Acta Neuropathologica Communications最新文献

{"title":"Enhancing heme synthesis attenuates pathological α-synuclein propagation in vivo.","authors":"Masami Masuda-Suzukake, Masato Hasegawa, Takashi Nonaka","doi":"10.1186/s40478-026-02336-5","DOIUrl":"10.1186/s40478-026-02336-5","url":null,"abstract":"<p><p>Intraneuronal α-synuclein (αS) accumulation is a central event in the pathogenesis of Parkinson's disease and dementia with Lewy bodies. The spread of αS pathology throughout the central nervous system contributes to disease progression via seed-dependent propagation, yet disease-modifying therapies remain unavailable. We previously reported that porphyrin compounds inhibit αS aggregation in vitro; however, because of their high molecular weight, porphyrins poorly penetrate the blood-brain barrier (BBB). Heme, a porphyrin derivative, is synthesized from 5-aminolevulinic acid (5-ALA) via the heme biosynthetic pathway. In this study, we investigated whether 5-ALA modulates αS accumulation and propagation. Although porphyrin compounds inhibited αS seeding in vitro, 5-ALA itself did not. However, treatment of mouse primary neurons with 5-ALA enhanced heme synthesis and suppressed seed-dependent αS aggregation, suggesting a potential role for intracellular heme in modulating αS propagation. We further evaluated the effects of 5-ALA in an in vivo αS propagation model. Preformed αS fibrils were unilaterally injected into the striatum of wild-type mice, followed by oral administration of 5-ALA at three doses (0, 1.7, and 20 mg/kg/day) for 4 weeks. Biochemical analyses demonstrated that 5-ALA significantly reduced the propagation of sarkosyl-insoluble αS to the contralateral hemisphere. Immunohistochemical analyses revealed a marked reduction in phosphorylated αS pathology in the amygdala and substantia nigra in the 5-ALA-treated groups. Collectively, these findings indicate that oral administration of 5-ALA suppresses αS propagation in vivo, potentially through enhancement of intracellular heme synthesis. Modulation of the heme biosynthetic pathway may represent a novel therapeutic strategy for synucleinopathies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13465251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203621","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 vascular and neurological characteristics of CADASIL are recapitulated in Notch3 mutant zebrafish, implicating a role for type IV collagen in disease progression.","authors":"Tohgo Kanoh, Shiho Oubayashi, Kengo Furukawa, Kosuke Fujimoto, Amane Inoue, Takamasa Mizoguchi, Masashi Yamaguchi, Azusa Takahashi-Nakaguchi, Yoshinori Hasegawa, Osamu Ohara, Ichio Aoki, Motoyuki Itoh","doi":"10.1186/s40478-026-02333-8","DOIUrl":"10.1186/s40478-026-02333-8","url":null,"abstract":"<p><p>CADASIL is a hereditary cerebral small vessel disease caused by NOTCH3 mutations, leading to age-dependent vascular and neurological impairments. Despite its clinical impact, the underlying pathogenic mechanisms remain poorly understood, partly because existing murine models often fail to fully replicate the broad pathological spectrum observed in humans. Here, we established and characterized a novel zebrafish (Danio rerio) model carrying the Notch3 p.C680S mutation. Our mutant zebrafish mimicked key age-related CADASIL features, including cerebrovascular dysfunction, telencephalic atrophy, cognitive impairment, and the deposition of granular osmiophilic material (GOM). Integrated transcriptomic and proteomic analyses revealed a significant downregulation of type IV collagen-related molecules, including serpinh1b, col4a1, and col4a2. These molecular findings were corroborated by immunostaining, which confirmed reduced perivascular accumulation of type IV collagen around cerebral blood vessels. Furthermore, AlphaFold 3-based structural modeling categorized the p.C680S variant as a \"nonconventional\" NOTCH3 mutation. These findings validate the zebrafish as a valuable vertebrate model for CADASIL and raise the possibility that diminished type IV collagen levels contribute to CADASIL pathogenesis, particularly in cases of nonconventional NOTCH3 mutations.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154782","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":"Polymeric lysosome-targeting chimeras for extracellular α-synuclein degradation in Parkinson's disease.","authors":"Arghya Bhattacharya, Hailah M Almohaimeed, Waheeb Sami Aggad, Amany I Almars, Osama Mohammed Abdulaziz Altowaijri, Hadeel Abdulrahman Waggas, Nuha M Bauthman, Zuhair M Mohammedsaleh, Tahani Ahmad ALMatrafi, Fayez M Saleh, Daniel Ejim Uti","doi":"10.1186/s40478-026-02335-6","DOIUrl":"10.1186/s40478-026-02335-6","url":null,"abstract":"<p><p>Disease progression in Parkinson's disease has been driven by extracellular α-synuclein prion-like seeding throughout the course of the disease and therefore not just by the intracellular accumulation of the protein in isolated aggregates. Current therapies utilizing PROTACs cannot address the extra-cellular effects of α-synuclein spreading in this manner. This article proposes PolyTACs (Polymeric Lysosome-Targeting Chimeras) as hybrid antibody-polymer conjugates which use neuronal exofacial thiol groups produced because of DJ-1/GSH dysregulation to capture α-synuclein pathological conformers before they can be derepressed (seeded pathological aggregates) into the cytoplasm. The hybridity of these antibodies (oligomers and fibrils) combined with pyridyl disulfide linkages in the multi-valent polymer allows these compounds to circumvent LTR co-option, and to be trafficked to lysosomes via a non-clathrin pathway. The delivery route for these agents is intended to be via intra-nasal, thereby bypassing many of the issues associated with delivery through the BBB. Delivery to patients will be guided by thiol profiling in cerebrospinal fluid to assist in inclusion-exclusion criteria for patients in prodromal trials. With these developments, it is anticipated that this new class of agent may provide a modular framework adaptable to other proteinopathies such as tau and TDP-43, pending further validation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148012","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":"Temporal dynamics of neuroplasticity and neurodegeneration in the central auditory system following noise-induced hearing loss: a multimodal imaging and histological study.","authors":"Víctor Giménez-Esbrí, Susanne Schwitzer, Susanne Mueller, Stefan Koch, Marco Foddis, Stefan Donat, Jan Schmoranzer, Niclas Gimber, Janina Zeqiraj, Dietmar Basta, Philipp Boehm-Sturm, Moritz Gröschel","doi":"10.1186/s40478-026-02252-8","DOIUrl":"10.1186/s40478-026-02252-8","url":null,"abstract":"<p><p>Noise-induced hearing loss (NIHL) is a sensorineural disorder that provokes complex neuroplastic and neurodegenerative changes within the central nervous system (CNS). This study investigated the temporal dynamics of neuronal density, axonal integrity and glutamatergic and GABAergic neurotransmission in the central inferior colliculus (CIC) and the ventral medial geniculate body of the thalamus (MGV) after NIHL. To achieve this, a correlative multimodal approach combining audiometric, magnetic resonance imaging (MRI) and histological biomarkers was performed. Adult mice were noise-exposed to broadband white noise (5-20 kHz) for 3 h at either high (115 dB SPL) or moderate (90 dB SPL) intensity, while unexposed mice served as controls. Separate cohorts of mice were investigated 1, 7, 56 and 84 days post-exposure using in vivo magnetic resonance imaging (MRI) techniques: Voxel-based morphometry (VBM) of gray matter density (GMD), diffusion MRI (dMRI) of microstructural connectivity, and proton magnetic resonance spectroscopy (1H-MRS) for glutamate and GABA quantification. Frequency-specific auditory brainstem responses (ABR) were recorded at 4, 8, 16 and 32 kHz before and after exposure to examine hearing threshold (HT) shifts. Brains were subsequently processed for fluorescence immunohistochemistry (FIHC) targeting NeuN, DAPI, NF, VGAT, VGLUT1 and VGLUT2. Mice exposed to 115 dB exhibited sustained HT elevations up to 84 days, suggesting a NIHL phenotype. Neurofilament (NF) expression significantly increased in the CIC and MGV 1d after 115 dB noise exposure, suggesting early axonal stress followed by normalization. dMRI alterations were observed 7d after 90 dB noise exposure. Glutamate and GABA decreases 84d after 90 dB exposure were also detected by 1H-MRS. No consistent changes in GMD or neuronal density were observed. Correlation analyses revealed weak relationships across audiometric, MRI and histological parameters. Overall, these findings reveal rapid neuroplastic adaptations following NIHL, and underscore the need for more sensitive biomarkers to detect early CNS consequences of NIHL.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13227874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148000","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: From origins to nomenclature: illuminating the landscape of CNS fibroblasts and fibroblast-like cells.","authors":"Jianing Lin, Kuo Liao, Sebastian A Lewandowski","doi":"10.1186/s40478-026-02338-3","DOIUrl":"10.1186/s40478-026-02338-3","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142377","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":"ATM-kinase deficiency triggers early multi-compartment remodeling of the cerebellar microenvironment.","authors":"Francesca Montarolo, Luna Berrino, Anita Maria Rominto, Matilde Loddo, Ilaria Balbo, Anastasia Ricci, Giulia Pia Servetto, Ginevra Mango, Kenta Yamamoto, Roberta Parolisi, Antonio Bertolotto, Ruggero Vigliaturo, Michele Menotta, Shan Zha, Filippo Tempia, Eriola Hoxha","doi":"10.1186/s40478-026-02332-9","DOIUrl":"10.1186/s40478-026-02332-9","url":null,"abstract":"<p><p>Ataxia Telangiectasia (A-T) is a neurodegenerative disorder characterized by early onset, cerebellar ataxia and progressive motor decline. The causative gene, ATM (A-T Mutated), encodes a Ser/Thr kinase, that belongs to the phosphoinositide 3-kinase-related protein kinase family and is crucial for the response to DNA double-strand breaks. While ATM is classically known for its role in the DNA damage response, increasing evidence points to its critical function in maintaining cellular homeostasis, particularly in the central nervous system (CNS). Yet the mechanisms linking ATM-kinase deficiency to cerebellar circuit dysfunction remain poorly defined. Using a CNS Nestin-Cre-restricted mouse model carrying a kinase-dead Atm allele combined with a null allele (Atm^KDF/CNS-KO), we integrated proteomics, structural and ultrastructural analyses, electrophysiology, and behavioral testing to understand how the loss of Atm kinase activity influence the cerebellar microenvironment from the earliest stages of the disease. Proteomic profiling revealed alterations across four major pathways in Atm^KDF/CNS-KO mice, such as disorganization of the extracellular matrix (ECM), astrocytosis, downregulation of myelin and oligodendrocyte lineage proteins and changes in neuronal excitability. Histological and electron microscopy analyses confirmed increased ECM deposition, astrocytosis and reduction of myelin content without axonal or oligodendrocyte loss, consistent with impaired myelination at early stages. These microenvironmental changes were associated to Purkinje cell dark cell degeneration and increased intrinsic excitability, demonstrating early circuit dysfunction in the absence of overt neuronal loss. Consistently, the compromised cerebellar output is confirmed by the progressive motor impairment developed by Atm^KDF/CNS-KO mice. Our findings indicate that Atm kinase deficiency disrupts cerebellar homeostasis through interconnected and bidirectional mechanisms involving ECM remodeling, astrocytosis, impaired oligodendrocyte functioning and altered intrinsic excitability, reflecting a network level destabilization of the cerebellar microenvironment.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051853","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 hydrocephalus-like phenotype in NOTCH2NLC-related neuronal intranuclear inclusion disease: clinicopathological features and therapeutic implications.","authors":"Shaoping Zhong, Yangye Lian, Binbin Zhou, Jingzhen Liang, Yuzhe Li, Luyao Huang, Xing Chen, Yi Yan, Wei Sun, Rongkui Luo, Hui Lu, Jianying Liu, Fan Hu, Xin Wang, Jing Ding","doi":"10.1186/s40478-026-02337-4","DOIUrl":"10.1186/s40478-026-02337-4","url":null,"abstract":"<p><p>NOTCH2NLC-related neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder with marked clinical heterogeneity and an increasingly recognized phenotypic spectrum. Although hydrocephalus-like presentations, i.e. ventriculomegaly with concomitant with cognition, motor, and/or bladder dysfunctions, have been observed in NIID sporadically, their prevalence, clinicopathological characteristics, and potential clinical implications remain poorly understood. This retrospective cohort study systematically characterized this newly recognized hydrocephalus-like phenotype. We conducted an MRI-based screening to identify previously undiagnosed NIID cases from a cohort of 498 adults with imaging diagnosis of communicating hydrocephalus. Four such cases were identified and incorporated into our NIID cohort, with genetic and pathological confirmation. A total of 68 NIID patients were analyzed, of whom 19 (27.9%) exhibited marked ventriculomegaly (Evans index > 0.34) disproportionate to parenchymal atrophy and were grouped as ventriculomegalic NIID. Compared with those without ventriculomegaly, these patients were associated with male predominance, more frequent walking difficulty, and less frequent tremor. Nearly half of ventriculomegalic cases (9/19) fulfilled the idiopathic normal pressure hydrocephalus-like clinical triad. Radiological features included markedly enlarged ventricles, smaller callosal angle, less frequent diffusion-weighted imaging hyperintensities, and overrepresented periventricular-dominant white matter lesion pattern. A subset of ventriculomegalic NIID patients (5/8) showed improvement in gait, cognition, and/or urinary function following cerebrospinal fluid drainage, and two patients who underwent ventriculoperitoneal shunt surgery experienced sustained clinical benefit. Brain autopsy was performed in one ventriculomegalic NIID patient, revealing widespread intranuclear inclusions, particularly in ependymal and choroid plexus epithelial cells and astrocytes, alongside dysmorphic astrocytes and loss of aquaporin-4 polarization. Collectively, our findings suggest that a hydrocephalus-like phenotype with distinctive clinical and radiological features is relatively common in NIID and frequently misdiagnosed as idiopathic normal pressure hydrocephalus. Pathological alterations in the ependyma, choroid plexus, and astrocytes and subsequently disturbed cerebrospinal fluid dynamics may contribute to its pathogenesis. Some patients might benefit from shunt surgery, highlighting a possible symptomatic and partially reversible component and broadening therapeutic opportunities in this otherwise progressive neurodegenerative disorder.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051907","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":"VAPB confers selective neuroprotection by driving autophagic degradation of pathogenic aggregates in ALS.","authors":"Priyanka Tripathi, Haihong Guo, Alfred Yamoah, Ramkumar Mathur, Panagiotis Doukas, Alice Dreser, Christopher Marvin Jesse, Eleonora Aronica, Andreas Hermann, Harry Steinbusch, Gary Anthony Brook, Joachim Weis, Anand Goswami","doi":"10.1186/s40478-026-02298-8","DOIUrl":"10.1186/s40478-026-02298-8","url":null,"abstract":"<p><p>During the progression of amyotrophic lateral sclerosis (ALS), only specific motor neurons (MNs) preferentially deteriorate, while others are spared until the disease reaches its end stage. Resilient MNs possess several protective factors, yet the precise molecular mechanism(s) underlying selective neuronal vulnerability remains poorly understood. Vesicle-associated membrane protein (VAMP)-binding protein B (VAPB) is an endoplasmic reticulum (ER) protein involved in protein quality control (PQC) mechanisms, including unfolded protein response (UPR) as well as autophagy. A dominantly inherited P56S mutation in the VAPB gene has been linked to ALS8, atypical ALS, and late-onset spinal muscular atrophy (SMA). The P56S VAPB mutation causes ER-associated inclusions, disorganization, and ER stress, contributing to MN degeneration through toxic gain and loss of function. Over-expression of VAPB protein confers neuroprotection in a mouse model of ALS, and increased levels of neuronal VAPB inversely correlate with the absence of pathological aggregates. We hypothesize that VAPB is crucial for motor neuron survival by promoting autophagic degradation of ALS-associated aggregates, while lack of VAPB confers neuronal vulnerability. We analyzed the brain and spinal cord from sporadic (s) and familial (f) ALS patients, comparing patterns of VAPB immunoreactivity using immunohistochemistry, complemented by Western and dot blot analysis. Pathophysiological insights from these studies were further explored using cell culture models, including MNs derived from induced pluripotent stem cells (iPSCs). Consistent with our hypothesis we observed that MNs/neurons resistant to ALS exhibited elevated levels of VAPB and were devoid of pathogenic aggregates. Similarly, ALS-resistant oculomotor neurons showed increased VAPB immunoreactivity compared to normal controls. VAPB was often found to be sequestered within toxic aggregates alongside autophagy-related proteins in the lumbar spinal cord MNs. Notably, a compensatory increase in VAPB immunoreactivity was observed at the C-bouton synapse, suggesting a potential alternative mechanism of neuroprotection. Supporting these findings, in vitro experiments indicated that VAPB overexpression promoted autophagy and assisted in clearing ALS-associated RNA-binding protein aggregates. In summary, VAPB promotes selective neuronal survival by facilitating the autophagic clearance of toxic aggregates. Abnormal VAPB accumulations likely disrupt these neuroprotective processes.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13255306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051856","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":"Comprehensive characterization of spinal ependymomas in NF2-Schwannomatosis.","authors":"Pauline Marijon, Yu Teranishi, Franck Bielle, Marc Sanson, Matthieu Peyre, Michel Kalamarides","doi":"10.1186/s40478-026-02331-w","DOIUrl":"10.1186/s40478-026-02331-w","url":null,"abstract":"<p><strong>Background: </strong>Spinal ependymomas (SE) account for 10% of ependymomas and are the most frequent spinal glial tumors. NF2-related Schwannomatosis (NF2-SWN) patients are predisposed to multiple SE in addition to other tumors, schwannomas and meningiomas. Surgery remains the main treatment option, but mays lead to severe morbidity. In many cases, it is the cystic rather than the solid component of the tumor that drives neurological symptoms and ultimately necessitates surgical intervention. Understanding tumor and associated cyst formation is therefore important to develop new therapeutic approaches.</p><p><strong>Methods: </strong>This clinical and radiological study includes 33 NF2-SWN with a long-term follow-up and 11 sporadic SE patients. Tumor and cyst characteristics were assessed, and histopathological analyses performed, including multiplex immunohistochemistry and RNA sequencing.</p><p><strong>Results: </strong>Radiological analysis revealed that peritumoral edema frequently precedes cystic formation. Histological analysis showed that macrophage infiltration, particularly by SPP1-positive macrophages, was associated with cystic growth in NF2-SWN SE. RNAseq analysis identified distinct immune microenvironments differentiating NF2-SWN from sporadic SE, including differences in VEGF-C expression. Consistent with these results, AXITINIB, a selective inhibitor of VEGFR and VEGFR3 which acts as the receptor for VEGF-C, was proposed to a NF2-SWN patient with a progressing cystic SE and resulted in clinical improvement accompanied by a reduction in the peritumoral cyst.</p><p><strong>Conclusion: </strong>These results support a role for VEGF signaling and macrophage-mediated microenvironmental changes in edema and cystic growth of NF2-SWN SE. The observed clinical response to AXITINIB in an index patient suggests that new combinations of anti-angiogenic therapies may represent a promising early targeted approach.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051820","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":"Pituitary blastoma in a dog: comparative clinical, imaging, and pathologic features of a newly recognized and rare human entity.","authors":"Giuseppe Giglia, Cristian Falzone, Mariagiovanna Lorena Graceffa, Silvia Uccella, Maria Teresa Mandara","doi":"10.1186/s40478-026-02281-3","DOIUrl":"10.1186/s40478-026-02281-3","url":null,"abstract":"<p><p>Pituitary blastoma (PitB) is an exceedingly rare tumor originating from the anterior pituitary gland, first documented in 2008 in humans. It is considered pathognomonic for DICER1 syndrome, primarily affecting children, although cases in adults have been noted. Clinical manifestations vary widely, attributed to hormone hypersecretion (such as Cushing's syndrome) and mass-related effects (like visual impairment and intracranial pressure changes). Histopathologically, PitB exhibits distinct features: proliferating Rathke's epithelium with rosette formations, adenohypophyseal neuroendocrine cells expressing ACTH and occasionally GH, and primitive small blastemal cells. This report describes the first case of PitB in a dog, presenting with ACTH-dependent hypercortisolism. The canine patient exhibited clinical signs consistent with ACTH-hypersecretion related to a pituitary mass. Histologically, the pituitary mass revealed hallmark features resembling human PitB. Immunohistochemistry confirmed ACTH expression and nuclear expression of TBX19 (TPIT), supporting a corticotroph lineage. CAM 5.2 expression in tubule-forming cells suggested an immature epithelial origin, likely from Rathke's pouch. Although DICER1 mutation analysis was not performed due to technical limitations with FFPE tissue, this case raises the possibility of a similar pathogenetic mechanism in dogs. This canine case expands the known species range of PitB and highlights important clinical, morphological and immunohistochemical parallels with the human counterpart, providing new insights into comparative pituitary tumor pathology.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13383401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004037","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}