Acta Neuropathologica Communications最新文献

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Downregulation of STAT3 transcription factor reverses synaptotoxic phenotype of reactive astrocytes associated with prion diseases. STAT3转录因子的下调可逆转与朊病毒疾病相关的反应性星形细胞的突触毒性表型。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-15 DOI: 10.1186/s40478-025-02028-6
Rajesh Kushwaha, Kara Molesworth, Natallia Makarava, Ilia V Baskakov
{"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}
引用次数: 0
Shaking into deficits: investigating behavioural and neuropathological outcomes associated with a novel preclinical model of infant abusive head trauma. 摇成缺陷:调查与婴儿虐待性头部创伤的新型临床前模型相关的行为和神经病理结果。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-15 DOI: 10.1186/s40478-025-02029-5
Sydney A Harris, Marissa Sgro, Sabrina Salberg, Crystal Li, Elaina Vlassopoulos, Madeleine Smith, Bridgette D Semple, Holly R Chinnery, Richelle Mychasiuk
{"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}
引用次数: 0
Genomic and immune profiling of breast cancer brain metastases. 乳腺癌脑转移的基因组和免疫分析。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-12 DOI: 10.1186/s40478-025-02001-3
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
{"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}
引用次数: 0
Astrocytes carrying LRRK2 G2019S exhibit increased levels of clusterin chaperone via miR-22-5p and reduced ability to take up α-synuclein fibrils. 携带LRRK2 G2019S的星形胶质细胞通过miR-22-5p表现出增加的簇蛋白伴侣水平,并降低了摄取α-突触核蛋白原纤维的能力。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-12 DOI: 10.1186/s40478-025-02015-x
Alice Filippini, Giulia Carini, Alessandro Barbon, Massimo Gennarelli, Isabella Russo
{"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}
引用次数: 0
Expanding clinicopathologic knowledge in high-grade glioma with pleomorphic and pseudopapillary features (HPAP): a report of two cases. 扩展具有多形性和假乳头状特征的高级别胶质瘤(HPAP)的临床病理知识:附两例报告。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-12 DOI: 10.1186/s40478-025-02017-9
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
{"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}
引用次数: 0
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. TgF344-AD大鼠睡眠期间海马振荡活动的部分正常化与阿尔茨海默病早期斑块期胆碱能突触的增加相一致。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-10 DOI: 10.1186/s40478-025-02016-w
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
{"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":"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}
引用次数: 0
Altered CD4 T cell response in oligometatastic non-small cell lung cancer brain metastasis. 低转移性非小细胞肺癌脑转移中CD4 T细胞应答的改变。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-09 DOI: 10.1186/s40478-025-02011-1
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
{"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":"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<sup>+</sup> T cell compartment, with increased CD4<sup>+</sup> T<sub>H</sub>17 cells, and higher IL-17 levels in NSCLC BM patients compared to healthy individuals. Furthermore, CD4<sup>+</sup> T cells in BM patients exhibited lower CD73 expression and reduced effector memory differentiation. There was also decreased intratumoral infiltration and a distinct CD4<sup>+</sup> 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<sup>+</sup> and T regulatory cells of oligo-synchronous (BM simulantously with primary-tumor diagnosis) BM. These findings suggest that CD4<sup>+</sup> 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<sup>+</sup> 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}
引用次数: 0
Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences. THY-Tau22小鼠tau病模型的时间转录组学变化显示细胞类型和性别特异性差异。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-07 DOI: 10.1186/s40478-025-02013-z
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
{"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":"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}
引用次数: 0
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. 少突胶质细胞特异性的人α -突触核蛋白过表达导致TgM83小鼠MBP水平升高和炎症反应,模拟多系统萎缩的病理特征。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-07 DOI: 10.1186/s40478-025-02014-y
Sam Chi-Hao Liu, Koping Chang, Meng-Ling Chen, Ming-Che Kuo, Teh-Cheng Wang, Ruey-Meei Wu
{"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":"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}
引用次数: 0
Correction: Investigating genotype-phenotype correlation of limb-girdle muscular dystrophy R8: association of clinical severity, protein biological function and protein oligomerization. 纠正:研究肢带肌营养不良R8的基因型-表型相关性:临床严重程度、蛋白质生物学功能和蛋白质寡聚化的关联。
IF 6.2 2区 医学
Acta Neuropathologica Communications Pub Date : 2025-05-06 DOI: 10.1186/s40478-025-02004-0
Xiongda Liang, Jiameng Si, Hongting Xie, Yuqing Guan, Wanying Lin, Zezhang Lin, Ganwei Zheng, Xiaofeng Wei, Xingbang Xiong, Zhengfei Zhuang, Xuan Shang
{"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}
引用次数: 0
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