Neuropathology and Applied Neurobiology最新文献

{"title":"NLRP3 promotes radiation-induced brain injury by regulating microglial pyroptosis.","authors":"Wan Zhang, Qiheng Wu, Xiaonan Zhang, Yue Qin, Lianxuan Gao, Shushu Hu, Shasha Du, Chen Ren","doi":"10.1111/nan.12992","DOIUrl":"10.1111/nan.12992","url":null,"abstract":"<p><strong>Purpose: </strong>Radiation-induced brain injury, one of the side effects of cranial radiotherapy in tumour patients, usually results in durable and serious cognitive disorders. Microglia are important innate immune-effector cells in the central nervous system. However, the interaction between microglia and neurons in radiation-induced brain injury remains uncharacterised.</p><p><strong>Methods and materials: </strong>We established a microglia-neuron indirect co-culture model to assess the interaction between them. Microglia exposed to radiation were examined for pyroptosis using lactate dehydrogenase (LDH) release, Annexin V/PI staining, SYTOX staining and western blot. The role of nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) was investigated in microglia exposed to radiation and in mouse radiation brain injury model through siRNA or inhibitor. Mini-mental state examination and cytokines in blood were performed in 23 patients who had experienced cranial irradiation.</p><p><strong>Results: </strong>Microglia exerted neurotoxic features after radiation in the co-culture model. NLRP3 was up-regulated in microglia exposed to radiation, and then caspase-1 was activated. Thus, the gasdermin D protein was cleaved, and it triggered pyroptosis in microglia, which released inflammatory cytokines. Meanwhile, treatment with siRNA NLRP3 in vitro and NLRP3 inhibitor in vivo attenuated the damaged neuron cell and cognitive impairment, respectively. What is more, we found that the patients after radiation with higher IL-6 were observed to have a decreased MMSE score.</p><p><strong>Conclusions: </strong>These findings indicate that radiation-induced pyroptosis in microglia may promote radiation-induced brain injury via the secretion of neurotoxic cytokines. NLRP3 was evaluated as an important mediator in radiation-induced pyroptosis and a promising therapeutic target for radiation-induced brain injury.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"50 3","pages":"e12992"},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141238000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accurate and comprehensive evaluation of O6-methylguanine-DNA methyltransferase promoter methylation by nanopore sequencing.","authors":"Skarphedinn Halldorsson, Richard Mark Nagymihaly, Areeba Patel, Petter Brandal, Ioannis Panagopoulos, Henning Leske, Marius Lund-Iversen, Felix Sahm, Einar O Vik-Mo","doi":"10.1111/nan.12984","DOIUrl":"10.1111/nan.12984","url":null,"abstract":"<p><strong>Aims: </strong>The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter region is essential in evaluating the prognosis and predicting the drug response in patients with glioblastoma. In this study, we evaluated the utility of using nanopore long-read sequencing as a method for assessing methylation levels throughout the MGMT CpG-island, compared its performance to established techniques and demonstrated its clinical applicability.</p><p><strong>Methods: </strong>We analysed 165 samples from CNS tumours, focusing on the MGMT CpG-island using nanopore sequencing. Oxford Nanopore Technologies (ONT) MinION and PromethION flow cells were employed for single sample or barcoded assays, guided by a CRISPR/Cas9 protocol, adaptive sampling or as part of a whole genome sequencing assay. Methylation data obtained through nanopore sequencing were compared to results obtained via pyrosequencing and methylation bead arrays. Hierarchical clustering was applied to nanopore sequencing data for patient stratification.</p><p><strong>Results: </strong>Nanopore sequencing displayed a strong correlation (R² = 0.91) with pyrosequencing results for the four CpGs of MGMT analysed by both methods. The MGMT-STP27 algorithm's classification was effectively reproduced using nanopore data. Unsupervised hierarchical clustering revealed distinct patterns in methylated and unmethylated samples, providing comparable survival prediction capabilities. Nanopore sequencing yielded high-confidence results in a rapid timeframe, typically within hours of sequencing, and extended the analysis to all 98 CpGs of the MGMT CpG-island.</p><p><strong>Conclusions: </strong>This study presents nanopore sequencing as a valid and efficient method for determining MGMT promotor methylation status. It offers a comprehensive view of the MGMT promoter methylation landscape, which enables the identification of potentially clinically relevant subgroups of patients. Further exploration of the clinical implications of patient stratification using nanopore sequencing of MGMT is warranted.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"50 3","pages":"e12984"},"PeriodicalIF":5.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle.","authors":"Kittichate Visuttijai, Carola Hedberg-Oldfors, Daniel J Costello, Niamh Bermingham, Anders Oldfors","doi":"10.1111/nan.12995","DOIUrl":"10.1111/nan.12995","url":null,"abstract":"<p><strong>Aims: </strong>Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult polyglucosan body disease (APBD, GBE1), polyglucosan body myopathies associated with RBCK1 deficiency (PGBM1, RBCK1) or glycogenin-1 deficiency (PGBM2, GYG1). While the storage material primarily comprises glycans, this study aimed to gain deeper insights into the protein components by proteomic profiling of the storage material in glycogenin-1 deficiency.</p><p><strong>Methods: </strong>We employed molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45-year-old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy.</p><p><strong>Results: </strong>The muscle tissue exhibited a complete absence of glycogenin-1 due to a novel homozygous deep intronic variant in GYG1 (c.7+992T>G), introducing a pseudo-exon causing frameshift and a premature stop codon. Accumulated proteins in the polyglucosan bodies constituted components of glycogen metabolism, protein quality control pathways and desmin. Muscle fibres containing polyglucosan bodies frequently exhibited depletion of normal glycogen.</p><p><strong>Conclusions: </strong>The absence of glycogenin-1, a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin, mirroring findings in RBCK1 deficiency. These results suggest shared pathogenic pathways across different diseases exhibiting polyglucosan storage. Such insights have implications for therapy in these rare yet devastating and presently untreatable disorders.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"50 3","pages":"e12995"},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amino-terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains.","authors":"Oliver Wirths, Christina Lehnen, Merle Fricke, Ivan Talucci, Hans-Wolfgang Klafki, Barbara Morgado, Sandra Lehmann, Carolina Münch, Thomas Liepold, Jens Wiltfang, Agueda Rostagno, Jorge Ghiso, Hans Michael Maric, Olaf Jahn, Sascha Weggen","doi":"10.1111/nan.12991","DOIUrl":"10.1111/nan.12991","url":null,"abstract":"<p><strong>Aims: </strong>The aggregation and deposition of amyloid-β (Aβ) peptides in the brain is thought to be the initial driver in the pathogenesis of Alzheimer's disease (AD). Aside from full-length Aβ peptides starting with an aspartate residue in position 1, both N-terminally truncated and elongated Aβ peptides are produced by various proteases from the amyloid precursor protein (APP) and have been detected in brain tissues and body fluids. Recently, we demonstrated that the particularly abundant N-terminally truncated Aβ4-x peptides are generated by ADAMTS4, a secreted metalloprotease that is exclusively expressed in the oligodendrocyte cell population. In this study, we investigated whether ADAMTS4 might also be involved in the generation of N-terminally elongated Aβ peptides.</p><p><strong>Methods: </strong>We used cell-free and cell-based assays in combination with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF) and electrochemiluminescence sandwich immunoassays to identify and quantify N-terminally elongated Aβ peptide variants. Antibodies against these Aβ variants were characterised by peptide microarrays and employed for the immunohistochemical analyses of human brain samples.</p><p><strong>Results: </strong>In this study, we discovered additional ADAMTS4 cleavage sites in APP. These were located N-terminal to Asp-(1) in the Aβ peptide sequence between residues Glu-(-7) and Ile-(-6) as well as Glu-(-4) and Val-(-3), resulting in the release of N-terminally elongated Aβ-6-x and Aβ-3-x peptides, of which the latter serve as a component in a promising Aβ-based plasma biomarker. Aβ-6/-3-40 peptides were detected in supernatants of various cell lines and in the cerebrospinal fluid (CSF), and ADAMTS4 enzyme activity promoted the release of Aβ-6/-3-x peptides. Furthermore, by immunohistochemistry, a subset of AD cases displayed evidence of extracellular and vascular localization of N-terminally elongated Aβ-6/-3-x peptides.</p><p><strong>Discussion: </strong>The current findings implicate ADAMTS4 in both the pathological process of Aβ peptide aggregation and in the early detection of amyloid pathology in AD.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"50 3","pages":"e12991"},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 50, Issue 3","authors":"Sang Won Cheung, Ekta Bhavnani, David G. Simmons, Mark C. Bellingham, Peter G. Noakes","doi":"10.1111/nan.12993","DOIUrl":"https://doi.org/10.1111/nan.12993","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"6 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141188889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interferon‐gamma contributes to disease progression in the Ndufs4(−/−) model of Leigh syndrome","authors":"Allison R. Hanaford, Asheema Khanna, Katerina James, Vivian Truong, Ryan Liao, Yihan Chen, Michael Mulholland, Ernst‐Bernhard Kayser, Kino Watanabe, Erin Shien Hsieh, Margaret Sedensky, Philip G. Morgan, Vandana Kalia, Surojit Sarkar, Simon C. Johnson","doi":"10.1111/nan.12977","DOIUrl":"https://doi.org/10.1111/nan.12977","url":null,"abstract":"AimLeigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi‐system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2 years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the <jats:italic>Ndufs4</jats:italic>(−/−) mouse model of LS: treatment of <jats:italic>Ndufs4</jats:italic>(−/−) mice with the macrophage‐depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon‐gamma (IFNγ) and interferon gamma‐induced protein 10 (IP10) were found to be significantly elevated in <jats:italic>Ndufs4</jats:italic>(−/−) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFNγ and IP10 in LS.MethodsTo establish the role of IFNγ and IP10 in LS, we generated IFNγ and IP10 deficient <jats:italic>Ndufs4</jats:italic>(−/−)/<jats:italic>Ifng</jats:italic>(−/−) and <jats:italic>Ndufs4</jats:italic>(−/−)/<jats:italic>IP10</jats:italic>(−/−) double knockout animals, as well as IFNγ and IP10 heterozygous, <jats:italic>Ndufs4</jats:italic>(−/−)/<jats:italic>Ifng</jats:italic>(+/−) and <jats:italic>Ndufs4</jats:italic>(−/−)/<jats:italic>IP10</jats:italic>(+/−), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFNγ and IP10 in LS.ResultsLoss of IP10 does not significantly impact the onset or progression of disease in the <jats:italic>Ndufs4</jats:italic>(−/−) model. IFNγ loss significantly extends survival and delays disease progression in a gene dosage‐dependent manner, though the benefits are modest compared to Csf1r inhibition.ConclusionsIFNγ contributes to disease onset and progression in LS. Our findings suggest that IFNγ targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFNγ alone would likely yield only modest benefits in LS.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"167 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140828331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting the relevance of Hirano bodies in neurodegenerative diseases","authors":"Koji Yoshida, Shelley L. Forrest, Shojiro Ichimata, Hidetomo Tanaka, Tomoya Kon, Maria Carmela Tartaglia, Charles H. Tator, Anthony E. Lang, Naoki Nishida, Gabor G. Kovacs","doi":"10.1111/nan.12978","DOIUrl":"https://doi.org/10.1111/nan.12978","url":null,"abstract":"AimsHirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases.MethodsThis cross‐sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (<jats:italic>n</jats:italic> = 91), Lewy body disease (LBD, <jats:italic>n</jats:italic> = 87), progressive supranuclear palsy (PSP, <jats:italic>n</jats:italic> = 36), multiple system atrophy (MSA, <jats:italic>n</jats:italic> = 14) and controls (<jats:italic>n</jats:italic> = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions.ResultsThe morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod‐shaped HB (CHB), (2) balloon‐shaped HB (BHB) and the newly described (3) string‐shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP‐43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA.ConclusionsThis study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"19 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140630059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adult brain tumour research in 2024: Status, challenges and recommendations","authors":"Karin Purshouse, Helen J. Bulbeck, Alasdair G. Rooney, Karen E. Noble, Ross D. Carruthers, Gerard Thompson, Petra Hamerlik, Christina Yap, Kathreena M. Kurian, Sarah J. Jefferies, Juanita S. Lopez, Michael D. Jenkinson, C. Oliver Hanemann, Lucy F. Stead","doi":"10.1111/nan.12979","DOIUrl":"https://doi.org/10.1111/nan.12979","url":null,"abstract":"In 2015, a groundswell of brain tumour patient, carer and charity activism compelled the UK Minister for Life Sciences to form a brain tumour research task and finish group. This resulted, in 2018, with the UK government pledging £20m of funding, to be paralleled with £25m from Cancer Research UK, specifically for neuro‐oncology research over the subsequent 5 years. Herein, we review if and how the adult brain tumour research landscape in the United Kingdom has changed over that time and what challenges and bottlenecks remain. We have identified seven universal brain tumour research priorities and three cross‐cutting themes, which span the research spectrum from bench to bedside and back again. We discuss the status, challenges and recommendations for each one, specific to the United Kingdom.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"43 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune system involvement in neuronal intranuclear inclusion disease","authors":"Lei Bao, Dandan Zuo, Xiaoying Qu, Yingying Cui, Keke Li, Jing Dong, Renjin Chen, Zunsheng Zhang, Guiyun Cui, Hao Chen","doi":"10.1111/nan.12976","DOIUrl":"https://doi.org/10.1111/nan.12976","url":null,"abstract":"<h2> CONFLICT OF INTEREST STATEMENT</h2>\u0000<p>The authors declare that they have no competing interests.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"2000 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response letter: Complexities in pericyte markers","authors":"Peter T. Nelson, Andras Sziraki, Junyue Cao","doi":"10.1111/nan.12975","DOIUrl":"https://doi.org/10.1111/nan.12975","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"2014 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}