Acta Neuropathologica最新文献

{"title":"Identification of a putative molecular subtype of adult-type diffuse astrocytoma with recurrent MAPK pathway alterations","authors":"Philipp Sievers, Franck Bielle, Kirsten Göbel, Daniel Schrimpf, Lucia Nichelli, Bertrand Mathon, Romain Appay, Henning B. Boldt, Hildegard Dohmen, Carmen Selignow, Till Acker, Ales Vicha, Horacio Martinetto, Leonille Schweizer, Ulrich Schüller, Sebastian Brandner, Pieter Wesseling, Simone Schmid, David Capper, Zied Abdullaev, Kenneth Aldape, Andrey Korshunov, Sandro M. Krieg, Wolfgang Wick, Stefan M. Pfister, Andreas von Deimling, David E. Reuss, David T. W. Jones, Felix Sahm","doi":"10.1007/s00401-024-02766-2","DOIUrl":"10.1007/s00401-024-02766-2","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11258072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722845","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}

{"title":"Anti-Ku + myositis: an acquired inflammatory protein-aggregate myopathy","authors":"Marie-Therese Holzer,&nbsp;Akinori Uruha,&nbsp;Andreas Roos,&nbsp;Andreas Hentschel,&nbsp;Anne Schänzer,&nbsp;Joachim Weis,&nbsp;Kristl G. Claeys,&nbsp;Benedikt Schoser,&nbsp;Federica Montagnese,&nbsp;Hans-Hilmar Goebel,&nbsp;Melanie Huber,&nbsp;Sarah Léonard-Louis,&nbsp;Ina Kötter,&nbsp;Nathalie Streichenberger,&nbsp;Laure Gallay,&nbsp;Olivier Benveniste,&nbsp;Udo Schneider,&nbsp;Corinna Preusse,&nbsp;Martin Krusche,&nbsp;Werner Stenzel","doi":"10.1007/s00401-024-02765-3","DOIUrl":"10.1007/s00401-024-02765-3","url":null,"abstract":"<div><p>Myositis with anti-Ku-autoantibodies is a rare inflammatory myopathy associated with various connective tissue diseases. Histopathological studies have identified inflammatory and necrotizing aspects, but a precise morphological analysis and pathomechanistic disease model are lacking. We therefore aimed to carry out an in-depth morpho-molecular analysis to uncover possible pathomechanisms. Muscle biopsy specimens from 26 patients with anti-Ku-antibodies and unequivocal myositis were analyzed by immunohistochemistry, immunofluorescence, transcriptomics, and proteomics and compared to biopsy specimens of non-disease controls, immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Clinical findings and laboratory parameters were evaluated retrospectively and correlated with morphological and molecular features. Patients were mainly female (92%) with a median age of 56.5 years. Isolated myositis and overlap with systemic sclerosis were reported in 31%, respectively. Isolated myositis presented with higher creatine kinase levels and cardiac involvement (83%), whereas systemic sclerosis-overlap patients often had interstitial lung disease (57%). Histopathology showed a wide spectrum from mild to pronounced myositis with diffuse sarcolemmal MHC-class I (100%) and -II (69%) immunoreactivity, myofiber necrosis (88%), endomysial inflammation (85%), thickened capillaries (84%), and vacuoles (60%). Conspicuous sarcoplasmic protein aggregates were p62, BAG3, myotilin, or immunoproteasomal beta5i-positive. Proteomic and transcriptomic analysis identified prominent up-regulation of autophagy, proteasome, and hnRNP-related cell stress. To conclude, Ku + myositis is morphologically characterized by myofiber necrosis, MHC-class I and II positivity, variable endomysial inflammation, and distinct protein aggregation varying from IBM and IMNM, and it can be placed in the spectrum of scleromyositis and overlap myositis. It features characteristic sarcoplasmic protein aggregation on an acquired basis being functionally associated with altered chaperone, proteasome, and autophagy function indicating that Ku + myositis exhibit aspects of an acquired inflammatory protein-aggregate myopathy.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618978","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}

{"title":"Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma","authors":"Timothy E. Richardson,&nbsp;Jamie M. Walker,&nbsp;Dolores Hambardzumyan,&nbsp;Steven Brem,&nbsp;Kimmo J. Hatanpaa,&nbsp;Mariano S. Viapiano,&nbsp;Balagopal Pai,&nbsp;Melissa Umphlett,&nbsp;Oren J. Becher,&nbsp;Matija Snuderl,&nbsp;Samuel K. McBrayer,&nbsp;Kalil G. Abdullah,&nbsp;Nadejda M. Tsankova","doi":"10.1007/s00401-024-02761-7","DOIUrl":"10.1007/s00401-024-02761-7","url":null,"abstract":"<div><p>In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous <i>CDKN2A</i> deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618979","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}

{"title":"DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson’s disease, and progressive supranuclear palsy: a cross-comparative investigation","authors":"Megha Murthy,&nbsp;Katherine Fodder,&nbsp;Yasuo Miki,&nbsp;Naiomi Rambarack,&nbsp;Eduardo De Pablo Fernandez,&nbsp;Lasse Pihlstrøm,&nbsp;Jonathan Mill,&nbsp;Thomas T. Warner,&nbsp;Tammaryn Lashley,&nbsp;Conceição Bettencourt","doi":"10.1007/s00401-024-02764-4","DOIUrl":"10.1007/s00401-024-02764-4","url":null,"abstract":"<div><p>Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by neuronal loss and gliosis, with oligodendroglial cytoplasmic inclusions (GCIs) containing α-synuclein being the primary pathological hallmark. Clinical presentations of MSA overlap with other parkinsonian disorders, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), posing challenges in early diagnosis. Numerous studies have reported alterations in DNA methylation in neurodegenerative diseases, with candidate loci being identified in various parkinsonian disorders including MSA, PD, and PSP. Although MSA and PSP present with substantial white matter pathology, alterations in white matter have also been reported in PD. However, studies comparing the DNA methylation architectures of white matter in these diseases are lacking. We therefore aimed to investigate genome-wide DNA methylation patterns in the frontal lobe white matter of individuals with MSA (<i>n</i> = 17), PD (<i>n</i> = 17), and PSP (<i>n</i> = 16) along with controls (<i>n</i> = 15) using the Illumina EPIC array, to identify shared and disease-specific DNA methylation alterations. Genome-wide DNA methylation profiling of frontal lobe white matter in the three parkinsonian disorders revealed substantial commonalities in DNA methylation alterations in MSA, PD, and PSP. We further used weighted gene correlation network analysis to identify disease-associated co-methylation signatures and identified dysregulation in processes relating to Wnt signaling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport to be shared between these parkinsonian disorders. Our overall analysis points toward more similarities in DNA methylation patterns between MSA and PD, both synucleinopathies, compared to that between MSA and PD with PSP, which is a tauopathy. Our results also highlight several shared DNA methylation changes and pathways indicative of converging molecular mechanisms in the white matter contributing toward neurodegeneration in all three parkinsonian disorders.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11245434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589390","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}

{"title":"Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases.","authors":"Feizhi Song, Valerija Kovac, Behnam Mohammadi, Jessica L Littau, Franka Scharfenberg, Andreu Matamoros Angles, Ilaria Vanni, Mohsin Shafiq, Leonor Orge, Giovanna Galliciotti, Salma Djakkani, Luise Linsenmeier, Maja Černilec, Katrina Hartman, Sebastian Jung, Jörg Tatzelt, Julia E Neumann, Markus Damme, Sarah K Tschirner, Stefan F Lichtenthaler, Franz L Ricklefs, Thomas Sauvigny, Matthias Schmitz, Inga Zerr, Berta Puig, Eva Tolosa, Isidro Ferrer, Tim Magnus, Marjan S Rupnik, Diego Sepulveda-Falla, Jakob Matschke, Lojze M Šmid, Mara Bresjanac, Olivier Andreoletti, Susanne Krasemann, Simote T Foliaki, Romolo Nonno, Christoph Becker-Pauly, Cecile Monzo, Carole Crozet, Cathryn L Haigh, Markus Glatzel, Vladka Curin Serbec, Hermann C Altmeppen","doi":"10.1007/s00401-024-02763-5","DOIUrl":"10.1007/s00401-024-02763-5","url":null,"abstract":"<p><p>Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":"2"},"PeriodicalIF":9.3,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11233397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557729","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}

{"title":"Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status","authors":"Haoshen Shi,&nbsp;Nazanin Mirzaei,&nbsp;Yosef Koronyo,&nbsp;Miyah R. Davis,&nbsp;Edward Robinson,&nbsp;Gila M. Braun,&nbsp;Ousman Jallow,&nbsp;Altan Rentsendorj,&nbsp;V. Krishnan Ramanujan,&nbsp;Justyna Fert-Bober,&nbsp;Andrei A. Kramerov,&nbsp;Alexander V. Ljubimov,&nbsp;Lon S. Schneider,&nbsp;Warren G. Tourtellotte,&nbsp;Debra Hawes,&nbsp;Julie A. Schneider,&nbsp;Keith L. Black,&nbsp;Rakez Kayed,&nbsp;Maj-Linda B. Selenica,&nbsp;Daniel C. Lee,&nbsp;Dieu-Trang Fuchs,&nbsp;Maya Koronyo-Hamaoui","doi":"10.1007/s00401-024-02760-8","DOIUrl":"10.1007/s00401-024-02760-8","url":null,"abstract":"<div><p>This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer’s disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (<i>n</i> = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (<i>n</i> = 30) and non-AD dementia (<i>n</i> = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR₂₀₉-tau; 4.1-fold), and Oligo-tau (T22⁺, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR₂₀₉-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (<i>ρ</i> = 0.63–0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (<i>ρ</i> = 0.69–0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (<i>ρ</i> = 0.67–0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aβ₄₂ and arterial Aβ₄₀ forms (<i>r</i> = 0.76–0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11233395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557693","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}

{"title":"Chronic traumatic encephalopathy (CTE) in the context of longstanding intimate partner violence.","authors":"M Tiemensma, R W Byard, R Vink, A J Affleck, P Blumbergs, M E Buckland","doi":"10.1007/s00401-024-02757-3","DOIUrl":"10.1007/s00401-024-02757-3","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":"1"},"PeriodicalIF":9.3,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11230984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141553988","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}

{"title":"Xenografted human iPSC-derived neurons with the familial Alzheimer’s disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator","authors":"Wenhui Qu,&nbsp;Matti Lam,&nbsp;Julie J. McInvale,&nbsp;Jason A. Mares,&nbsp;Sam Kwon,&nbsp;Nelson Humala,&nbsp;Aayushi Mahajan,&nbsp;Trang Nguyen,&nbsp;Kelly A. Jakubiak,&nbsp;Jeong-Yeon Mun,&nbsp;Thomas G. Tedesco,&nbsp;Osama Al-Dalahmah,&nbsp;Syed A. Hussaini,&nbsp;Andrew A. Sproul,&nbsp;Markus D. Siegelin,&nbsp;Philip L. De Jager,&nbsp;Peter Canoll,&nbsp;Vilas Menon,&nbsp;Gunnar Hargus","doi":"10.1007/s00401-024-02755-5","DOIUrl":"10.1007/s00401-024-02755-5","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is the most common cause of dementia, and disease mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying the familial AD <i>APP</i>^<i>V717I</i> mutation after cell injection into the mouse forebrain. <i>APP</i>^<i>V717I</i> mutant iPSCs and isogenic controls were differentiated into neurons revealing enhanced Aβ₄₂ production, elevated phospho-tau, and impaired neurite outgrowth in APP^V717I neurons. Two months after transplantation, APP^V717I and control neural cells showed robust engraftment but at 12 months post-injection, APP^V717I grafts were smaller and demonstrated impaired neurite outgrowth compared to controls, while plaque and tangle pathology were not seen. Single-nucleus RNA-sequencing of micro-dissected grafts, performed 2 months after cell injection, identified significantly altered transcriptome signatures in APP^V717I iPSC-derived neurons pointing towards dysregulated synaptic function and axon guidance. Interestingly, APP^V717I neurons showed an increased expression of genes, many of which are also upregulated in postmortem neurons of AD patients including the transmembrane protein LINGO2. Downregulation of LINGO2 in cultured APP^V717I neurons rescued neurite outgrowth deficits and reversed key AD-associated transcriptional changes related but not limited to synaptic function, apoptosis and cellular senescence. These results provide important insights into transcriptional dysregulation in xenografted APP^V717I neurons linked to synaptic function, and they indicate that LINGO2 may represent a potential therapeutic target in AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449324","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}

{"title":"Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury","authors":"Fari Ryan,&nbsp;Christian Blex,&nbsp;The Dung Ngo,&nbsp;Marcel A. Kopp,&nbsp;Bernhard Michalke,&nbsp;Vivek Venkataramani,&nbsp;Laura Curran,&nbsp;Jan M. Schwab,&nbsp;Klemens Ruprecht,&nbsp;Carolin Otto,&nbsp;Priya Jhelum,&nbsp;Antje Kroner,&nbsp;Samuel David","doi":"10.1007/s00401-024-02758-2","DOIUrl":"10.1007/s00401-024-02758-2","url":null,"abstract":"<div><p>We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury. While iron is stored safely in ferritin in the injured spinal cord, it can, however, be released by NCOA4-mediated shuttling of ferritin to autophagosomes for degradation (ferritinophagy). This leads to the release of redox active iron that can cause free radical damage. Expression of NCOA4 is increased after SCI, mainly in macrophages. Increase in the ratio of redox active ferrous (Fe²⁺) to ferric iron (Fe³⁺) is also detected after SCI by capillary electrophoresis inductively coupled mass spectrometry. These changes are accompanied by other hallmarks of ferroptosis, i.e., deficiency in various elements of the antioxidant glutathione (GSH) pathway. We also detect increases in enzymes that repair membrane lipids (ACSL4 and LPCAT3) and thus promote on-going ferroptosis. These changes are associated with increased levels of 4-hydroxynonenal (4-HNE), a toxic lipid peroxidation product. Mice with mild SCI (30 kdyne force) treated with the ferroptosis inhibitor (UAMC-3203-HCL) either early or delayed times after injury showed improvement in locomotor recovery and secondary damage. Cerebrospinal fluid and serum samples from human SCI cases show evidence of increased iron storage (ferritin), and other iron related molecules, and reduction in GSH. Collectively, these data suggest that ferroptosis contributes to secondary damage after SCI and highlights the possible use of ferroptosis inhibitors to treat SCI.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02758-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141439855","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}

{"title":"Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer’s Coordinating Center database","authors":"Davis C. Woodworth,&nbsp;Katelynn M. Nguyen,&nbsp;Lorena Sordo,&nbsp;Kiana A. Scambray,&nbsp;Elizabeth Head,&nbsp;Claudia H. Kawas,&nbsp;María M. Corrada,&nbsp;Peter T. Nelson,&nbsp;S. Ahmad Sajjadi","doi":"10.1007/s00401-024-02728-8","DOIUrl":"10.1007/s00401-024-02728-8","url":null,"abstract":"<div><p>TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer’s Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies (“Other TDP-43”). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer’s disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417166","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}