Acta Neuropathologica Communications最新文献

{"title":"Partial normalization of hippocampal oscillatory activity during sleep in TgF344-AD rats coincides with increased cholinergic synapses at early-plaque stage of Alzheimer's disease.","authors":"Monica van den Berg, Loran Heymans, Daniëlle Toen, Mohit A Adhikari, Johan Van Audekerke, Marlies Verschuuren, Isabel Pintelon, Winnok H De Vos, Annemie Van der Linden, Marleen Verhoye, Georgios A Keliris","doi":"10.1186/s40478-025-02016-w","DOIUrl":"https://doi.org/10.1186/s40478-025-02016-w","url":null,"abstract":"<p><p>Sleep alterations are known to occur in Alzheimer's disease (AD), before cognitive symptoms become apparent, and are thought to play an important role in the pathophysiology of AD. However, knowledge on the extent of macro- and microstructural changes of sleep during early, presymptomatic stages of AD is limited. We hypothesize that Aβ-induced perturbations of neuronal activity disrupt this oscillatory activity during sleep at pre-plaque stages of AD. In this study, we aimed to assess hippocampal oscillatory activity during sleep at pre- and early-plaque stages of AD, by performing 24-hour hippocampal electrophysiological measurements in TgF344-AD rats and wildtype littermates at pre- and early-plaque stages of AD. To provide a mechanistic understanding, histological analysis was performed to quantify GABA-ergic, glutamatergic and cholinergic synapses. We observed a differential impact of AD on hippocampal activity during rapid eye movement (REM) and non-REM (NREM) sleep, in the absence of robust changes in circadian rhythm. TgF344-AD rats demonstrated increased duration of sharp wave-ripples during NREM sleep, irrespective of age. Interestingly, a significantly decreased theta-gamma coupling was observed in TgF344-AD rats, prior to amyloid plaque deposition, which was partially restored at the early-plaque stage. The partial recovery of hippocampal activity during REM sleep coincided with an increased number of cholinergic synapses in the hippocampus during the early-plaque stage in TgF344-AD rats, suggestive of basal forebrain cholinergic compensation mechanisms. The results from this study reveal early changes in hippocampal activity prior to Aβ plaque deposition in AD. In addition, the current findings imply an important role of the cholinergic system to compensate for AD-related network alterations, thereby partially restoring sleep architecture and hippocampal activity.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"96"},"PeriodicalIF":6.2,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951733","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":"Altered CD4 T cell response in oligometatastic non-small cell lung cancer brain metastasis.","authors":"Mais Alsousli, Cecile L Maire, Andras Piffko, Jakob Matschke, Laura Glau, Merle Reetz, Svenja Schneegans, Gresa Emurlai, Benedikt Asey, Alessandra Rünger, Sven Peine, Jolanthe Kropidlowski, Jens Gempt, Markus Glatzel, Manfred Westphal, Eva Tolosa, Katrin Lamszus, Klaus Pantel, Simon A Joosse, Malte Mohme, Harriet Wikman","doi":"10.1186/s40478-025-02011-1","DOIUrl":"https://doi.org/10.1186/s40478-025-02011-1","url":null,"abstract":"<p><p>Lung cancer is the leading cause of cancer mortality globally, with brain metastasis (BM) in 40% of advanced non-small-cell lung cancer (NSCLC) cases. In 15% of these cases, the brain is the sole affected organ (oligometastasis), which correlates with a better prognosis compared to widespread disease. It remains unclear if brain-only metastasis without systemic spread is due to the immune system's ability to control systemic tumor progression. We studied the immune cell compositions in NSCLC patients with BM, identifying novel patterns associated with BM, and specifcally with either oligo- or polymetastatic spread. Multi-parametric immune phenotyping of peripheral blood primarily showed alterations in the CD4⁺ T cell compartment, with increased CD4⁺ T_H17 cells, and higher IL-17 levels in NSCLC BM patients compared to healthy individuals. Furthermore, CD4⁺ T cells in BM patients exhibited lower CD73 expression and reduced effector memory differentiation. There was also decreased intratumoral infiltration and a distinct CD4⁺ T cell profile in oligo-synchronous BM, both in the tumor microenvironment and peripheral blood, compared to polymetastatic BM patients. Additionally, CD73 was significantly upregulated in CD4⁺ and T regulatory cells of oligo-synchronous (BM simulantously with primary-tumor diagnosis) BM. These findings suggest that CD4⁺ T cells play a crucial role in the biology of NSCLC BM and potentially contribute to differences in metastatic patterns, as oligo-synchronous BM shows a more significant alteration in the CD4⁺ T cell immune profile, both locally at the tumor site and systemically.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"95"},"PeriodicalIF":6.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958305","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 transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences.","authors":"Muhammad Ali, Pierre Garcia, Laetitia P Lunkes, Alessia Sciortino, Melanie H Thomas, Tony Heurtaux, Kamil Grzyb, Rashi Halder, Alexander Skupin, Luc Buée, David Blum, Manuel Buttini, Enrico Glaab","doi":"10.1186/s40478-025-02013-z","DOIUrl":"https://doi.org/10.1186/s40478-025-02013-z","url":null,"abstract":"<p><strong>Background: </strong>Tauopathies, including Alzheimer's disease (AD) and frontotemporal dementia (FTD), display sex-specific differences in prevalence and progression, but the underlying molecular mechanisms remain unclear. Single-cell transcriptomic analysis of animal models can reveal how AD pathology affects different cell types across sex and age.</p><p><strong>Objective: </strong>To understand sex-specific and sex-dimorphic transcriptomic changes in different cell types and their age-dependence in the THY-Tau22 mouse model of AD-linked tauopathy.</p><p><strong>Methods: </strong>We applied single-cell RNA sequencing (scRNA-seq) to cortical tissue from male and female THY-Tau22 and wild-type mice at 17 months of age, when they had prominent tau inclusion pathology, and compared the results with corresponding data previously obtained at 7 months of age. Using differential statistical analysis for individual genes, pathways, and gene regulatory networks, we identified sex-specific, sex-dimorphic, and sex-neutral changes, and looked at how they evolved over age. To validate the most robust findings across distinct mouse models and species, the results were compared with cortical scRNA-seq data from the transgenic hAPP-based Tg2576 mouse model and human AD.</p><p><strong>Results: </strong>We identified several significant sex-specific and sex-dimorphic differentially expressed genes in neurons, microglia, astrocytes and oligodendrocytes, including both cross-sectional changes and alterations from 7 months to 17 months of age. Key pathways affected in a sex-dependent manner across age included neurotransmitter signaling, RNA processing and splicing, stress response pathways, and protein degradation pathways. In addition, network analysis revealed the AD-associated genes Clu, Mbp, Fos and Junb as relevant regulatory hubs. Analysis of age-dependent changes highlighted genes and pathways associated with inflammatory response (Malat1, Cx3cr1), protein homeostasis (Cst3), and myelin maintenance (Plp1, Cldn11, Mal) that showed consistent sex-dependent changes as the THY-Tau22 mice aged. Multiple genes with established implications in AD, including the long non-coding RNA gene Malat1, displayed concordant sex-specific changes in mouse models and human AD.</p><p><strong>Conclusions: </strong>This study provides a comprehensive single-cell transcriptomic characterization of sex-linked and age-dependent changes in the THY-Tau22 tauopathy model, revealing new insights into the interplay between age-dependent AD-like pathologies and sex. The identified sex-specific changes and their conservation across models and human AD highlight molecular targets for further preclinical investigation of sex-specific therapeutic strategies in AD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"93"},"PeriodicalIF":6.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957503","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":"Oligodendrocyte-specific overexpression of human alpha-synuclein results in elevated MBP levels and inflammatory responses in TgM83 mice, mimicking the pathological features of multiple system atrophy.","authors":"Sam Chi-Hao Liu, Koping Chang, Meng-Ling Chen, Ming-Che Kuo, Teh-Cheng Wang, Ruey-Meei Wu","doi":"10.1186/s40478-025-02014-y","DOIUrl":"https://doi.org/10.1186/s40478-025-02014-y","url":null,"abstract":"<p><p>Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by parkinsonism, cerebellar dysfunction, and autonomic failure. Key pathological features of MSA include the formation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes (OLs), myelin loss, and neuroinflammation. Although both inflammation and myelination are known to be critical in MSA, the roles of myelin proteins and their relationship with inflammation have often been overlooked. In this study, we injected AAV-Olig001 vectors carrying either human SNCA (AAV-hSNCA) or eGFP (AAV-eGFP) into the striatum of TgM83 transgenic mice, which express the A53T mutant form of human alpha-synuclein (αSyn), as well as into wild-type (WT) mice. We then assessed myelin protein expression and inflammatory responses. TgM83 mice injected with AAV-hSNCA exhibited demyelination, increased activation of microglia and astrocytes, and altered cytokine and chemokine profiles (including IL-1α, IL-10, IL-12(p40), CCL2, CCL3, CCL4, and CCL5), compared to both WT mice and TgM83 mice injected with AAV-eGFP. Interestingly, myelin basic protein (MBP) levels were significantly elevated around the injection site in TgM83 mice injected with AAV-hSNCA. Notably, we observed a positive correlation between MBP expression and inflammatory markers, as indicated by Iba1 and GFAP staining. These findings suggest that hSNCA overexpression is associated with increased MBP levels and enhanced inflammatory responses, implicating that MBP and myelination processes may play previously underappreciated roles in the pathogenesis of MSA.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"94"},"PeriodicalIF":6.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962152","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: Investigating genotype-phenotype correlation of limb-girdle muscular dystrophy R8: association of clinical severity, protein biological function and protein oligomerization.","authors":"Xiongda Liang, Jiameng Si, Hongting Xie, Yuqing Guan, Wanying Lin, Zezhang Lin, Ganwei Zheng, Xiaofeng Wei, Xingbang Xiong, Zhengfei Zhuang, Xuan Shang","doi":"10.1186/s40478-025-02004-0","DOIUrl":"https://doi.org/10.1186/s40478-025-02004-0","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"92"},"PeriodicalIF":6.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954969","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":"Identification and characterization of tertiary lymphoid structures in brain metastases.","authors":"Sadaf S Mughal, Yvonne Reiss, Jörg Felsberg, Lasse Meyer, Jadranka Macas, Silja Schlue, Tatjana Starzetz, Karl Köhrer, Tanja Fehm, Volkmar Müller, Katrin Lamszus, Dirk Schadendorf, Iris Helfrich, Harriet Wikman, Anna Berghoff, Benedikt Brors, Karl H Plate, Guido Reifenberger","doi":"10.1186/s40478-025-02007-x","DOIUrl":"10.1186/s40478-025-02007-x","url":null,"abstract":"<p><p>Brain metastases (BrM) are the most common cancers in the brain and linked to poor prognosis. Given the high incidence and often limited treatment options, understanding the complexity of the BrM tumor microenvironment is crucial for the development of novel therapeutic strategies. We performed transcriptome-wide gene expression profiling combined with spatial immune cell profiling to characterize the tumor immune microenvironment in 95 patients with BrM from different primary tumors. We found that BrM from lung carcinoma and malignant melanoma showed overall higher immune cell infiltration as compared to BrM from breast carcinoma. RNA sequencing-based immune cell deconvolution revealed gene expression signatures indicative of tertiary lymphoid structures (TLS) in subsets of BrM, mostly from lung cancer and melanoma. This finding was corroborated by multiplex immunofluorescence staining of immune cells in BrM tissue sections. Detection of TLS signatures was more common in treatment-naïve BrM and associated with prolonged survival after BrM diagnosis in lung cancer patients. Our findings highlight the cellular diversity of the tumor immune microenvironment in BrM of different cancer types and suggest a role of TLS formation for BrM patient outcome.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"91"},"PeriodicalIF":6.2,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954971","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":"Systemic IGF-1 administration prevents traumatic brain injury induced gut permeability, dysmorphia, dysbiosis, and the increased number of immature dentate granule cells.","authors":"Lavanya Venkatasamy, Jaclyn Iannucci, Aleksandr Pereverzev, Jonathan Hoar, Emily Huber, Angel Ifegbo, Reagan Dominy, Yumna El-Hakim, Kathiresh Kumar Mani, Alan Dabney, Rachel Pilla, Farida Sohrabji, Lee A Shapiro","doi":"10.1186/s40478-025-01998-x","DOIUrl":"https://doi.org/10.1186/s40478-025-01998-x","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) occurs in 2-3 million Americans each year and is a leading cause of death and disability. Among the many physiological consequences of TBI, the hypothalamic pituitary axis (HPA) is particularly vulnerable, including a reduction in growth hormone (GH) and insulin-like growth factor (IGF-1). Clinical and preclinical supplementation of IGF-1 after TBI has exhibited beneficial effects. IGF-1 receptors are prominently observed in many tissues, including in the brain and in the gastrointestinal (GI) system. In addition to causing damage in the brain, TBI also induces GI system damage, including inflammation and alterations to intestinal permeability and the gut microbiome. The goal of this study was to assess the effects of systemic IGF-1 treatment in a rat model of TBI on GI outcomes. Because GI dysfunction has been linked to hippocampal dysfunction, we also examined proliferation and immature granule cells in the hippocampal dentate gyrus. 10-week-old male rats were treated with an intraperitoneal (i.p.) dose of IGF-1 at 4 and 24 h after lateral fluid percussion injury (FPI). At 3- and 35-days post-injury (DPI), gut permeability, gut dysmorphia, the fecal microbiome, and the hippocampus were assessed. FPI-induced permeability of the blood-gut-barrier, as measured by elevated gut metabolites in the blood, and this was prevented by the IGF-1 treatment. Gut dysmorphia and alterations to the microbiome were also observed after FPI and these effects were ameliorated by IGF-1, as was the increase in immature granule cells in the hippocampus. These findings suggest that IGF-1 can target gut dysfunction and damage after TBI, in addition to its role in influencing adult hippocampal neurogenesis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"90"},"PeriodicalIF":6.2,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958069","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":"Combination therapy of adagrasib and abemaciclib in non-small cell lung cancer brain metastasis models genomically characterized by KRAS-G12C and homozygous loss of CDKN2A.","authors":"Christian Migliarese, Yinon Sadeh, Consuelo Torrini, Fatma Turna Demir, Naema Nayyar, Erika Yamazawa, Yuu Ishikawa, Nazanin Ijad, Elizabeth J Summers, Adam Elliott, Lisa Rahbaek, Barbara Saechao, Jill Hallin, Priscilla K Brastianos, Hiroaki Wakimoto","doi":"10.1186/s40478-025-01993-2","DOIUrl":"https://doi.org/10.1186/s40478-025-01993-2","url":null,"abstract":"<p><p>KRAS mutations are prevalent in brain metastases (BM) from non-small cell lung cancer (NSCLC). The activity of KRAS-G12C selective, brain-penetrant small molecule inhibitor adagrasib was recently demonstrated in preclinical models of BM and patients with BM carrying KRAS-G12C, leading to a clinical trial investigating this therapeutic approach. However, co-existing genomic drivers such as homozygous deletion of CDKN2A/B may impact the utility of adagrasib. We therefore explored the combination therapy employing adagrasib and abemaciclib, a brain-penetrant CDK4/6 inhibitor, in NSCLC BM models driven by KRAS-G12C and CDKN2A loss. In both adagrasib-resistant SW1573 cells and adagrasib-responsive H2122 cells, combination of adagrasib and abemaciclib was slightly synergistic in inhibiting cell viability in vitro through targeting the KRAS-ERK and CDK4/6-Rb signaling pathways. Combination treatment was necessary to activate caspase 3/7-mediated apoptosis in SW1573 cells, while adagrasib alone and in combination comparably elicited apoptosis in H2122 cells. In vivo, combination treatment with adagrasib (75 mg/kg) twice daily and abemaciclib (50 mg/kg) daily was associated with body weight loss (about 10%) in mice bearing orthotopic BM derived with SW1573 or H2122 cells, requiring 50% dose reduction of adagrasib in some animals. Notably, combination treatment, but neither monotherapy, extended animal survival in the SW1573 model. On the other hand, adagrasib monotherapy and combination were similarly effective at prolonging survival, while abemaciclib monotherapy was ineffective in the H2122 model. Pharmacokinetic studies confirmed brain-penetrant properties of both agents and revealed drug-drug interactions as abemaciclib exposures in the plasma and brains were increased by the presence of adagrasib. Immunohistochemistry demonstrated on-target pharmacodynamic effects of both agents in BM in mice. Our work thus supports that the combination treatment of adagrasib and abemaciclib can offer a therapeutic strategy in NSCLC BM genomically characterized by KRAS-G12C and CDKN2A loss.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"88"},"PeriodicalIF":6.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956164","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":"Activated alpha 9 integrin expression enables sensory pathway reconstruction after spinal cord injury.","authors":"Katerina Stepankova, Barbora Smejkalova, Lucia Machova Urdzikova, Katerina Haveliková, Fred de Winter, Stepanka Suchankova, Joost Verhaagen, Vit Herynek, Rostislav Turecek, Jessica Kwok, James Fawcett, Pavla Jendelova","doi":"10.1186/s40478-025-01995-0","DOIUrl":"https://doi.org/10.1186/s40478-025-01995-0","url":null,"abstract":"<p><p>Full recovery from spinal cord injury requires axon regeneration to re-establish motor and sensory pathways. In mammals, the failure of sensory and motor axon regeneration has many causes intrinsic and extrinsic to neurons, amongst which is the lack of adhesion molecules needed to interact with the damaged spinal cord. This study addressed this limitation by expressing the integrin adhesion molecule α9, along with its activator kindlin-1, in sensory neurons via adeno-associated viral (AAV) vectors. This enabled sensory axons to regenerate through spinal cord injuries and extend to the brainstem, restoring sensory pathways, touch sensation and sensory behaviours. One of the integrin ligands in the injured spinal cord is tenascin-C, which serves as a substrate for α9β1 integrin, a key receptor in developmental axon guidance. However, the adult PNS and CNS neurons lack this receptor. Sensory neurons were transduced with α9 integrin (which pairs with endogenous β1 to form a α9β1 tenascin receptor) together with the integrin activator kindlin-1. Regeneration from sensory neurons transduced with α9integrin and kindlin-1 was examined after C4 and after T10 dorsal column lesions with C6,7 and L4,5 sensory ganglia injected with AAV1 vectors. In animals treated with α9 integrin and kindlin-1, sensory axons regenerated through tenascin-C-expressing connective tissue strands and bridges across the lesions and then re-entered the CNS tissue. Many axons regenerated rostrally to the level of the medulla. Axons grew through the dorsal grey matter rather than their normal pathway the dorsal columns. Growth was slow, axons taking 12 weeks to grow from T10 to the medulla, a distance of 4-5 cm. Functional recovery was confirmed through cFos activation in neurons rostral to the injury after nerve stimulation and VGLUT1/2 staining indicating new synapse formation above the lesion. Behavioural recovery was seen in both heat and mechanical sensation, as well as tape removal tests. This approach demonstrates the potential of integrin-based therapies for long distance sensory axon regeneration and functional recovery following thoracic and partial recovery after cervical spinal cord injury.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"89"},"PeriodicalIF":6.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958996","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":"GSK3 acts as a switch for transcriptional programs in a model of low-grade gliomagenesis.","authors":"Marilin S Koch, Minh Deo, Lena-Marie Schmitt, Michael S Hoetker, Şevin Turcan","doi":"10.1186/s40478-025-02006-y","DOIUrl":"https://doi.org/10.1186/s40478-025-02006-y","url":null,"abstract":"<p><p>Mutations in isocitrate dehydrogenase (IDH)1/2 are defining drivers of low-grade gliomagenesis. However, mutant IDH alone is not sufficient for malignant transformation, and additional events are required for the development of low-grade glioma. While specific genetic lesions have been identified to contribute to low-grade gliomagenesis, less is known about the signaling pathways involved in the acquisition of malignancy. To identify prerequisites of IDH mutant tumorigenesis, we modulated pathways previously implicated in glioma initiation using a tractable in vitro model system for early IDH1^R132H-dependent gliomagenesis. Through the use of chemical compounds, we targeted WNT/GSK3, TGF-β and NOTCH-signaling, assessing their functional, transcriptional, and translational impacts. Expression of LGG-related marker L1CAM was affected by perturbation of all pathways, though only modulation of WNT/GSK3-signaling resulted in profound molecular transformation, including glioma-associated genes and programs regulating cellular architecture and cell replication. This was accompanied by altered cell morphology, migration capacity, and enhanced proliferation. Transcription factor RUNX2 was identified as a potential downstream effector, whose inhibition abrogated cell proliferation. Disrupted WNT/GSK3 signaling in a model system of early low-grade gliomagenesis fundamentally impacted cell fate, as demonstrated by a reshaped transcriptional landscape, aberrant transcription factor activity, extracellular matrix restructuring, and altered proliferation capacity. Our data suggests that GSK3 may play a central role during low-grade gliomagenesis, warranting further investigation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"87"},"PeriodicalIF":6.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955337","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}