Acta Neuropathologica Communications最新文献_第9页

CD155 and its receptors in glioma: prospects for emerging immune checkpoint inhibitors. 胶质瘤中的CD155及其受体：新兴免疫检查点抑制剂的前景

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-22 DOI: 10.1186/s40478-026-02327-6

Mingyao Huang, Youchen Cui, Xiaoqian Wang, Yang Weng, Huiyan Huang, Weiwei Su, Shan Zhao, Yan Li

{"title":"CD155 and its receptors in glioma: prospects for emerging immune checkpoint inhibitors.","authors":"Mingyao Huang, Youchen Cui, Xiaoqian Wang, Yang Weng, Huiyan Huang, Weiwei Su, Shan Zhao, Yan Li","doi":"10.1186/s40478-026-02327-6","DOIUrl":"10.1186/s40478-026-02327-6","url":null,"abstract":"Glioma is an aggressive brain malignancy characterized by a markedly immunosuppressive microenvironment and limited response to conventional treatments. CD155, also known as the poliovirus receptor, is frequently overexpressed in glioma and plays a key role in immune escape. By interacting with inhibitory receptors such as TIGIT and CD96, as well as the activating receptor CD226, CD155 modulates the tumor immune landscape. These interactions suppress the cytotoxic activity of T cells and natural killer (NK) cells while promoting immunoregulatory phenotypes, thereby impairing immune-mediated tumor cell elimination and supporting tumor progression. The balance among these receptor-ligand interactions is critical in determining immune outcomes. Targeting the CD155 axis has emerged as a potential therapeutic strategy. Approaches including monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor (CAR)-engineered immune cells are being developed to counteract immune suppression and restore antitumor responses. This review summarizes the structural and functional features of CD155 and its associated receptors, examines their roles in glioma immune evasion, and discusses recent advances and challenges in developing therapies targeting this pathway. Modulation of CD155-related signaling may offer new opportunities to improve treatment outcomes in glioma.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004067","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

Characterization of a distinct form of vimentin in the neurodegenerative brain. 神经退行性脑中一种不同形式的波形蛋白的特征。

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-22 DOI: 10.1186/s40478-026-02324-9

Abdulkhalek Dakhel, Johanna Vestin, Vilmantas Giedraitis, Dag Nyholm, Martin Ingelsson, Anna Erlandsson

{"title":"Characterization of a distinct form of vimentin in the neurodegenerative brain.","authors":"Abdulkhalek Dakhel, Johanna Vestin, Vilmantas Giedraitis, Dag Nyholm, Martin Ingelsson, Anna Erlandsson","doi":"10.1186/s40478-026-02324-9","DOIUrl":"10.1186/s40478-026-02324-9","url":null,"abstract":"Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated proteins, leading to neuronal and glial dysfunction. Compelling data indicate that changes in vimentin expression, structure, and localization reflect alterations in cellular homeostasis and may correlate with disease progression. Yet, the involvement of abnormal vimentin in AD and PD remains unclear. Here, we have thoroughly characterized the distribution of modified, disease-associated vimentin in the AD and PD brain parenchyma, as well as in cerebrospinal fluid (CSF), hiPSC-derived astrocytes and organoids. For this purpose, we used the form-specific vimentin antibody [84-1], originally generated to recognize abnormal vimentin on the surface of sarcoma cells. The 84-1 vimentin reactivity pattern was characterized through immunohistochemistry and proximity ligation assay. Moreover, proteomic analysis, Western blot, and ELISA were performed to quantify 84-1 vimentin levels and gain insights into its molecular features. Our data demonstrate that 84-1 can identify a distinct population of vimentin in the human brain that shows low affinity to commonly used vimentin antibodies. The 84-1 vimentin is enriched in disease conditions and forms distinct deposits in the affected regions of the AD and PD brain, often colocalizing with pathological protein aggregates. Interestingly, the 84-1 vimentin pool consists mainly of cleaved proteoforms and reduction-resistant aggregates. Moreover, 84-1 vimentin levels are elevated in the CSF of AD and PD patients as well as in the culture medium of human astrocytes exposed to αSyn or Aβ fibrils. Taken together, our data highlights the importance of modified vimentin in neurodegeneration and presents 84-1 vimentin as a potential biomarker and future treatment target for AD and PD.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004094","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

Dysregulated oligodendrocyte and myelin dynamics as an early pathological feature of neuropil degeneration in Alzheimer's disease: an ultrastructural study. 少突胶质细胞和髓磷脂动力学失调是阿尔茨海默病神经变性的早期病理特征：一项超微结构研究。

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-18 DOI: 10.1186/s40478-026-02320-z

Alev Erisir, Erin E Maher, Zoe Anderson, Sahil Chawla, Lauren Hanley, Annie Zhao, Kerem Birisik, Ezgi Sila Toklucu, Elif Nedret Keskinoz

{"title":"Dysregulated oligodendrocyte and myelin dynamics as an early pathological feature of neuropil degeneration in Alzheimer's disease: an ultrastructural study.","authors":"Alev Erisir, Erin E Maher, Zoe Anderson, Sahil Chawla, Lauren Hanley, Annie Zhao, Kerem Birisik, Ezgi Sila Toklucu, Elif Nedret Keskinoz","doi":"10.1186/s40478-026-02320-z","DOIUrl":"10.1186/s40478-026-02320-z","url":null,"abstract":"Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by the accumulation of amyloid‑β plaques and neurofibrillary tangles. Increasing evidence suggests that white‑matter degeneration and myelin disruption occur early in disease progression and may contribute to neuropathological vulnerability. Here, we performed ultrastructural analyses in the 3xTg and 5xFAD mouse models of AD across developmental stages (3-12 months of age), including ages preceding overt amyloid plaque formation or neuronal loss. We identify a spectrum of oligodendrocyte‑ and myelin‑associated abnormalities, including single‑membrane herniations, myelin outfolds, and ectopic myelination of neuronal processes, which are evident as early as 3 months of age and are frequently associated with altered neuropil architecture and incipient dystrophic neurite morphology. These malformations were confirmed to be oligodendrocyte‑derived through O4 immunolabeling. Collectively, our findings reveal early, widespread myelin‑associated ultrastructural alterations that form a consistent structural component of neuritic pathology in AD models. We propose that dysregulated oligodendrocyte membrane remodeling represents an early pathological feature of AD, providing a framework for future studies examining how glial pathology intersects with neuronal degeneration and plaque‑associated neuritic remodeling.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969528","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

Dissecting acute neuronal responses to glioblastoma using a dual-interface human iPSC neuronal culture platform. 使用双界面人类iPSC神经元培养平台解剖胶质母细胞瘤的急性神经元反应。

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-16 DOI: 10.1186/s40478-026-02312-z

Ouada Nebie, Niyi Adelakun, Brian Fries, Luke Kollin, Liwen Zhang, Akhil Medikonda, Monica Venere, Pierre Giglio, Nam Chu, Nhat Le

{"title":"Dissecting acute neuronal responses to glioblastoma using a dual-interface human iPSC neuronal culture platform.","authors":"Ouada Nebie, Niyi Adelakun, Brian Fries, Luke Kollin, Liwen Zhang, Akhil Medikonda, Monica Venere, Pierre Giglio, Nam Chu, Nhat Le","doi":"10.1186/s40478-026-02312-z","DOIUrl":"10.1186/s40478-026-02312-z","url":null,"abstract":"Glioblastoma (GB) hijacks neuronal circuits to promote tumor progression, but the earliest neuronal responses remain poorly defined. We developed a dual-interface human iPSC-derived neuronal model to study acute paracrine signaling triggered by GB cells from two sources: serum-adapted U-87MG and serum-free NU-757. Within 24 h, exposed neurons displayed synaptic remodeling and activation of GB-related signaling cascades. Neurons exposed to U-87MG showed decreased dendritic spine number alongside increased total ERK and phospho-p38α at spines (1). In the soma, total ERK accumulated in the nucleus while phospho-ERK was primarily cytoplasmic; nuclear p38 and cytoplasmic MLK2 also increased (2). Conversely, NU-757 exposure enhanced spine growth but reduced postsynaptic density, NMDAR, and synaptophysin levels (3). Both total and phospho-ERK showed increased nuclear localization with NU-757, while total MLK2 and p38α levels remained stable but exhibited elevated nuclear (4) and spine localization. Pharmacological MEK/ERK inhibition reduced U-87MG proliferation and migration and restored neuronal spine numbers. This model system reveals source-dependent, compartment-specific signaling dynamics that govern synaptic vulnerability and provides a platform for investigating GB initiation, recurrence, and progression, as well as therapies targeting tumor growth and neural circuit remodeling.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947440","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

Investigation of the myelin-amyloid interplay in Alzheimer's disease: insights from novel dsCMA imaging in mouse and human brains. 阿尔茨海默病中髓磷脂-淀粉样蛋白相互作用的研究：来自小鼠和人脑新型dsCMA成像的见解

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-14 DOI: 10.1186/s40478-026-02317-8

Hanpeng Xu, Sumit Nanda, Jiandong Sun, Mitchell Rudd, Lin Gou, Haley Marks, Christopher K Williams, Shino Magaki, Harry V Vinters, Houri Hintiryan, Hong-Wei Dong

{"title":"Investigation of the myelin-amyloid interplay in Alzheimer's disease: insights from novel dsCMA imaging in mouse and human brains.","authors":"Hanpeng Xu, Sumit Nanda, Jiandong Sun, Mitchell Rudd, Lin Gou, Haley Marks, Christopher K Williams, Shino Magaki, Harry V Vinters, Houri Hintiryan, Hong-Wei Dong","doi":"10.1186/s40478-026-02317-8","DOIUrl":"10.1186/s40478-026-02317-8","url":null,"abstract":"Myelin deterioration impairs neural communication and may contribute to neurodegenerative diseases such as Alzheimer's disease (AD). However, the spatiotemporal relationship between myelin degeneration and AD pathology remains unclear. We developed a novel imaging method-double-scan Cyto- and myelo-architecture (dsCMA)-that integrates multi-fluorescent labeling of cytoarchitecture and pathological markers with brightfield myelin staining on the same tissue sections. Coupled with computational tools for automated detection and quantification of amyloid-beta (Aβ) plaques and myelinated axons, dsCMA enables systematic analysis of Aβ-myelin interactions in 5xFAD mice and postmortem human AD tissues. In mice, we identified progressive, region-specific myelin disruption associated with Aβ accumulation, particularly in the hippocampus and cortex. Human samples revealed variable Aβ-myelin spatial relationships across individuals and regions, with evidence supporting a potential myelin origin for some plaques. These findings offer new insights into Aβ-myelin interplay and establish dsCMA as a scalable platform for histopathological analysis in translational and longitudinal AD research.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939824","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

Multimodal profiling of immune responses reveals innate-adaptive immune imbalance in human bornavirus encephalitis. 免疫反应的多模态分析揭示了人病毒性脑炎的先天适应性免疫失衡。

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-14 DOI: 10.1186/s40478-026-02319-6

Nicola Jungbäck, Przemyslaw Grochowski, Daniel Hieber, Moritz Dinser, Zuzanna Mielewczyk, Thomas Pfefferkorn, Birgit Muntau, Thomas Richter, Georg Rieder, Antonios Bayas, Klaus Hirschbühl, Bruno Märkl, Patrick Adam, Dennis Tappe, Friederike Liesche-Starnecker

{"title":"Multimodal profiling of immune responses reveals innate-adaptive immune imbalance in human bornavirus encephalitis.","authors":"Nicola Jungbäck, Przemyslaw Grochowski, Daniel Hieber, Moritz Dinser, Zuzanna Mielewczyk, Thomas Pfefferkorn, Birgit Muntau, Thomas Richter, Georg Rieder, Antonios Bayas, Klaus Hirschbühl, Bruno Märkl, Patrick Adam, Dennis Tappe, Friederike Liesche-Starnecker","doi":"10.1186/s40478-026-02319-6","DOIUrl":"10.1186/s40478-026-02319-6","url":null,"abstract":"Human bornavirus encephalitis (BVE) is a rare, emerging and fatal zoonotic disease mainly caused by the Borna disease virus 1 (BoDV-1), a non-cytolytic RNA virus. Despite increasing recognition, the immunopathogenesis of human BoDV-1 infection remains insufficiently characterised. Complete coronal and sagittal brain sections from four fatal BoDV-1 cases were analysed using digitised immunohistochemistry to quantify viral distribution and tissue responses. Transcriptome-based analyses characterised local immune cell profiles in relation to viral loads measured by RT-qPCR. BoDV-1 viral loads varied substantially between cases but showed region-specific enrichment in the basal ganglia and hippocampus, correlating with lymphocyte presence and reactive microglia and astrocytes. Immune cell deconvolution revealed viral load-dependent modulation dominated by innate immune and glial populations, including metabolic and reactive astrocyte states, IFNγ-responsive microglia, and dendritic cells, macrophages, neutrophils, basophils, and CD8⁺ T cells. This was accompanied by induction of interferon-stimulated genes, antigen presentation, protein synthesis, and oxidative stress pathways, with a transcriptional signature resembling non-lytic viral and autoimmune-like neuroinflammatory conditions rather than lytic infections. These findings support a model of BoDV-1 encephalitis characterised by a prominent innate immune response and comparatively limited adaptive immune signatures. This imbalance might potentially contribute to impaired viral clearance and extensive tissue damage, a possible relationship that warrants further investigation.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13181928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939814","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

Glioblastoma cells utilize evolutionarily adapted cell metabolism to promote their malignant proliferation. 胶质母细胞瘤细胞利用进化适应的细胞代谢促进其恶性增殖。

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-13 DOI: 10.1186/s40478-026-02318-7

Maxim M Bespalov, Vasiliki Gkini, Zeynep Iloglu, Seiya Yamada, Akira Nemoto, Pauliina Filppu, Kalevi Trontti, Liliia Andriichuk, Olli Pietiläinen, Vadim Le Joncour, Anni I Nieminen, Pirjo Laakkonen, Takashi Namba

{"title":"Glioblastoma cells utilize evolutionarily adapted cell metabolism to promote their malignant proliferation.","authors":"Maxim M Bespalov, Vasiliki Gkini, Zeynep Iloglu, Seiya Yamada, Akira Nemoto, Pauliina Filppu, Kalevi Trontti, Liliia Andriichuk, Olli Pietiläinen, Vadim Le Joncour, Anni I Nieminen, Pirjo Laakkonen, Takashi Namba","doi":"10.1186/s40478-026-02318-7","DOIUrl":"10.1186/s40478-026-02318-7","url":null,"abstract":"Glioblastoma is the most aggressive primary brain tumor in adults, with limited therapeutic success and, therefore, poor prognosis. Its malignancy is partly driven by the high proliferative capacity of glioblastoma cells, yet the underlying molecular mechanisms remain unclear. Recent studies have revealed transcriptomic similarities between glioblastoma cells and human fetal neural stem/progenitor cells (NSCs), suggesting that glioblastoma may exploit developmental programs that promote NSC proliferation. Fetal human NSCs rely on glutaminolysis-a metabolic pathway induced by the human-specific mitochondrial protein ARHGAP11B-to sustain proliferation. Here, we show that ARHGAP11B expression correlates with glioma malignancy and is essential for glioblastoma cell proliferation, implicating a critical role of glutaminolysis in tumor growth. Among glutaminolysis-related enzymes, glutamic-oxaloacetic transaminase 2 (GOT2) shows a strong positive correlation with glioma grade and poor patient prognosis. Functional assays reveal that GOT2 knockdown significantly suppresses glioblastoma cell growth, indicating that GOT2-mediated glutaminolysis is critical for their proliferation. Metabolomic profiling further shows that GOT2 is required for nucleotide precursor synthesis, underscoring its role in supporting DNA replication. Consistently, GOT2 depletion reduces the proportion of glioblastoma cells in the S phase of the cell cycle. These findings suggest glioblastoma cells hijack an evolutionarily adapted metabolic program to support malignant growth.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925415","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

Age-dependent peripheral dissemination of α-synuclein seeds: mechanistic basis for blood-based early detection of Parkinson's disease. α-突触核蛋白种子年龄依赖性外周播散：血液早期检测帕金森病的机制基础

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-13 DOI: 10.1186/s40478-026-02322-x

Yaoyun Kuang, Hengxu Mao, Hao Lin, Wei Dai, Zhongqiang Su, Ying Luo, Wen-Quan Zou, Xin-Ling Yang, Ping-Yi Xu

{"title":"Age-dependent peripheral dissemination of α-synuclein seeds: mechanistic basis for blood-based early detection of Parkinson's disease.","authors":"Yaoyun Kuang, Hengxu Mao, Hao Lin, Wei Dai, Zhongqiang Su, Ying Luo, Wen-Quan Zou, Xin-Ling Yang, Ping-Yi Xu","doi":"10.1186/s40478-026-02322-x","DOIUrl":"10.1186/s40478-026-02322-x","url":null,"abstract":"Early diagnosis of Parkinson's disease (PD) before extensive neurodegeneration is a critical unmet need, largely due to the absence of sensitive, minimally or non-invasive biomarkers for the prodromal stage. Here, we primarily use α-synuclein (α-Syn) preformed fibril (PFF)-induced mouse models to investigate the mechanistic basis of peripheral α-Syn dissemination, and additionally perform a small exploratory analysis of a serum-based α-Syn seed amplification assay (SAA) in a prodromal human cohort as proof-of-concept. In the PFF model, misfolded α-Syn propagated broadly throughout the CNS and the periphery well before motor symptom onset, with middle-aged mice exhibiting exacerbated pathology, reflecting age-related vulnerability. Proteomic profiling linked α-Syn-induced neurodegeneration to neuroinflammatory signaling, while microglia depletion significantly reduced both central α-Syn accumulation and peripheral spread, implicating activated microglia as key contributors to disease progression. As an exploratory translational step, we applied serum α-Syn SAA to a small cross-sectional cohort of isolated REM sleep behavior disorder (iRBD; n = 25) individuals and matched healthy controls (n = 25). Combining the blood-brain barrier (BBB) integrity marker S100B with SAA yielded 64% sensitivity and 100% specificity versus healthy controls. Collectively, our findings delineate a mechanistic framework linking microglia-driven neuroinflammation, BBB disruption, and peripheral α-Syn dissemination, and provide preliminary evidence that serum α-Syn SAA combined with BBB biomarkers is a mechanistically plausible candidate strategy for early PD detection.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925418","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

Knockout of Rab27b exacerbates neuropathology in alpha-synuclein mouse models. 敲除Rab27b会加重α -突触核蛋白小鼠模型的神经病理。

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-12 DOI: 10.1186/s40478-026-02321-y

Kasandra Scholz, Mary A Gannon, Lehmann Matheny, Rohma Syed, William J Stone, Carley Craig, Roschongporn Ekkatine, Talene A Yacoubian

{"title":"Knockout of Rab27b exacerbates neuropathology in alpha-synuclein mouse models.","authors":"Kasandra Scholz, Mary A Gannon, Lehmann Matheny, Rohma Syed, William J Stone, Carley Craig, Roschongporn Ekkatine, Talene A Yacoubian","doi":"10.1186/s40478-026-02321-y","DOIUrl":"10.1186/s40478-026-02321-y","url":null,"abstract":"Parkinson's Disease (PD) and other synucleinopathies are characterized by the formation of inclusions comprised of alpha-synuclein (αsyn) among other proteins, but the mechanisms by which these inclusions form and cause toxicity are not well understood. We have previously reported that the small GTPase Rab27b modulates autophagic-lysosomal function in neurons and supports lysosomal degradation of αsyn across multiple αsyn cellular models. Knockout (KO) and knockdown (KD) of Rab27b damage lysosomal degradative capacity and exacerbate αsyn pathology, while Rab27b overexpression is conversely protective in cellular αsyn models. Elevations of Rab27b seen in human synucleinopathies suggest a compensatory role for Rab27b in these disorders. Here, we examined the role Rab27b plays in vivo in the context of both A53T genetic αsyn overexpression and viral AAV αsyn overexpression mouse models. Rab27b knockout in A53T+ mice did not alter motor behavior or survival. However, Rab27b knockout increased proteinase-K resistant αsyn in the cortex, striatum, and substantia nigra of A53T mice starting as early as six months of age. Additionally, Rab27b KO increased phosphorylated S129 αsyn in the cortex and nigra. Astrocyte and microglial activation were also observed upon Rab27b KO in the A53T model. In the AAV αsyn model, Rab27b KO resulted in dopaminergic cell loss in the nigra, which was not observed in WT mice. Collectively, we report that loss of Rab27b results in elevated neuropathology in PD-relevant brain regions, validating its role as a therapeutic target in synucleinopathies.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13339369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925469","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

Decreased PP2A expression and activity represent a therapeutic target for plexiform neurofibroma. 减少PP2A的表达和活性是丛状神经纤维瘤的治疗靶点。

IF 6.5 2区医学

Acta Neuropathologica Communications Pub Date : 2026-05-11 DOI: 10.1186/s40478-026-02315-w

Minghui Yue, Yixiao Wang, Jiabao Gu, Cheng Zhang, Yang Chen, Aruna Gao, Kwangmin Choi, Zhaoming Wu, Zhichao Wang, Jay Pundavela, Nancy Ratner, Yanan Yu

{"title":"Decreased PP2A expression and activity represent a therapeutic target for plexiform neurofibroma.","authors":"Minghui Yue, Yixiao Wang, Jiabao Gu, Cheng Zhang, Yang Chen, Aruna Gao, Kwangmin Choi, Zhaoming Wu, Zhichao Wang, Jay Pundavela, Nancy Ratner, Yanan Yu","doi":"10.1186/s40478-026-02315-w","DOIUrl":"10.1186/s40478-026-02315-w","url":null,"abstract":"In neurofibromatosis type 1 (NF1), loss-of-function mutations in the NF1 gene increase activation of the RAS-MEK-ERK signaling cascade, driving tumorigenesis. MEK inhibitors (MEKi) inhibit tumor growth and significantly shrink nerve tumors (neurofibromas). However, MEKi treatment alone fails to eradicate tumor cells, and tumor regrowth occurs after drug withdrawal, highlighting the limitations of targeting the single MEK pathway. An alternative strategy is to promote dephosphorylation of hyperactive kinases that drive tumor growth by enhancing phosphatase activity. We identified deregulated expression of genes encoding subunits of the PP2A phosphatase in neurofibroma and neurofibroma Schwann cells. We confirmed significant reductions in both the expression and enzymatic activity of the PP2A A and C subunits. FTY720, a compound known to restore PP2A phosphatase activity, inhibited tumor sphere formation by mouse and human neurofibroma Schwann cell progenitor cells, suppressed the proliferation of both primary and immortalized neurofibroma-derived Schwann cells, and induced cell apoptosis in vitro. Furthermore, treatment with FTY720-alone or in combination with MEKi-significantly suppressed tumor number and reduced tumor burden in remaining tumors in a murine model of NF1, highlighting the promise of using FTY720 as a novel therapeutic strategy in NF1.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147872997","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