Acta Neuropathologica最新文献

{"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}

{"title":"Co-registration of MALDI-MSI and histology demonstrates gangliosides co-localize with amyloid beta plaques in Alzheimer’s disease","authors":"Nikita Ollen-Bittle,&nbsp;Shervin Pejhan,&nbsp;Stephen H. Pasternak,&nbsp;C. Dirk Keene,&nbsp;Qi Zhang,&nbsp;Shawn N. Whitehead","doi":"10.1007/s00401-024-02759-1","DOIUrl":"10.1007/s00401-024-02759-1","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is a progressive neurological condition characterized by impaired cognitive function and behavioral alterations. While AD research historically centered around mis-folded proteins, advances in mass spectrometry techniques have triggered increased exploration of the AD lipidome with lipid dysregulation emerging as a critical player in AD pathogenesis. Gangliosides are a class of glycosphingolipids enriched within the central nervous system. Previous work has suggested a shift in a-series gangliosides from complex (GM1) to simple (GM2 and GM3) species may be related to the development of neurodegenerative disease. In addition, complex gangliosides with 20 carbon sphingosine chains have been shown to increase in the aging brain. In this study, we utilized matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) to interrogate the in situ relationship of a-series gangliosides with either 18 or 20 carbon sphingosine chains (d18:1 or d20:1, respectively) in the post-mortem human AD brain. Here, we expanded upon previous literature and demonstrated a significant decrease in the GM1 d20:1 to GM1 d18:1 ratio in regions of the dentate gyrus and entorhinal cortex in AD relative to control brain tissue. Then, we demonstrated that the MALDI-MSI profile of GM3 co-localizes with histologically confirmed amyloid beta (Aβ) plaques and found a significant increase in both GM1 and GM3 in proximity to Aβ plaques. Collectively, this study demonstrates a perturbation of the ganglioside profile in AD, and validates a pipeline for MALDI-MSI and classic histological staining in the same tissue sections. This demonstrates feasibility for integrating untargeted mass spectrometry imaging approaches into a digital pathology framework.</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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417167","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}

{"title":"Annexin A11 aggregation in FTLD–TDP type C and related neurodegenerative disease proteinopathies","authors":"John L. Robinson,&nbsp;EunRan Suh,&nbsp;Yan Xu,&nbsp;Howard I. Hurtig,&nbsp;Lauren Elman,&nbsp;Corey T. McMillan,&nbsp;David J. Irwin,&nbsp;Sílvia Porta,&nbsp;Vivianna M. Van Deerlin,&nbsp;Edward B. Lee","doi":"10.1007/s00401-024-02753-7","DOIUrl":"10.1007/s00401-024-02753-7","url":null,"abstract":"<div><p>TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD–TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in <i>ANXA11</i>. Annexin A11 aggregation has not been described in sporadic ALS, FTLD–TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare <i>ANXA11</i> variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD–TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3–6%) of sporadic and genetic forms of FTLD–TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic <i>ANXA11</i> p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, <i>ANXA11</i> p.P75S. By immunoblot, FTLD–TDP with annexinopathy and <i>ANXA11</i> variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to <i>ANXA11</i> p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.</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/PMC11186923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417165","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":"Inter-alpha-trypsin inhibitor heavy chain H3 is a potential biomarker for disease activity in myasthenia gravis","authors":"Christina B. Schroeter,&nbsp;Christopher Nelke,&nbsp;Frauke Stascheit,&nbsp;Niklas Huntemann,&nbsp;Corinna Preusse,&nbsp;Vera Dobelmann,&nbsp;Lukas Theissen,&nbsp;Marc Pawlitzki,&nbsp;Saskia Räuber,&nbsp;Alice Willison,&nbsp;Anna Vogelsang,&nbsp;Adela Della Marina,&nbsp;Hans-Peter Hartung,&nbsp;Nico Melzer,&nbsp;Felix F. Konen,&nbsp;Thomas Skripuletz,&nbsp;Andreas Hentschel,&nbsp;Simone König,&nbsp;Michaela Schweizer,&nbsp;Kai Stühler,&nbsp;Gereon Poschmann,&nbsp;Andreas Roos,&nbsp;Werner Stenzel,&nbsp;Andreas Meisel,&nbsp;Sven G. Meuth,&nbsp;Tobias Ruck","doi":"10.1007/s00401-024-02754-6","DOIUrl":"10.1007/s00401-024-02754-6","url":null,"abstract":"<div><p>Myasthenia gravis is a chronic antibody-mediated autoimmune disease disrupting neuromuscular synaptic transmission. Informative biomarkers remain an unmet need to stratify patients with active disease requiring intensified monitoring and therapy; their identification is the primary objective of this study. We applied mass spectrometry-based proteomic serum profiling for biomarker discovery. We studied an exploration and a prospective validation cohort consisting of 114 and 140 anti-acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis patients, respectively. For downstream analysis, we applied a machine learning approach. Protein expression levels were confirmed by ELISA and compared to other myasthenic cohorts, in addition to myositis and neuropathy patients. Anti-AChR-Ab levels were determined by a radio receptor assay. Immunohistochemistry and immunofluorescence of intercostal muscle biopsies were employed for validation in addition to interactome studies of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3). Machine learning identified ITIH3 as potential serum biomarker reflective of disease activity. Serum levels correlated with disease activity scores in the exploration and validation cohort and were confirmed by ELISA. Lack of correlation between anti-AChR-Ab levels and clinical scores underlined the need for biomarkers. In a subgroup analysis, ITIH3 was indicative of treatment responses. Immunostaining of muscle specimens from these patients demonstrated ITIH3 localization at the neuromuscular endplates in myasthenia gravis but not in controls, thus providing a structural equivalent for our serological findings. Immunoprecipitation of ITIH3 and subsequent proteomics lead to identification of its interaction partners playing crucial roles in neuromuscular transmission. This study provides data on ITIH3 as a potential pathophysiological-relevant biomarker of disease activity in myasthenia gravis. Future studies are required to facilitate translation into clinical practice.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02754-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334429","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":"Brain vasculature accumulates tau and is spatially related to tau tangle pathology in Alzheimer’s disease","authors":"Zachary Hoglund,&nbsp;Nancy Ruiz-Uribe,&nbsp;Eric del Sastre,&nbsp;Benjamin Woost,&nbsp;Elizabeth Bader,&nbsp;Joshua Bailey,&nbsp;Bradley T. Hyman,&nbsp;Theodore Zwang,&nbsp;Rachel E. Bennett","doi":"10.1007/s00401-024-02751-9","DOIUrl":"10.1007/s00401-024-02751-9","url":null,"abstract":"<div><p>Insoluble pathogenic proteins accumulate along blood vessels in conditions of cerebral amyloid angiopathy (CAA), exerting a toxic effect on vascular cells and impacting cerebral homeostasis. In this work, we provide new evidence from three-dimensional human brain histology that tau protein, the main component of neurofibrillary tangles, can similarly accumulate along brain vascular segments. We quantitatively assessed n = 6 Alzheimer’s disease (AD), and n = 6 normal aging control brains and saw that tau-positive blood vessel segments were present in all AD cases. Tau-positive vessels are enriched for tau at levels higher than the surrounding tissue and appear to affect arterioles across cortical layers (I–V). Further, vessels isolated from these AD tissues were enriched for N-terminal tau and tau phosphorylated at T181 and T217. Importantly, tau-positive vessels are associated with local areas of increased tau neurofibrillary tangles. This suggests that accumulation of tau around blood vessels may reflect a local clearance failure. In sum, these data indicate that tau, like amyloid beta, accumulates along blood vessels and may exert a significant influence on vasculature in the setting of AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11182845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330046","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}