Acta Neuropathologica Communications最新文献

{"title":"Histomorphological variations in progressive multifocal leukoencephalopathy correlated with JCV replication in brain lesions: insights from 91 patients.","authors":"Kenta Takahashi, Yuko Sato, Hideki Hasegawa, Harutaka Katano, Tadaki Suzuki","doi":"10.1186/s40478-025-02027-7","DOIUrl":"10.1186/s40478-025-02027-7","url":null,"abstract":"<p><p>Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by JC polyomavirus (JCV). The histopathology of PML is morphologically diverse and characterized by the classical triad of demyelination, enlarged oligodendroglial nuclei, and bizarre astrocytes. Pathological diagnostic criteria for PML require both the classical triad and viral detection in brain tissue. However, the frequency of this triad in surgical pathology specimens and its correlation with disease progression and viral loads remain unclear. In this study, 117 brain tissues from 91 pathologically confirmed PML patients were investigated. PML histopathology was found to be spatially and temporally pleomorphic, and not all brain tissues exhibited the complete classical triad. The sensitivity of quantitative PCR for detecting JCV in brain tissues was 100%, whereas that of immunohistochemistry (IHC) was 83.5-87.8%. Viral loads in biopsy samples were significantly higher than those in autopsy samples and decreased over time after disease onset. To systematically characterize PML lesions from the outer border to the demyelinated center, we developed a histological classification based on the classical triad and macrophage infiltration. This classification correlated with viral loads, with subtypes characterized by abundant enlarged oligodendroglial nuclei at the demyelination border exhibiting the highest levels of JCV DNA. Pathological variability was influenced by spatial and temporal factors rather than by underlying diseases, although PML associated with acquired immunodeficiency syndrome exhibited more severe demyelination. In conclusion, histomorphological variability in PML reflects viral replication activity, emphasizing the importance of comprehensive pathological evaluation. Combining histomorphology, tissue-based PCR for viral DNA detection, and IHC for viral antigens is crucial for assessing disease progression. Early brain biopsy from the demyelination border offers the best opportunity for a definitive diagnosis of PML and may guide therapy targeting active lesions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"106"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the brain: exploring the impact of animal models of leptomeningeal disease from solid tumors.","authors":"Jillyn R Turunen, Priya Kumthekar, Atique U Ahmed","doi":"10.1186/s40478-025-01959-4","DOIUrl":"10.1186/s40478-025-01959-4","url":null,"abstract":"<p><p>Leptomeningeal disease (LMD) is a devastating manifestation of late-stage cancer which currently suffers from a lack of effective therapeutics. Unfortunately, a significant obstacle preventing the widespread development and testing of therapeutics for LMD is the lack of biologically accurate animal models. We provide overviews of six types of animal models of leptomeningeal metastasis from solid tumors: injection of tumor cells into the cerebrospinal fluid (CSF), blood, or brain parenchyma; subcutaneous or mammary fat pad injection of tumor cells; the LeptoM/LM-phenotype model; and genetic manipulation. We identify the pros and cons of each model and suggest broad areas of future research that could improve each model in terms of its similarity to human LMD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"103"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092532","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 transcriptomics reveal PI3K-AKT and metabolic alterations in aggressive, treatment-resistant lactotroph pituitary neuroendocrine tumors.","authors":"Florencia Martinez-Mendoza, Sergio Andonegui-Elguera, Ernesto Sosa-Eroza, Erick Gomez-Apo, Aurea Escobar-España, Carolina Gonzalez-Torres, Javier Gaytan-Cervantes, Alam Palma-Guzman, Hugo Torres-Flores, Alberto Moscona-Nissan, Silvia Hinojosa-Alvarez, Jesús Hernandez-Perez, Roció A Chavez-Santoscoy, Gerardo Guinto, Gerardo Y Guinto-Nishimura, Blas E Lopez-Felix, Erick U Zepeda-Fernandez, Erick M Estrada-Estrada, Victor Correa-Correa, Pedro A Gonzalez-Zavala, Marco A Asenscio-Montiel, Miguel A Garcia-Vargas, Emmanuel Cantu-Chavez, Rocio L Arreola-Rosales, Keiko Taniguchi-Ponciano, Daniel Marrero-Rodriguez, Moisés Mercado","doi":"10.1186/s40478-025-02025-9","DOIUrl":"10.1186/s40478-025-02025-9","url":null,"abstract":"<p><p>Clinically aggressive lactotroph pituitary neuroendocrine tumors (PitNET) are invasive tumors with an unusually rapid growth rate despite maximally tolerated doses of dopamine agonist (DA). We aimed to unravel the molecular heterogeneity of lactotroph PitNET and to identify biomarkers of aggressiveness and resistance to pharmacological treatment. A total of 13 patients harboring DA-resistant lactotroph PitNET were included in this study. Visium Spatial Transcriptomics (ST), whole transcriptome sequencing (WTS), and whole exome sequencing (WES) were performed in tumors from 4 of these patients; WTS and WES was carried out in 5; tumors from two patients underwent ST and WES and tumors from two other patients underwent only ST. Tumors were classified as null or partial responders according to their response to DA treatment. The eight PitNET analyzed by ST exhibited significant intratumoral heterogeneity, with clones showing alterations in PI3K/AKT and lipid metabolism pathways, particularly inositol phosphate, glycerophospholipid, and sphingolipid metabolism. The cell-cell communication analysis showed FGF-FGFR ligand receptor interaction whilst the transcription factors RXRA and CREM showed participation in both groups. A trajectory exploration was performed by including all PitNET together in a single analysis to determine whether there was a tendency or molecular pathway showing a differentiation pattern that would guide the transition from a partially responsive PitNET to a completely unresponsive one. We did not observe any such pattern. All of these findings were corroborated in the cohort of DA-resistant PitNETs in which only bulk WTS and WES were performed. The bulk WTS corroborated lipid metabolism and PI3K-AKT pathway alteration in PitNET, whereas the WES showed only SF3β1 and TP53 variants in one tumor each. Our work suggests that the PI3K/AKT pathway may constitute a molecular target at which to aim therapeutic strategies designed to treat aggressive and DA-resistant lactotroph PitNET.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"107"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101294","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":"hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation.","authors":"Ian Weidling, Christina N Preiss, Sarah E Chancellor, Gyan Srivastava, Lauren Gibilisco, Gen Lin, Melanie Shackett Brennan, Janice Lee, Lindsay M Roth, Olga Morozova, Kyong Nyon Nam, Nehal R Patel, Qing Liu, J K Thomas, Peter Reinhardt, Ruven Wilkens, Dagmar E Ehrnhoefer, Andreas Striebinger, Stefan Barghorn, Christina Xanthopoulos, Marie-Theres Weil, Sandra Biesinger, Miroslav Cik, Nandini Romanul, Kiran Yanamandra, Alessandra M Welker, Jessica Wu, Laura Gasparini, Jan Stöhr, Xavier Langlois, Justine D Manos","doi":"10.1186/s40478-025-02000-4","DOIUrl":"10.1186/s40478-025-02000-4","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by the accumulation and spread of Tau intraneuronal inclusions throughout most of the telencephalon, leaving hindbrain regions like the cerebellum and spinal cord largely spared. These neuropathological observations, along with the identification of specific vulnerable sub-populations from AD brain-derived single nuclei transcriptomics, suggest that a subset of brain regions and neuronal subtypes possess a selective vulnerability to Tau pathology. Given the inability to culture neurons from patient brains, a disease-relevant in vitro model which recapitulates these features would serve as a critical tool to validate modulators of vulnerability and resilience. Using our recently established platform for inducing endogenous Tau aggregation in human induced pluripotent stem cell (hiPSC)-derived cortical excitatory neurons via application of AD brain-derived exogenous Tau aggregates, we explored whether Tau aggregates preferentially induce aggregation in specific neuronal subtypes. We compared Tau seeding in hiPSC-derived neuron subtypes representing regional identities across the forebrain, midbrain, and hindbrain. Higher susceptibility (i.e. more Tau aggregation) was consistently observed among cortical neuron subtypes, with CTIP2-positive, somatostatin (SST)-positive cortical inhibitory neurons showing the greatest aggregation levels across hiPSC lines from multiple donors. hiPSC-neurons also delineated between the disease-specific vulnerabilities of different protein aggregates, as α-synuclein preformed fibrils showed an increased propensity to induce aggregates in midbrain dopaminergic (mDA)-like neurons, mimicking Parkinson's disease (PD)-specific susceptibility. Aggregate uptake and degradation rates were insufficient to explain differential susceptibility. The absence of a consistent transcriptional response following aggregate seeding further indicated that intrinsic neuronal subtype-specific properties could drive susceptibility. The present data provides evidence that hiPSC-neurons exhibit features of selective neuronal vulnerability which manifest in a cell autonomous manner, suggesting that mining intrinsic (or basal) transcriptomic signatures of more vulnerable compared to more resilient hiPSC-neurons could uncover the molecular underpinnings of differential susceptibility to protein aggregation found in a variety of neurodegenerative diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"108"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101291","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":"Age-dependent interactions of APOE isoform 4 and Alzheimer's disease neuropathology: findings from the NACC.","authors":"Cellas A Hayes, Roland J Thorpe, Michelle C Odden","doi":"10.1186/s40478-025-02012-0","DOIUrl":"10.1186/s40478-025-02012-0","url":null,"abstract":"<p><p>Alzheimer's disease related pathologies, neurodegenerative pathologies, and vascular neuropathologies are common in older adults at death. Previous studies using the National Alzheimer's Coordinating Center (NACC) have not investigated the association between age at death and apolipoprotein E (APOE) ε4 and the prevalence of neuropathologies found at autopsy. We used autopsy confirmed neuropathology data from the NACC to examine the interactive effects of age and APOE ε4 on various neuropathologies (N = 5,843) using modified Poisson regression to estimate the prevalence ratios. Significant interactions between APOE ε4 and age at death were observed for neuritic plaques, Braak staging, diffuse neuritic plaques, and Lewy body disease pathology, with the effect of APOE ε4 decreasing at older ages. In contrast, a significant positive interaction was found for hemorrhages/microbleeds, indicating that the association between APOE ε4 and microbleeds strengthens with increasing age. These findings suggest that future therapeutic strategies should consider both genetic risk and age to effectively target AD progression.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"102"},"PeriodicalIF":6.2,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092528","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":"Downregulation of STAT3 transcription factor reverses synaptotoxic phenotype of reactive astrocytes associated with prion diseases.","authors":"Rajesh Kushwaha, Kara Molesworth, Natallia Makarava, Ilia V Baskakov","doi":"10.1186/s40478-025-02028-6","DOIUrl":"10.1186/s40478-025-02028-6","url":null,"abstract":"<p><p>In neurodegenerative diseases, including prion diseases, astrocytes adopt reactive phenotypes that persist throughout disease progression. While astrocyte reactivity may initially serve as a protective response to prion infection, it transitions into a neurotoxic phenotype that disrupts homeostatic functions and exacerbates disease pathology. The transcription factor Stat3 has been recognized as a master regulator of astrocyte reactivity in neurodegenerative diseases, yet its role in prion disease-associated astrocyte reactive phenotypes remains unexplored. The current study addresses this gap by investigating the effects of Stat3 deletion in reactive astrocytes isolated from prion-infected mice. We demonstrate that Stat3 deletion mitigates the reactive astrocyte phenotype and alleviates their synaptotoxic effects. Stat3-dependent activation of astrocytes was reproduced by co-culturing naïve astrocytes with reactive microglia isolated from prion-infected animals or exposing them to microglia-conditioned media. A cytokine array profiling of 40 molecules revealed partially overlapping inflammatory signatures in reactive microglia and astrocytes, with IL-6 prominently upregulated in both cell types. Notably, IL-6 treatment elevated phosphorylated Stat3 levels in naïve astrocytes and triggered astrocyte reactivity. These findings indicate that the synaptotoxic phenotype of astrocytes in prion diseases can be sustained by reactive microglia and self-reinforced in a cell-autonomous manner. Our work highlights the pivotal role of Stat3 signaling in astrocyte activation and suggests that Stat3 inhibition may suppress the reactive phenotype of astrocytes associated with prion diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"101"},"PeriodicalIF":6.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075305","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":"Shaking into deficits: investigating behavioural and neuropathological outcomes associated with a novel preclinical model of infant abusive head trauma.","authors":"Sydney A Harris, Marissa Sgro, Sabrina Salberg, Crystal Li, Elaina Vlassopoulos, Madeleine Smith, Bridgette D Semple, Holly R Chinnery, Richelle Mychasiuk","doi":"10.1186/s40478-025-02029-5","DOIUrl":"10.1186/s40478-025-02029-5","url":null,"abstract":"<p><p>Abusive head trauma (AHT) resulting from violent shaking and whiplash-induced brain injury by a caregiver, is the leading cause of abusive mortality and morbidity in children. Cerebral oedema is common in survivors of AHT. While many children may initially appear behaviourally asymptomatic or present with non-specific symptoms following the AHT, deficits often emerge later in childhood. Additionally, AHTs are frequently repetitive, with a single child likely to experience multiple AHTs. Despite the prevalence of AHT, the mechanisms that lead to brain pathology and the latent emergence of behavioural deficits are poorly understood, and there is a paucity of preclinical, small animal models to investigate the biology and cumulative effects of repetitive injuries. This study aimed to develop a preclinical model of repetitive AHT and subsequently examine alterations in gene expression, cell types, and early adolescent behaviour. Mice were placed on a 400 rpm shaking device for 60s. This was repeated one, three, or five times throughout the neonatal development period (postnatal days (P)8-12). Injured mice initially displayed no overt behavioural changes compared to uninjured controls; however, in adolescence (P40-45) they later developed deficits in socialisation and thermal nociception. Further, alterations in the expression of genes involved in growth, cell damage, and development were observed in the brains of injured mice, along with an increase in white matter cells and evidence of blood-brain barrier leakage. This novel preclinical model of AHT provides a valuable platform for exploring diagnostic biomarkers and potential therapeutic interventions for children with an AHT.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"100"},"PeriodicalIF":6.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075309","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":"Genomic and immune profiling of breast cancer brain metastases.","authors":"Amanda E D Van Swearingen, Marissa R Lee, Layne W Rogers, Alexander B Sibley, Pixu Shi, Xiaodi Qin, Michael Goodin, Katelyn Seale, Kouros Owzar, Carey K Anders","doi":"10.1186/s40478-025-02001-3","DOIUrl":"10.1186/s40478-025-02001-3","url":null,"abstract":"<p><strong>Background: </strong>Brain metastases (BrM) arising from breast cancer (BC) are an increasing consequence of advanced disease, with up to half of patients with metastatic HER2 + or triple negative BC experiencing central nervous system (CNS) recurrence. The genomic alterations driving CNS recurrence, along with contributions of the immune microenvironment, particularly by intrinsic subtype, remain unclear.</p><p><strong>Methods: </strong>We characterized the genomic and immune landscape of BCBrM from a cohort of 42 patients by sequencing whole-exome DNA (WES) and total RNA libraries from frozen and FFPE BrM and FFPE extracranial tumors (ECT). Analyses included PAM50 intrinsic subtypes, somatic mutations, copy number variations (CNV), pathway alterations, immune cell type deconvolution, and associations with clinical outcomes RESULTS: Intrinsic subtype calls were concordant for the majority of BrM-ECT pairs (60%). Across all BrM and ECT samples, the most common somatic gene mutation was TP53 (64%, 30/47). For patients with matched FFPE BrM-FFPE ECT, alterations tended to be conserved across tissue type, although differential somatic mutations and CNV in specific genes were observed. Several genomic pathways were differentially expressed between patient-matched BrM-ECT; MYC targets, DNA damage repair, cholesterol homeostasis, and oxidative phosphorylation were higher in BrM, while immune-related pathways were lower in BrM. Deconvolution of immune populations between BrM-ECT demonstrated activated dendritic cell populations were higher in BrM compared to ECT. Increased expression of several oncogenic preselected pathways in BrM were associated with inferior survival, including DNA damage repair, inflammatory response, and oxidative phosphorylation CONCLUSIONS: Collectively, this study illustrates that while some genomic alterations are shared between BrM and ECT, there are also unique aspects of BrM including somatic mutations, CNV, pathway alterations, and immune landscape. A deeper understanding of differences inherent to BrM will contribute to the development of BrM-tailored therapeutic strategies. Additional analyses are warranted in larger cohorts, particularly with additional matched BrM-ECT.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"99"},"PeriodicalIF":6.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957307","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":"Astrocytes carrying LRRK2 G2019S exhibit increased levels of clusterin chaperone via miR-22-5p and reduced ability to take up α-synuclein fibrils.","authors":"Alice Filippini, Giulia Carini, Alessandro Barbon, Massimo Gennarelli, Isabella Russo","doi":"10.1186/s40478-025-02015-x","DOIUrl":"10.1186/s40478-025-02015-x","url":null,"abstract":"<p><p>Accumulating evidence highlights that dysfunction of astrocyte biology might contribute to Parkinson's disease (PD) onset and progression. Leucine-rich repeat kinase 2 (LRRK2), a gene linked to genetic and familial PD, has been reported to affect astrocytic-related functions, including the ingestion of alpha-synuclein (α-syn) aggregates. In this context, we recently showed that the extracellular chaperone clusterin (Clu) binds to and limits the uptake of alpha-syn fibrils by astrocytes. Thus, starting from these premises, we explored whether LRRK2 G2019S affects aggregated α-syn ingestion through the Clu-related pathway and the underlying molecular mechanisms. We first validated in our LRRK2 G2019S knock-in (KI) mouse strain that primary astrocytes exhibited an impaired ability to ingest fibrillary α-syn. Then, we investigated whether LRRK2 G2019S affects this pathway through the modulation of Clu. In this regard, we collected several results showing that LRRK2 regulates Clu levels in astrocytes. Specifically, brain slices and primary astrocytes from KI mice with the LRRK2 G2019S pathological mutation exhibit increased levels of Clu protein compared to their respective wild-type (WT). Accordingly, we observed an opposite effect in brain slices and primary astrocytes from LRRK2 knock-out (KO) mice in comparison to their respective WT. To gain insights into the molecular mechanism underlying LRRK2-dependent Clu modulation, we found that LRRK2 controls Clu expression at the translation level through the action of miR-22-5p. In addition, we demonstrated that treatment with miR-22-5p mimic improves the ability of LRRK2 G2019S-KI astrocytes to take up α-syn pffs. Taken together, our findings indicate that the LRRK2-Clu pathway is involved in the ingestion of a-syn fibrils and that the impairment of α-syn uptake in LRRK2 G2019S-KI astrocytes is associated to Clu levels. Future studies will allow us to understand whether the modulation of astrocytic LRRK2 G2019S-Clu pathway might attenuate the neuronal spreading of α-syn pathology in PD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"98"},"PeriodicalIF":6.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957509","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":"Expanding clinicopathologic knowledge in high-grade glioma with pleomorphic and pseudopapillary features (HPAP): a report of two cases.","authors":"Sabrina Rossi, Isabella Giovannoni, Sara Patrizi, Andrea Mafficcini, Eleonora Piccirilli, Giuseppe Kenneth Ricciardi, Giacomina Megaro, Francesca Arienzo, Chantal Tancredi, Emanuele Agolini, Andrea Carai, Angela Mastronuzzi, Caterina Giannini, Franco Locatelli, Rita Alaggio, Giovanna Stefania Colafati, Viola Alesi, Evelina Miele, Valeria Barresi","doi":"10.1186/s40478-025-02017-9","DOIUrl":"10.1186/s40478-025-02017-9","url":null,"abstract":"<p><p>High-grade glioma with pleomorphic and pseudopapillary features (HPAP) is a recently identified methylation cluster comprised of relatively circumscribed gliomas enriched for variants in TP53, RB1, NF1, NF2, BRAF and with a more favorable clinical outcome than IDH-wildtype glioblastoma. Here, we present two cases occurring in young adults, one of which occurred in the background of NF2-related schwannomatosis. Both cases demonstrated characteristic histologic features including ependymoma-like areas (Case #1) and an astroblastoma-like phenotype (Case #2), as well as archetypal pseudopapillary structures and pleomorphic tumor cells. High-grade features were present and pathogenic variants in RB1 and TP53 were detected. Cytogenetic analysis revealed aneuploidy involving multiple whole chromosomes, including copy neutral LOH in chromosome 13 (Case #1). Both cases were classified as \"no match\" using the Heidelberg Brain Tumor Classifier (v12.5 and 12.8). Results from a preliminary classification model (\"Bethesda Classifier\") were consistent with HPAP. Confirmatory dimensionality reduction (t-SNE) showed clustering within (Case #2) or near (Case #1) the HPAP group. Patient #1 is currently receiving maintenance temozolomide following concomitant chemo-radiotherapy, 10 months post-surgery. Patient #2, treated with temozolomide, remains disease-free at 42 months. Our study highlights additional clinical and pathologic insights into this proposed tumor type and may suggest an association with NF2-related schwannomatosis and evolution from low-grade precursors. These observations support the consideration of HPAP as a distinct clinicopathological entity.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"97"},"PeriodicalIF":6.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951721","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}