Neuropathology and Applied Neurobiology最新文献

{"title":"Tuberous sclerosis complex-1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's disease.","authors":"Bryan A Adriaanse,&nbsp;Sinead Brady,&nbsp;Minghui Wang,&nbsp;Daniel J Beard,&nbsp;Jonathan I Spencer,&nbsp;Jonathan Pansieri,&nbsp;Brad A Sutherland,&nbsp;Margaret M Esiri,&nbsp;Alastair M Buchan,&nbsp;Zameel Cader,&nbsp;Bin Zhang,&nbsp;Gabriele C DeLuca","doi":"10.1111/nan.12904","DOIUrl":"https://doi.org/10.1111/nan.12904","url":null,"abstract":"<p><strong>Aims: </strong>Selective neuronal vulnerability of hippocampal Cornu Ammonis (CA)-1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex-1 (TSC1; hamartin) and mTOR-related proteins in hippocampal CA1 and CA3 subfields.</p><p><strong>Methods: </strong>A human post-mortem cohort of mild (n = 7) and severe (n = 10) AD and non-neurological controls (n = 9) was used for quantitative and semi-quantitative analyses. We also developed an in vitro TSC1 knockdown model in rat hippocampal neurons, and transcriptomic analyses of TSC1 knockdown neuronal cultures were performed.</p><p><strong>Results: </strong>We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex-1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1 knockdown experiments showed accelerated cell death independent of amyloid-beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD-related pathways.</p><p><strong>Conclusions: </strong>Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippocampus. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 3","pages":"e12904"},"PeriodicalIF":5.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10073220","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":"Corrigendum.","authors":"","doi":"10.1111/nan.12905","DOIUrl":"https://doi.org/10.1111/nan.12905","url":null,"abstract":"The authors regret that in Bergh et al., the funding information for Åsa Petersén was incomplete. The complete funding information is provided below: This work was supported by research grants to RYC and ÅP from the Swedish Research Council (grant numbers 2013/03537 and 2018/02559), ALF grant from Region Skåne, the Royal Physiographic Society of Lund (grant numbers 2016-37869, 2018-39651 and 2019-40523), the Swedish Brain Foundation (grant numbers FO2016-0121 and FO2018-0080), the Åhlén Foundation (grant number mA28/ h17), the Fredrik and Ingrid Thurings Foundation (grant number 2017-00316) and NEURO Sweden (2017 and 2019). RYC was supported by a Swedish Society for Medical Research (SSMF) Postdoctoral Fellowship (grant number P15-0017). ÅP was supported by a research grant from Knut and Alice Wallenberg Foundation (grant number 2019.0467). The authors apologise for any inconvenience this may have caused.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 3","pages":"e12905"},"PeriodicalIF":5.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9683823","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":"Increased number and domain of interlaminar astrocytes in layer I of the temporal cortex in epilepsy.","authors":"Nan Zhou,&nbsp;Zhen Fan,&nbsp;Yusheng Tong,&nbsp;Xing Xiao,&nbsp;Yongsheng Xie,&nbsp;Zengxin Qi,&nbsp;Liang Chen","doi":"10.1111/nan.12913","DOIUrl":"https://doi.org/10.1111/nan.12913","url":null,"abstract":"<p><strong>Aim: </strong>The functions of the interlaminar astrocytes in layer I of the human cortex are currently unknown. Here, we aimed to explore whether there is any morphological remodelling of interlaminar astrocytes in layer I of the temporal cortex in epilepsy.</p><p><strong>Methods: </strong>Tissues were obtained from 17 epilepsy surgery patients and 17 post-mortem age-matched controls. In addition, 10 Alzheimer's disease (AD) patients and 10 age-matched controls were used as the disease control group. Paraffin sections (6 μm) and frozen sections (35 or 150 μm) of inferior temporal gyrus tissue were used for immunohistochemistry. With the use of tissue transparency, 3D reconstruction and hierarchical clustering, we performed a quantitative morphological analysis of astrocytes.</p><p><strong>Results: </strong>Upper and lower zones were identified in layer I of the human cortex. Compared with the astrocytes in layers IV-V, layer I interlaminar astrocytes occupied a significantly smaller volume and exhibited shorter and fewer process intersections. Increased Chaslin's gliosis (consisting of types I and II subpial interlaminar astrocytes) and number of glial fibrillary acidic protein (GFAP)-immunoreactive interlaminar astrocytes in layer I of the temporal cortex were confirmed in patients with epilepsy. There was no difference in the number of interlaminar astrocytes in layer I between AD and age-matched control groups. Using tissue transparency and 3D reconstruction technology, the astrocyte domain in the human temporal cortex was classified into four clusters, among which the interlaminar astrocytes in cluster II were more abundant in epilepsy, showing specific topological structures in patients with epilepsy. Furthermore, there was a significant increase in the astrocyte domain of interlaminar cells in layer I of the temporal cortex in patients with epilepsy.</p><p><strong>Conclusion: </strong>The observed significant astrocytic structural remodelling in the temporal cortex of epilepsy patients showed that the astrocyte domain in layer I may play an important role in temporal lobe epilepsy.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 3","pages":"e12913"},"PeriodicalIF":5.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9695353","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":"Motor neuron involvement threatens survival in spinocerebellar ataxia type 1.","authors":"Giulia Coarelli,&nbsp;Maya Tchikviladzé,&nbsp;Pauline Dodet,&nbsp;Isabelle Arnulf,&nbsp;Perrine Charles,&nbsp;Frederic Tankeré,&nbsp;Thomas Similowski,&nbsp;Danielle Seilhean,&nbsp;Alexis Brice,&nbsp;Charles Duyckaerts,&nbsp;Alexandra Durr","doi":"10.1111/nan.12897","DOIUrl":"https://doi.org/10.1111/nan.12897","url":null,"abstract":"Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France Department of Genetics, Pitié-Salpêtrière Charles-Foix University Hospital, Assistance Publique – Hôpitaux de Paris (AP-HP), Paris, 75013, France Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, AP-HP, Paris, France; ICM, Sorbonne Université, Inserm U 1127, CNRS UMR, Paris, 7225, France Department of Otolaryngology-Head and Neck Surgery, Pitié-Salpêtrière Charles-Foix University Hospital, Assistance Publique – Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, 75013, France Département R3S (Respiration, Réanimation, Réhabilitation respiratoire, Sommeil), Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique; AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, site Pitié-Salpêtrière, Paris, F-75013, France Laboratoire de Neuropathologie R. Escourolle, Pitié-Salpêtrière Charles-Foix University Hospital, Assistance Publique – Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, 75013, France","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 2","pages":"e12897"},"PeriodicalIF":5.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9366537","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":"Muscleblind-like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development.","authors":"Chia-Wei Huang,&nbsp;Kuang-Yung Lee,&nbsp;Peng-Tzu Lin,&nbsp;Fang-Shin Nian,&nbsp;Haw-Yuan Cheng,&nbsp;Chien-Hui Chang,&nbsp;Cheng-Yen Liao,&nbsp;Yen-Lin Su,&nbsp;Carol Seah,&nbsp;Ching Li,&nbsp;Yu-Fu Chen,&nbsp;Mei-Hsuan Lee,&nbsp;Jin-Wu Tsai","doi":"10.1111/nan.12890","DOIUrl":"https://doi.org/10.1111/nan.12890","url":null,"abstract":"Muscleblind‐like 2 (MBNL2) plays a crucial role in regulating alternative splicing during development and mouse loss of MBNL2 recapitulates brain phenotypes in myotonic dystrophy (DM). However, the mechanisms underlying DM neuropathogenesis during brain development remain unclear. In this study, we aim to investigate the impact of MBNL2 elimination on neuronal development by Mbnl2 conditional knockout (CKO) mouse models.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 2","pages":"e12890"},"PeriodicalIF":5.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9423814","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":"Soluble amyloid-β dimers are resistant to amyloid-β prion conversion in vivo suggesting antiprion properties.","authors":"Else F van Gerresheim,&nbsp;Andreas Müller-Schiffmann,&nbsp;Sandra Schäble,&nbsp;Bastijn Koopmans,&nbsp;Maarten Loos,&nbsp;Carsten Korth","doi":"10.1111/nan.12895","DOIUrl":"https://doi.org/10.1111/nan.12895","url":null,"abstract":"According to the instructions for authors, short communications should be published without abstract.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 2","pages":"e12895"},"PeriodicalIF":5.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9721544","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":"TDP-43 pathology and functional deficits in wild-type and ALS/FTD mutant cyclin F mouse models.","authors":"Annika van Hummel, Miheer Sabale, Magdalena Przybyla, Julia van der Hoven, Gabriella Chan, Astrid F Feiten, Roger S Chung, Lars M Ittner, Yazi D Ke","doi":"10.1111/nan.12902","DOIUrl":"10.1111/nan.12902","url":null,"abstract":"<p><strong>Aims: </strong>Amyotrophic lateral sclerosis (ALS) is characterised by a progressive loss of upper and lower motor neurons leading to muscle weakness and eventually death. Frontotemporal dementia (FTD) presents clinically with significant behavioural decline. Approximately 10% of cases have a known family history, and disease-linked mutations in multiple genes have been identified in FTD and ALS. More recently, ALS and FTD-linked variants have been identified in the CCNF gene, which accounts for an estimated 0.6% to over 3% of familial ALS cases.</p><p><strong>Methods: </strong>In this study, we developed the first mouse models expressing either wild-type (WT) human CCNF or its mutant pathogenic variant S621G to recapitulate key clinical and neuropathological features of ALS and FTD linked to CCNF disease variants. We expressed human CCNF WT or CCNF^S621G throughout the murine brain by intracranial delivery of adeno-associated virus (AAV) to achieve widespread delivery via somatic brain transgenesis.</p><p><strong>Results: </strong>These mice developed behavioural abnormalities, similar to the clinical symptoms of FTD patients, as early as 3 months of age, including hyperactivity and disinhibition, which progressively deteriorated to include memory deficits by 8 months of age. Brains of mutant CCNF_S621G mice displayed an accumulation of ubiquitinated proteins with elevated levels of phosphorylated TDP-43 present in both CCNF_WT and mutant CCNF_S621G mice. We also investigated the effects of CCNF expression on interaction targets of CCNF and found elevated levels of insoluble splicing factor proline and glutamine-rich (SFPQ). Furthermore, cytoplasmic TDP-43 inclusions were found in both CCNF_WT and mutant CCNF_S621G mice, recapitulating the key hallmark of FTD/ALS pathology.</p><p><strong>Conclusions: </strong>In summary, CCNF expression in mice reproduces clinical presentations of ALS, including functional deficits and TDP-43 neuropathology with altered CCNF-mediated pathways contributing to the pathology observed.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 2","pages":"e12902"},"PeriodicalIF":5.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9360740","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":"DNA methylation-based classification of glioneuronal tumours synergises with histology and radiology to refine accurate molecular stratification.","authors":"Thomas J Stone, Kshitij Mankad, Ai Peng Tan, Wajanat Jan, Jessica C Pickles, Maria Gogou, Jane Chalker, Iwona Slodkowska, Emily Pang, Mark Kristiansen, Gaganjit K Madhan, Leysa Forrest, Deborah Hughes, Eleni Koutroumanidou, Talisa Mistry, Olumide Ogunbiyi, Saira W Ahmed, J Helen Cross, Mike Hubank, Darren Hargrave, Thomas S Jacques","doi":"10.1111/nan.12894","DOIUrl":"10.1111/nan.12894","url":null,"abstract":"<p><strong>Aims: </strong>Glioneuronal tumours (GNTs) are poorly distinguished by their histology and lack robust diagnostic indicators. Previously, we showed that common GNTs comprise two molecularly distinct groups, correlating poorly with histology. To refine diagnosis, we constructed a methylation-based model for GNT classification, subsequently evaluating standards for molecular stratification by methylation, histology and radiology.</p><p><strong>Methods: </strong>We comprehensively analysed methylation, radiology and histology for 83 GNT samples: a training cohort of 49, previously classified into molecularly defined groups by genomic profiles, plus a validation cohort of 34. We identified histological and radiological correlates to molecular classification and constructed a methylation-based support vector machine (SVM) model for prediction. Subsequently, we contrasted methylation, radiological and histological classifications in validation GNTs.</p><p><strong>Results: </strong>By methylation clustering, all training and 23/34 validation GNTs segregated into two groups, the remaining 11 clustering alongside control cortex. Histological review identified prominent astrocytic/oligodendrocyte-like components, dysplastic neurons and a specific glioneuronal element as discriminators between groups. However, these were present in only a subset of tumours. Radiological review identified location, margin definition, enhancement and T2 FLAIR-rim sign as discriminators. When validation GNTs were classified by SVM, 22/23 classified correctly, comparing favourably against histology and radiology that resolved 17/22 and 15/21, respectively, where data were available for comparison.</p><p><strong>Conclusions: </strong>Diagnostic criteria inadequately reflect glioneuronal tumour biology, leaving a proportion unresolvable. In the largest cohort of molecularly defined glioneuronal tumours, we develop molecular, histological and radiological approaches for biologically meaningful classification and demonstrate almost all cases are resolvable, emphasising the importance of an integrated diagnostic approach.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 2","pages":"e12894"},"PeriodicalIF":5.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9367728","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":"Schwann cells and myelin in human peripheral nerve: Major protein components vary with age, axon size and pathology.","authors":"Alan Pestronk,&nbsp;Robert E Schmidt,&nbsp;Robert Bucelli,&nbsp;Julia Sim","doi":"10.1111/nan.12898","DOIUrl":"https://doi.org/10.1111/nan.12898","url":null,"abstract":"<p><strong>Aims: </strong>We examined major protein components of Schwann cells (SCs) and myelin in normal and diseased human peripheral nerves.</p><p><strong>Methods: </strong>We evaluated distributions of neural cell adhesion molecule (NCAM), P0 protein (P0) and myelin basic protein (MBP) in frozen sections of 98 sural nerves.</p><p><strong>Results: </strong>Non-myelinating SC in normal adults contained NCAM, but not P0 or MBP. With chronic axon loss, SC without associated axons (Büngner band cells) often co-stained for both NCAM and P0. Onion bulb cells also co-stained for both P0 and NCAM. Infants had many SC with MBP but no P0. All myelin sheaths contained P0. Myelin around large, and some intermediate-sized, axons co-stained for both MBP and P0. Myelin on other intermediate-sized axons had P0, but no MBP. Regenerated axons often had sheaths with MBP, P0 and some NCAM. During active axon degeneration, myelin ovoids often co-stained for MBP, P0 and NCAM. Demyelinating neuropathy patterns included SC (NCAM) loss, and myelin with abnormally distributed, or reduced, P0.</p><p><strong>Conclusions: </strong>Peripheral nerve SC and myelin have varied molecular phenotypes, related to age, axon size and nerve pathology. In normal adult peripheral nerve, myelin has two different patterns of molecular composition. MBP is mostly absent from myelin around a population of intermediate-sized axons, whereas P0 is present in myelin around all axons. Denervated SCs have a molecular signature that differs from normal SC types. With acute denervation, SCs may stain for both NCAM and MBP. Chronically denervated SCs often stain for both NCAM and P0.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 2","pages":"e12898"},"PeriodicalIF":5.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9690854","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":"Fibrocartilaginous cerebral and spinal emboli: A report of two cases with histopathological confirmation.","authors":"Fouzia Ziad,&nbsp;David Wang,&nbsp;Andrew Chancellor,&nbsp;Zakier Hussain,&nbsp;Adam El-Dieb,&nbsp;Sanjeevan Pasupati,&nbsp;Thomas Robertson","doi":"10.1111/nan.12896","DOIUrl":"https://doi.org/10.1111/nan.12896","url":null,"abstract":"Department of Pathology, Waikato Hospital, Hamilton, New Zealand Department of Medicine, Auckland City Hospital, Auckland, New Zealand Department of Neurology, Tauranga Hospital, Tauranga, New Zealand Department of Neurosurgery, Waikato Hospital, Hamilton, New Zealand Department of Radiology, Tauranga Hospital, Tauranga, New Zealand Department of Cardiology, Waikato Hospital, Hamilton, New Zealand Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 2","pages":"e12896"},"PeriodicalIF":5.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9721546","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}