Acta Neuropathologica最新文献

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Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer 天然朊病毒的冷冻电子显微镜结构:来自鹿的慢性消耗性疾病纤维蛋白
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-24 DOI: 10.1007/s00401-024-02813-y
Parvez Alam, Forrest Hoyt, Efrosini Artikis, Jakub Soukup, Andrew G. Hughson, Cindi L. Schwartz, Kent Barbian, Michael W. Miller, Brent Race, Byron Caughey
{"title":"Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer","authors":"Parvez Alam,&nbsp;Forrest Hoyt,&nbsp;Efrosini Artikis,&nbsp;Jakub Soukup,&nbsp;Andrew G. Hughson,&nbsp;Cindi L. Schwartz,&nbsp;Kent Barbian,&nbsp;Michael W. Miller,&nbsp;Brent Race,&nbsp;Byron Caughey","doi":"10.1007/s00401-024-02813-y","DOIUrl":"10.1007/s00401-024-02813-y","url":null,"abstract":"<div><p>Chronic wasting disease (CWD) is a widely distributed prion disease of cervids with implications for wildlife conservation and also for human and livestock health. The structures of infectious prions that cause CWD and other natural prion diseases of mammalian hosts have been poorly understood. Here we report a 2.8 Å resolution cryogenic electron microscopy-based structure of CWD prion fibrils from the brain of a naturally infected white-tailed deer expressing the most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie prion fibrils, our atomic model of CWD fibrils contains single stacks of PrP molecules forming parallel in-register intermolecular <i>β</i>-sheets and intervening loops comprising major N- and C-terminal lobes within the fibril cross-section. However, CWD fibrils from a natural cervid host differ markedly from the rodent structures in many other features, including a ~ 180° twist in the relative orientation of the lobes. This CWD structure suggests mechanisms underlying the apparent CWD transmission barrier to humans and should facilitate more rational approaches to the development of CWD vaccines and therapeutics.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02813-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer’s disease BACE1 自身抗体促进阿尔茨海默病的 Aβ 积累和神经退行性变
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-24 DOI: 10.1007/s00401-024-02814-x
Ye-Ran Wang, Xiao-Qin Zeng, Jun Wang, Christopher J. Fowler, Qiao-Xin Li, Xian-Le Bu, James Doecke, Paul Maruff, Ralph N. Martins, Christopher C. Rowe, Colin L. Masters, Yan-Jiang Wang, Yu-Hui Liu
{"title":"Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer’s disease","authors":"Ye-Ran Wang,&nbsp;Xiao-Qin Zeng,&nbsp;Jun Wang,&nbsp;Christopher J. Fowler,&nbsp;Qiao-Xin Li,&nbsp;Xian-Le Bu,&nbsp;James Doecke,&nbsp;Paul Maruff,&nbsp;Ralph N. Martins,&nbsp;Christopher C. Rowe,&nbsp;Colin L. Masters,&nbsp;Yan-Jiang Wang,&nbsp;Yu-Hui Liu","doi":"10.1007/s00401-024-02814-x","DOIUrl":"10.1007/s00401-024-02814-x","url":null,"abstract":"<div><p>The profile of autoantibodies is dysregulated in patients with Alzheimer’s disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET<sup>−</sup> CN, 169 Aβ-PET<sup>+</sup> cognitively normal subjects (preclinical AD), and 31 Aβ-PET<sup>+</sup> cognitively impaired subjects (Clinical AD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes MYB/MYBL1基因改变的神经胶质瘤经常携带MYB和MYBL1基因的截断和非生产性融合
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-18 DOI: 10.1007/s00401-024-02803-0
Hye-Jung Chung, Sharika Rajan, Zhichao Wu, Christina K. Ferrone, Mark Raffeld, Ina Lee, Jeffrey Gagan, Christopher Dampier, Zied Abdullaev, Manoj Tyagi, Patrick. J. Cimino, Martha Quezado, Kenneth Aldape
{"title":"MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes","authors":"Hye-Jung Chung,&nbsp;Sharika Rajan,&nbsp;Zhichao Wu,&nbsp;Christina K. Ferrone,&nbsp;Mark Raffeld,&nbsp;Ina Lee,&nbsp;Jeffrey Gagan,&nbsp;Christopher Dampier,&nbsp;Zied Abdullaev,&nbsp;Manoj Tyagi,&nbsp;Patrick. J. Cimino,&nbsp;Martha Quezado,&nbsp;Kenneth Aldape","doi":"10.1007/s00401-024-02803-0","DOIUrl":"10.1007/s00401-024-02803-0","url":null,"abstract":"<div><p>Astrocytomas that harbor recurrent genomic alterations in <i>MYB</i> or <i>MYBL1</i> are a group of Pediatric-type diffuse low-grade gliomas that were newly recognized in the 2021 WHO Classification of Tumors of the Central Nervous System. These tumors are described in the WHO classification as harboring fusions in <i>MYB</i> or <i>MYBL1</i>. In this report, we examine 14 consecutive cases in which a <i>MYB</i> or <i>MYBL1</i> alteration was identified, each with diagnostic confirmation by genome-wide DNA methylation profiling (6 Angiocentric gliomas and 8 Diffuse astrocytomas, <i>MYB-</i> or <i>MYBL1</i>-altered), for their specific genomic alterations in these genes. Using RNA sequencing, we find productive in-frame fusions of the <i>MYB</i> or <i>MYBL1</i> genes in only 5/14 cases. The remaining 9 cases show genomic alterations that result in truncation of the gene, without evidence of an in-frame fusion partner. Gene expression analysis showed overexpression of the <i>MYB</i>(<i>L1</i>) genes, regardless of the presence of a productive fusion. In addition, <i>QKI,</i> a recognized fusion partner common in angiocentric glioma, was generally up-regulated in these 14 cases, compared to a cohort comprising &gt;1000 CNS tumors of various types, regardless of whether a genomic alteration in <i>QKI</i> was present. Overall, the results show that truncations, in the absence of a productive fusion, of the <i>MYB</i>(<i>L1</i>) genes can likely drive the tumors and have implications for the analysis and diagnosis of Angiocentric glioma and Diffuse astrocytoma, <i>MYB-</i> or <i>MYBL1</i>-altered, especially for cases that are tested on panels designed to focus on fusion detection.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02803-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia 基于假设的已知阿尔茨海默病风险变异调查揭示了阿尔茨海默型痴呆症神经病理学病变的遗传基础
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-18 DOI: 10.1007/s00401-024-02815-w
Celeste Laureyssen, Fahri Küçükali, Jasper Van Dongen, Klara Gawor, Sandra O. Tomé, Alicja Ronisz, Markus Otto, Christine A. F. von Arnim, Philip Van Damme, Rik Vandenberghe, Dietmar Rudolf Thal, Kristel Sleegers
{"title":"Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia","authors":"Celeste Laureyssen,&nbsp;Fahri Küçükali,&nbsp;Jasper Van Dongen,&nbsp;Klara Gawor,&nbsp;Sandra O. Tomé,&nbsp;Alicja Ronisz,&nbsp;Markus Otto,&nbsp;Christine A. F. von Arnim,&nbsp;Philip Van Damme,&nbsp;Rik Vandenberghe,&nbsp;Dietmar Rudolf Thal,&nbsp;Kristel Sleegers","doi":"10.1007/s00401-024-02815-w","DOIUrl":"10.1007/s00401-024-02815-w","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (A<i>β</i>) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of <i>APH1B</i>, with tau-related pathology. Second, a relation between <i>APOE</i> and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of <i>APOE</i> with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, <i>α</i>-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between <i>TPCN1</i> (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of <i>ANK3</i>. We found association between <i>BIN1</i> (rs6733839) and α-synuclein pathology, and replicated a prior association between <i>USP6NL</i> (rs7912495) and Lewy body pathology. Additionally, we also found that <i>UMAD1</i> (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02815-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy 抗IgLON5疾病的神经病理学谱系和脑干tau病理学阶段:疾病相关tau病的最新神经病理学研究标准
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-14 DOI: 10.1007/s00401-024-02805-y
Ellen Gelpi, Raphael Reinecke, Carles Gaig, Alex Iranzo, Lidia Sabater, Laura Molina-Porcel, Iban Aldecoa, Verena Endmayr, Birgit Högl, Erich Schmutzhard, Werner Poewe, Bettina Pfausler, Mara Popovic, Janja Pretnar-Oblak, Frank Leypoldt, Jakob Matschke, Markus Glatzel, Elena Maria Erro, Ivonne Jerico, Maria Cristina Caballero, Maria Victoria Zelaya, Sara Mariotto, Anna Heidbreder, Ognian Kalev, Serge Weis, Stefan Macher, Evelyn Berger-Sieczkowski, Julia Ferrari, Christoph Reisinger, Nikolaus Klupp, Pentti Tienari, Osma Rautila, Marja Niemelä, Deniz Yilmazer-Hanke, Mar Guasp, Bas Bloem, Judith Van Gaalen, Benno Kusters, Maarten Titulaer, Nina L. Fransen, Joan Santamaria, Thimoty Dawson, Janice L. Holton, Helen Ling, Tamas Revesz, Liisa Myllykangas, Herbert Budka, Gabor G. Kovacs, Jan Lewerenz, Josep Dalmau, Francesc Graus, Inga Koneczny, Romana Höftberger
{"title":"Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy","authors":"Ellen Gelpi,&nbsp;Raphael Reinecke,&nbsp;Carles Gaig,&nbsp;Alex Iranzo,&nbsp;Lidia Sabater,&nbsp;Laura Molina-Porcel,&nbsp;Iban Aldecoa,&nbsp;Verena Endmayr,&nbsp;Birgit Högl,&nbsp;Erich Schmutzhard,&nbsp;Werner Poewe,&nbsp;Bettina Pfausler,&nbsp;Mara Popovic,&nbsp;Janja Pretnar-Oblak,&nbsp;Frank Leypoldt,&nbsp;Jakob Matschke,&nbsp;Markus Glatzel,&nbsp;Elena Maria Erro,&nbsp;Ivonne Jerico,&nbsp;Maria Cristina Caballero,&nbsp;Maria Victoria Zelaya,&nbsp;Sara Mariotto,&nbsp;Anna Heidbreder,&nbsp;Ognian Kalev,&nbsp;Serge Weis,&nbsp;Stefan Macher,&nbsp;Evelyn Berger-Sieczkowski,&nbsp;Julia Ferrari,&nbsp;Christoph Reisinger,&nbsp;Nikolaus Klupp,&nbsp;Pentti Tienari,&nbsp;Osma Rautila,&nbsp;Marja Niemelä,&nbsp;Deniz Yilmazer-Hanke,&nbsp;Mar Guasp,&nbsp;Bas Bloem,&nbsp;Judith Van Gaalen,&nbsp;Benno Kusters,&nbsp;Maarten Titulaer,&nbsp;Nina L. Fransen,&nbsp;Joan Santamaria,&nbsp;Thimoty Dawson,&nbsp;Janice L. Holton,&nbsp;Helen Ling,&nbsp;Tamas Revesz,&nbsp;Liisa Myllykangas,&nbsp;Herbert Budka,&nbsp;Gabor G. Kovacs,&nbsp;Jan Lewerenz,&nbsp;Josep Dalmau,&nbsp;Francesc Graus,&nbsp;Inga Koneczny,&nbsp;Romana Höftberger","doi":"10.1007/s00401-024-02805-y","DOIUrl":"10.1007/s00401-024-02805-y","url":null,"abstract":"<div><p>Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median &lt; 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: <i>stage 1</i> mild neurodegeneration without overt or only minimal tau pathology,<i> stage 2</i> moderate neurodegeneration and mild/ moderate tauopathy and <i>stage 3</i> prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02805-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142434932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway 神经元BAG3通过调节自噬-溶酶体途径减轻创伤性脑损伤引起的tau高磷酸化、突触功能障碍和认知缺陷。
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-11 DOI: 10.1007/s00401-024-02810-1
Nicholas Sweeney, Tae Yeon Kim, Cody T. Morrison, Liangping Li, Diana Acosta, Jiawen Liang, Nithin V. Datla, Julie A. Fitzgerald, Haoran Huang, Xianglan Liu, Gregory Huang Tan, Min Wu, Kate Karelina, Chelsea E. Bray, Zachary M. Weil, Douglas W. Scharre, Geidy E. Serrano, Takashi Saito, Takaomi C. Saido, Thomas G. Beach, Olga N. Kokiko-Cochran, Jonathan P. Godbout, Gail V. W. Johnson, Hongjun Fu
{"title":"Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway","authors":"Nicholas Sweeney,&nbsp;Tae Yeon Kim,&nbsp;Cody T. Morrison,&nbsp;Liangping Li,&nbsp;Diana Acosta,&nbsp;Jiawen Liang,&nbsp;Nithin V. Datla,&nbsp;Julie A. Fitzgerald,&nbsp;Haoran Huang,&nbsp;Xianglan Liu,&nbsp;Gregory Huang Tan,&nbsp;Min Wu,&nbsp;Kate Karelina,&nbsp;Chelsea E. Bray,&nbsp;Zachary M. Weil,&nbsp;Douglas W. Scharre,&nbsp;Geidy E. Serrano,&nbsp;Takashi Saito,&nbsp;Takaomi C. Saido,&nbsp;Thomas G. Beach,&nbsp;Olga N. Kokiko-Cochran,&nbsp;Jonathan P. Godbout,&nbsp;Gail V. W. Johnson,&nbsp;Hongjun Fu","doi":"10.1007/s00401-024-02810-1","DOIUrl":"10.1007/s00401-024-02810-1","url":null,"abstract":"<div><p>Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer’s disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02810-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Targeted whole-viral genome sequencing from formalin-fixed paraffin-embedded neuropathology specimens 从福尔马林固定石蜡包埋的神经病理标本中进行靶向全病毒基因组测序
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-09 DOI: 10.1007/s00401-024-02812-z
Charlotte Gorißen, Anne Albers, Viktoria Ruf, Emil Chteinberg, Reiner Siebert, Leonille Schweizer, Lukas Kaufmann, Joachim E. Kühn, Dennis Tappe, Tanja Kuhlmann, Christian Thomas
{"title":"Targeted whole-viral genome sequencing from formalin-fixed paraffin-embedded neuropathology specimens","authors":"Charlotte Gorißen,&nbsp;Anne Albers,&nbsp;Viktoria Ruf,&nbsp;Emil Chteinberg,&nbsp;Reiner Siebert,&nbsp;Leonille Schweizer,&nbsp;Lukas Kaufmann,&nbsp;Joachim E. Kühn,&nbsp;Dennis Tappe,&nbsp;Tanja Kuhlmann,&nbsp;Christian Thomas","doi":"10.1007/s00401-024-02812-z","DOIUrl":"10.1007/s00401-024-02812-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02812-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma 表观遗传景观重组和胚胎发育基因的重新激活与 IDH 突变星形细胞瘤的恶性程度有关
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-09 DOI: 10.1007/s00401-024-02811-0
Santoesha A. Ghisai, Levi van Hijfte, Wies R. Vallentgoed, C. Mircea S. Tesileanu, Iris de Heer, Johan M. Kros, Marc Sanson, Thierry Gorlia, Wolfgang Wick, Michael A. Vogelbaum, Alba A. Brandes, Enrico Franceschi, Paul M. Clement, Anna K. Nowak, Vassilis Golfinopoulos, Martin J. van den Bent, Pim J. French, Youri Hoogstrate
{"title":"Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma","authors":"Santoesha A. Ghisai,&nbsp;Levi van Hijfte,&nbsp;Wies R. Vallentgoed,&nbsp;C. Mircea S. Tesileanu,&nbsp;Iris de Heer,&nbsp;Johan M. Kros,&nbsp;Marc Sanson,&nbsp;Thierry Gorlia,&nbsp;Wolfgang Wick,&nbsp;Michael A. Vogelbaum,&nbsp;Alba A. Brandes,&nbsp;Enrico Franceschi,&nbsp;Paul M. Clement,&nbsp;Anna K. Nowak,&nbsp;Vassilis Golfinopoulos,&nbsp;Martin J. van den Bent,&nbsp;Pim J. French,&nbsp;Youri Hoogstrate","doi":"10.1007/s00401-024-02811-0","DOIUrl":"10.1007/s00401-024-02811-0","url":null,"abstract":"<div><p>Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from <i>CDKN2A/B</i> homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (<i>n</i> = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. <i>HOX</i>, <i>PAX,</i> and <i>TBX</i>) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02811-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline 颞叶癫痫微血管病变伴弥散核磁共振成像改变和认知能力下降
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-08 DOI: 10.1007/s00401-024-02809-8
Joan Liu, Lawrence Binding, Isha Puntambekar, Smriti Patodia, Yau Mun Lim, Alicja Mryzyglod, Fenglai Xiao, Shengning Pan, Remika Mito, Jane de Tisi, John S. Duncan, Sallie Baxendale, Matthias Koepp, Maria Thom
{"title":"Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline","authors":"Joan Liu,&nbsp;Lawrence Binding,&nbsp;Isha Puntambekar,&nbsp;Smriti Patodia,&nbsp;Yau Mun Lim,&nbsp;Alicja Mryzyglod,&nbsp;Fenglai Xiao,&nbsp;Shengning Pan,&nbsp;Remika Mito,&nbsp;Jane de Tisi,&nbsp;John S. Duncan,&nbsp;Sallie Baxendale,&nbsp;Matthias Koepp,&nbsp;Maria Thom","doi":"10.1007/s00401-024-02809-8","DOIUrl":"10.1007/s00401-024-02809-8","url":null,"abstract":"<div><p>White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, <i>p</i> &lt; 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, <i>p</i> &lt; 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, <i>p</i> &lt; 0.01) which was more marked the longer the duration of epilepsy (<i>p</i> &lt; 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (<i>p</i> &lt; 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02809-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 to: Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins 更正为扩增的 C9orf72 六核苷酸重复序列的双向转录本被翻译成聚集二肽重复序列蛋白
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2024-10-05 DOI: 10.1007/s00401-024-02806-x
Kohji Mori, Thomas Arzberger, Friedrich A. Grässer, Ilse Gijselinck, Stephanie May, Kristin Rentzsch, Shih‑Ming Weng, Martin H. Schludi, Julie van der Zee, Marc Cruts, Christine Van Broeckhoven, Elisabeth Kremmer, Hans A. Kretzschmar, Christian Haass, Dieter Edbauer
{"title":"Correction to: Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins","authors":"Kohji Mori,&nbsp;Thomas Arzberger,&nbsp;Friedrich A. Grässer,&nbsp;Ilse Gijselinck,&nbsp;Stephanie May,&nbsp;Kristin Rentzsch,&nbsp;Shih‑Ming Weng,&nbsp;Martin H. Schludi,&nbsp;Julie van der Zee,&nbsp;Marc Cruts,&nbsp;Christine Van Broeckhoven,&nbsp;Elisabeth Kremmer,&nbsp;Hans A. Kretzschmar,&nbsp;Christian Haass,&nbsp;Dieter Edbauer","doi":"10.1007/s00401-024-02806-x","DOIUrl":"10.1007/s00401-024-02806-x","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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