","url":null,"abstract":"<p><p>Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is the most common complication after acute carbon monoxide (CO) poisoning. However, the pathogenesis of DEACMP remains ambiguous. The neuroprotective role of GPNMB has been observed in amyotrophic lateral sclerosis and Parkinson's disease. GPNMB was elevated in the brain tissues of DEACMP rats, while its function in DEACMP remains unclear. In this study, a CO poisoning rat model and oxygen-glucose deprivation (OGD)-treated PC-12 cells were established as an in vivo and in vitro DEACMP model, respectively. The ferroptosis inhibitor Ferrostatin-1 (Fer-1) ameliorated cognitive impairment, inflammation and oxidative stress of rats with DEACMP as assessed by Morris Water Maze test, ELISA assay and commercial kits of oxidative markers. Immunofluorescence, qRT-PCR or western blot showed that GPNMB was elevated in CA1 hippocampal tissues of CO-poisoned rats. Additionally, TUNEL staining, ELISA assay and western blot revealed that GPNMB rescued OGD-induced cell apoptosis, inflammation and ferroptosis in PC-12 cells. Mechanistical study showed that STAT3 was a transcriptional activator of GPNMB as detected by luciferase and ChIP assays, and co-immunoprecipitation and immunofluorescence staining revealed that GPNMB stabilized HIF-1α by direct binding. Functionally, GPNMB protected against OGD-induced impairments via inducing HIF-1α. Furthermore, GPNMB attenuated cognitive impairment, oxidative stress and neuronal ferroptosis of rats with DEACMP. In conclusion, GPNMB/HIF-1α exhibited neuroprotective effects via suppressing ferroptosis in DEACMP.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"154"},"PeriodicalIF":6.2,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625246","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}
引用次数: 0
NSC-derived extracellular vesicles-mediates neuronal plasticity enhancement in vascular dementia via transferring miR-210. nsc来源的细胞外囊泡通过转移miR-210介导血管性痴呆的神经元可塑性增强。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-07-09 DOI: 10.1186/s40478-025-02073-1
Qunwen Pan, Yan Wang, Zhi Xiang, Yulan Yin, Yuyan Deng, Kesheng Xiao, Xiaobing Xu, Yahong Wang, Ganwen Deng, Xiaoxia Wang, Wangtao Zhong, Xiaotang Ma
{"title":"NSC-derived extracellular vesicles-mediates neuronal plasticity enhancement in vascular dementia via transferring miR-210.","authors":"Qunwen Pan, Yan Wang, Zhi Xiang, Yulan Yin, Yuyan Deng, Kesheng Xiao, Xiaobing Xu, Yahong Wang, Ganwen Deng, Xiaoxia Wang, Wangtao Zhong, Xiaotang Ma","doi":"10.1186/s40478-025-02073-1","DOIUrl":"10.1186/s40478-025-02073-1","url":null,"abstract":"<p><p>Chronic hypoperfusion-induced neuronal damage is the pathological basis of vascular dementia (VD). Hypoxia enhances the paracrine effects of neural stem cells (NSCs) by promoting neuroprotection and synaptic plasticity, which may be mediated by extracellular vehicles (EVs) secretion. In this study, we aimed to investigate the therapeutic effects and underlying mechanisms of hypoxic NSC-derived EVs (hypoxic NSC-EVs) in VD. Using Co-IP and Nanoparticle Tracking Analysis (NTA), we identified HIF-1α as a hypoxic adaptor protein that binds to RAB27A, promoting the localization of RAB27A with multivesicular bodies (MVBs). This interaction enhances the secretion of NSC-EVs under hypoxic condition. By miRNA sequencing, we observed that hypoxia increased the secretion of NSC-EVs and their enrichment of miR-210. Through a series of in vivo and in vitro gain- and loss-of-function experiments, we demonstrated that hypoxic NSC-EVs were more effective than normoxic NSC-EVs in improving cognitive function, increasing neuronal survival, enhancing synaptic plasticity and dendritic spine density, and reducing neuronal ROS production and apoptosis in the cortex and hippocampus of VD mice. Additionally, hypoxic NSC-EVs promoted neuronal viability, neurite elongation, and branching in oxygen-glucose-deprived (OGD) neurons by transferring miR-210. Rescue experiments revealed that silencing SPRED1, a target gene of miR-210, restored the diminished neuroprotective effects of miR-210 knockout NSC-EVs. Our findings suggest that the HIF-1α/RAB27A axis mediates the generation of hypoxic NSC-EVs, which amplifying their effects in promoting cognitive recovery after VD through the transfer of miR-210.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"152"},"PeriodicalIF":6.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599071","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}
引用次数: 0
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