Acta Neuropathologica最新文献

{"title":"Correction: Pyroptosis in Alzheimer’s disease: cell type‑specific activation in microglia, astrocytes and neurons","authors":"Sebastiaan Moonen, Marta J. Koper, Evelien Van Schoor, Jolien M. Schaeverbeke, Rik Vandenberghe, Christine A. F. von Arnim, Thomas Tousseyn, Bart De Strooper, Dietmar Rudolf Thal","doi":"10.1007/s00401-024-02841-8","DOIUrl":"10.1007/s00401-024-02841-8","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875209","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":"Amyloid-β oligomers increase the binding and internalization of tau oligomers in human synapses","authors":"Shrinath Kadamangudi,&nbsp;Michela Marcatti,&nbsp;Wen-Ru Zhang,&nbsp;Anna Fracassi,&nbsp;Rakez Kayed,&nbsp;Agenor Limon,&nbsp;Giulio Taglialatela","doi":"10.1007/s00401-024-02839-2","DOIUrl":"10.1007/s00401-024-02839-2","url":null,"abstract":"<div><p>In Alzheimer’s disease (AD), the propagation and spreading of CNS tau pathology closely correlates with cognitive decline, positioning tau as an attractive therapeutic target. Amyloid beta (Aβ) has been strongly implicated in driving tau spread, whereas primary tauopathies such as primary age-related tauopathy (PART)—which lack Aβ pathology—exhibit limited tau spread and minimal-to-no cognitive decline. Emerging evidence converges on a trans-synaptic mechanism of tau spread, facilitated by the transfer of misfolded tau aggregates (e.g. soluble oligomers). However, it is unclear whether Aβ oligomers modulate the binding and internalization of tau oligomers in human synapses. Our translationally focused paradigms utilize post-mortem brain specimens from Control, PART, and AD patients. Synaptosomes isolated from the temporal cortex of all three groups were incubated with preformed recombinant tauO (rtauO), ± preformed recombinant AβO (rAβO), and oligomer binding/internalization was quantified via flow cytometry following proteinase K (PK) digestion of surface-bound oligomers. TauO-synapse interactions were visualized using EM immunogold. Brain-derived tau oligomers (BDTO) from AD and PART PBS-soluble hippocampal fractions were co-immunoprecipitated and analyzed via mass spectrometry to compare synaptic tauO interactomes in primary and secondary tauopathies, thereby inferring the role of Aβ. AD synaptosomes, enriched in endogenous Aβ pathology, exhibited increased rtauO internalization compared to PART synaptosomes. This observation was mirrored in Control synaptosomes, where recombinant rAβO significantly increased rtauO binding and internalization. PK pre-treatment abolished this effect, implicating synaptic membrane proteins in AβO-mediated tauO internalization. While both PART and AD BDTO were broadly enriched in synaptic proteins, AD BDTO exhibited differential enrichment of endocytic proteins across pre- and post-synaptic compartments, whereas PART BDTO showed no significant synaptic enrichment. This study demonstrates that Aβ oligomers enhance tau oligomer binding and drive its internalization through synaptic membrane proteins. These findings offer novel mechanistic insights underlying pathological tau spreading directly within human synapses and emphasize the therapeutic potential of targeting Aβ-tau interactions.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02839-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826128","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":"TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury","authors":"Beate Hartmannsberger,&nbsp;Adel Ben-Kraiem,&nbsp;Sofia Kramer,&nbsp;Carolina Guidolin,&nbsp;Ida Kazerani,&nbsp;Kathrin Doppler,&nbsp;Dominique Thomas,&nbsp;Robert Gurke,&nbsp;Marco Sisignano,&nbsp;Pranav P. Kalelkar,&nbsp;Andrés J. García,&nbsp;Paula V. Monje,&nbsp;Michael Sammeth,&nbsp;Asma Nusrat,&nbsp;Alexander Brack,&nbsp;Susanne M. Krug,&nbsp;Claudia Sommer,&nbsp;Heike L. Rittner","doi":"10.1007/s00401-024-02840-9","DOIUrl":"10.1007/s00401-024-02840-9","url":null,"abstract":"<div><p>Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify targets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers—perineurium, capillaries and myelin—only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was elevated in rats not only at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy, indicating that sealing of the vascular barrier might be a novel approach in pain treatment. Hydroxyeicosatetraenoic acid (15R-HETE), a precursor of aspirin-triggered lipoxin A4, was specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (<i>Cd206)</i> were boosted and fibrinolytic pathways (<i>Plat)</i> were induced, while inflammation (<i>Tnfα)</i> and inflammasomes (<i>Nlrp3)</i> were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2–Cd206–TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen and boosting pain resolution in patients with chronic neuropathic pain.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02840-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825154","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":"Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy","authors":"Kristen Whitney,&nbsp;Won-Min Song,&nbsp;Abhijeet Sharma,&nbsp;Diana K. Dangoor,&nbsp;Kurt Farrell,&nbsp;Margaret M. Krassner,&nbsp;Hadley W. Ressler,&nbsp;Thomas D. Christie,&nbsp;Shrishtee Kandoi,&nbsp;Ruth H. Walker,&nbsp;Melissa J. Nirenberg,&nbsp;Steven J. Frucht,&nbsp;Giulietta M. Riboldi,&nbsp;Bin Zhang,&nbsp;Ana C. Pereira,&nbsp;John F. Crary","doi":"10.1007/s00401-024-02823-w","DOIUrl":"10.1007/s00401-024-02823-w","url":null,"abstract":"<div><p>Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) and analyzed 50,708 high quality nuclei targeting the diencephalon, including the subthalamic nucleus and adjacent structures, from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type-specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was activated in multiple vulnerable cell types and validated in independent snRNA-seq and bulk RNA-seq datasets. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02823-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790311","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":"Neurodegeneration in the cortical sulcus is a feature of chronic traumatic encephalopathy and associated with repetitive head impacts","authors":"Raymond Nicks,&nbsp;Arsal Shah,&nbsp;Spiro Anthony Stathas,&nbsp;Daniel Kirsch,&nbsp;Sarah M. Horowitz,&nbsp;Nicole Saltiel,&nbsp;Samantha M. Calderazzo,&nbsp;Morgane L. M. D. Butler,&nbsp;Kerry A. Cormier,&nbsp;Nurgul Aytan,&nbsp;Fatima Tu-Zahra,&nbsp;Rebecca Mathias,&nbsp;Farwa Faheem,&nbsp;Suzie Marcus,&nbsp;Elizabeth Spurlock,&nbsp;Lucas Fishbein,&nbsp;Camille D. Esnault,&nbsp;Alexandra Boden,&nbsp;Grace Rosen,&nbsp;Weiming Xia,&nbsp;Sarah Daley,&nbsp;Gaoyuan Meng,&nbsp;Brett R. Martin,&nbsp;Daniel H. Daneshvar,&nbsp;Christopher J. Nowinski,&nbsp;Michael L. Alosco,&nbsp;Jesse Mez,&nbsp;Yorghos Tripodis,&nbsp;Bertrand R. Huber,&nbsp;Victor E. Alvarez,&nbsp;Jonathan D. Cherry,&nbsp;Ann C. McKee,&nbsp;Thor D. Stein","doi":"10.1007/s00401-024-02833-8","DOIUrl":"10.1007/s00401-024-02833-8","url":null,"abstract":"<div><p>Neurodegeneration is a seminal feature of many neurological disorders. Chronic traumatic encephalopathy (CTE) is caused by repetitive head impacts (RHI) and is characterized by sulcal tau pathology. However, quantitative assessments of regional neurodegeneration in CTE have not been described. In this study, we quantified three key neurodegenerative measures, including cortical thickness, neuronal density, and synaptic proteins, in contact sport athletes (<i>n</i> = 185) and non-athlete controls (<i>n</i> = 52) within the sulcal depth, middle, and gyral crest of the dorsolateral frontal cortex. Cortical thickness and neuronal density were decreased within the sulcus in CTE compared to controls (<i>p</i>’s &lt; 0.05). Measurements of synaptic proteins within the gyral crest showed a reduction of α-synuclein with CTE stage (<i>p</i> = 0.002) and variable changes in PSD-95 density. After adjusting for age, multiple linear regression models demonstrated a strong association between the duration of contact sports play and cortical thinning (<i>p</i> = 0.001) and neuronal loss (<i>p</i> = 0.032) within the sulcus. Additional regression models, adjusted for tau pathology, suggest that within the sulcus, the duration of play was associated with neuronal loss predominantly through tau pathology. In contrast, the association of duration of play with cortical thinning was minimally impacted by tau pathology. Overall, CTE is associated with cortical atrophy and a predominant sulcal neurodegeneration. Furthermore, the duration of contact sports play is associated with measures of neurodegeneration that are more severe in the cortical sulcus and may occur through tau-dependent and independent mechanisms.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02833-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788535","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 isoAsp7-Aβ as a major Aβ variant in Alzheimer’s disease, dementia with Lewy bodies and vascular dementia","authors":"Sarah Schrempel,&nbsp;Anna Katharina Kottwitz,&nbsp;Anke Piechotta,&nbsp;Kathrin Gnoth,&nbsp;Luca Büschgens,&nbsp;Maike Hartlage-Rübsamen,&nbsp;Markus Morawski,&nbsp;Mathias Schenk,&nbsp;Martin Kleinschmidt,&nbsp;Geidy E. Serrano,&nbsp;Thomas G. Beach,&nbsp;Agueda Rostagno,&nbsp;Jorge Ghiso,&nbsp;Michael T. Heneka,&nbsp;Jochen Walter,&nbsp;Oliver Wirths,&nbsp;Stephan Schilling,&nbsp;Steffen Roßner","doi":"10.1007/s00401-024-02824-9","DOIUrl":"10.1007/s00401-024-02824-9","url":null,"abstract":"<div><p>The formation of amyloid-β (Aβ) aggregates in brain is a neuropathological hallmark of Alzheimer’s disease (AD). However, there is mounting evidence that Aβ also plays a pathogenic role in other types of dementia and that specific post-translational Aβ modifications contribute to its pathogenic profile. The objective of this study was to test the hypothesis that distinct types of dementia are characterized by specific patterns of post-translationally modified Aβ variants. We conducted a comparative analysis and quantified Aβ as well as Aβ with pyroglutamate (pGlu3-Aβ and pGlu11-Aβ), N-truncation (Aβ(4-X)), isoaspartate racemization (isoAsp7-Aβ and isoAsp27-Aβ), phosphorylation (pSer8-Aβ and pSer26-Aβ) or nitration (3NTyr10-Aβ) modification in <i>post mortem</i> human brain tissue from non-demented control subjects in comparison to tissue classified as pre-symptomatic AD (Pre-AD), AD, dementia with Lewy bodies and vascular dementia. Aβ modification-specific immunohistochemical labelings of brain sections from the posterior superior temporal gyrus were examined by machine learning-based segmentation protocols and immunoassay analyses in brain tissue after sequential Aβ extraction were carried out. Our findings revealed that AD cases displayed the highest concentrations of all Aβ variants followed by dementia with Lewy bodies, Pre-AD, vascular dementia and non-demented controls. With both analytical methods, we identified the isoAsp7-Aβ variant as a highly abundant Aβ form in all clinical conditions, followed by Aβ(4-X), pGlu3-Aβ, pGlu11-Aβ and pSer8-Aβ. These Aβ variants were detected in distinct plaque types of compact, coarse-grained, cored and diffuse morphologies and, with varying frequencies, in cerebral blood vessels. The 3NTyr10-Aβ, pSer26-Aβ and isoAsp27-Aβ variants were not found to be present in Aβ plaques but were detected intraneuronally. There was a strong positive correlation between isoAsp7-Aβ and Thal phase and a moderate negative correlation between isoAsp7-Aβ and performance on the Mini Mental State Examination. Furthermore, the abundance of all Aβ variants was highest in APOE 3/4 carriers. In aggregation assays, the isoAsp7-Aβ, pGlu3-Aβ and pGlu11-Aβ variants showed instant fibril formation without lag phase, whereas Aβ(4-X), pSer26-Aβ and isoAsp27-Aβ did not form fibrils. We conclude that targeting Aβ post-translational modifications, and in particular the highly abundant isoAsp7-Aβ variant, might be considered for diagnostic and therapeutic approaches in different types of dementia. Hence, our findings might have implications for current antibody-based therapies of AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02824-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760066","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":"MN1 immunohistochemistry is a sensitive diagnostic biomarker for primitive CNS tumors with MN1 fusion","authors":"Roxane Daniel,&nbsp;Arnault Tauziède-Espariat,&nbsp;Alice Métais,&nbsp;Charlotte Berthaud,&nbsp;Noémie Pucelle,&nbsp;Joelle Lacombe,&nbsp;Aurélien Collard,&nbsp;Fabrice Chrétien,&nbsp;Pascale Varlet","doi":"10.1007/s00401-024-02827-6","DOIUrl":"10.1007/s00401-024-02827-6","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02827-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142757901","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":"Raphe and ventrolateral medulla proteomics in sudden unexplained death in childhood with febrile seizure history","authors":"Dominique F. Leitner,&nbsp;Christopher William,&nbsp;Arline Faustin,&nbsp;Evgeny Kanshin,&nbsp;Matija Snuderl,&nbsp;Declan McGuone,&nbsp;Thomas Wisniewski,&nbsp;Beatrix Ueberheide,&nbsp;Laura Gould,&nbsp;Orrin Devinsky","doi":"10.1007/s00401-024-02832-9","DOIUrl":"10.1007/s00401-024-02832-9","url":null,"abstract":"<div><p>Sudden unexplained death in childhood (SUDC) is death of a child ≥ 12 months old that is unexplained after autopsy and detailed analyses. Among SUDC cases, ~ 30% have febrile seizure (FS) history, versus 2–5% in the general population. SUDC cases share features with sudden unexpected death in epilepsy (SUDEP) and sudden infant death syndrome (SIDS), in which brainstem autonomic dysfunction is implicated. To understand whether brainstem protein changes are associated with FS history in SUDC, we performed label-free quantitative mass spectrometry on microdissected midbrain dorsal raphe, medullary raphe, and the ventrolateral medulla (n = 8 SUDC-noFS, n = 11 SUDC-FS). Differential expression analysis between SUDC-FS and SUDC-noFS at <i>p</i> &lt; 0.05 identified 178 altered proteins in dorsal raphe, 344 in medullary raphe, and 100 in the ventrolateral medulla. These proteins were most significantly associated with increased eukaryotic translation initiation (<i>p</i> = 3.09 × 10^–7, z = 1.00), eukaryotic translation elongation (<i>p</i> = 6.31 × 10^–49, z = 6.01), and coagulation system (<i>p</i> = 1.32 × 10^–5, z = 1.00). The medullary raphe had the strongest enrichment for altered signaling pathways, including with comparisons to three other brain regions previously analyzed (frontal cortex, hippocampal dentate gyrus, cornu ammonus). Immunofluorescent tissue analysis of serotonin receptors identified 2.1-fold increased 5HT2A in the medullary raphe of SUDC-FS (<i>p</i> = 0.025). Weighted gene correlation network analysis (WGCNA) of case history indicated that longer FS history duration significantly correlated with protein levels in the medullary raphe and ventrolateral medulla; the most significant gene ontology biological processes were decreased cellular respiration (<i>p</i> = 9.8 × 10^–5, corr = − 0.80) in medullary raphe and decreased synaptic vesicle cycle (<i>p</i> = 1.60 × 10^–7, corr = − 0.90) in the ventrolateral medulla. Overall, FS in SUDC was associated with more protein differences in the medullary raphe and was related with increased translation-related signaling pathways. Future studies should assess whether these changes result from FS or may in some way predispose to FS or SUDC.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02832-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142736851","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":"Elevated expression of the retrotransposon LINE-1 drives Alzheimer’s disease-associated microglial dysfunction","authors":"Nainika Roy,&nbsp;Imdadul Haq,&nbsp;Jason C. Ngo,&nbsp;David A. Bennett,&nbsp;Andrew F. Teich,&nbsp;Philip L. De Jager,&nbsp;Marta Olah,&nbsp;Falak Sher","doi":"10.1007/s00401-024-02835-6","DOIUrl":"10.1007/s00401-024-02835-6","url":null,"abstract":"<div><p>Aberrant activity of the retrotransposable element long interspersed nuclear element-1 (LINE-1) has been hypothesized to contribute to cellular dysfunction in age-related disorders, including late-onset Alzheimer’s disease (LOAD). However, whether LINE-1 is differentially expressed in cell types of the LOAD brain, and whether these changes contribute to disease pathology is largely unknown. Here, we examined patterns of LINE-1 expression across neurons, astrocytes, oligodendrocytes, and microglia in human postmortem prefrontal cortex tissue from LOAD patients and cognitively normal, age-matched controls. We report elevated immunoreactivity of the open reading frame 1 protein (ORF1p) encoded by LINE-1 in microglia from LOAD patients and find that this immunoreactivity correlates positively with disease-associated microglial morphology. In human iPSC-derived microglia (iMG), we found that CRISPR-mediated transcriptional activation of LINE-1 drives changes in microglial morphology and cytokine secretion and impairs the phagocytosis of amyloid beta (Aβ). We also find LINE-1 upregulation in iMG induces transcriptomic changes genes associated with antigen presentation and lipid metabolism as well as impacting the expression of many AD-relevant genes. Our data posit that heightened LINE-1 expression may trigger microglial dysregulation in LOAD and that these changes may contribute to disease pathogenesis, suggesting a central role for LINE-1 activity in human LOAD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02835-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737084","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":"Functional profiling of murine glioma models highlights targetable immune evasion phenotypes","authors":"Nicholas Mikolajewicz,&nbsp;Nazanin Tatari,&nbsp;Jiarun Wei,&nbsp;Neil Savage,&nbsp;Adrian Granda Farias,&nbsp;Vassil Dimitrov,&nbsp;David Chen,&nbsp;Zsolt Zador,&nbsp;Kuheli Dasgupta,&nbsp;Magali Aguilera-Uribe,&nbsp;Yu-Xi Xiao,&nbsp;Seon Yong Lee,&nbsp;Patricia Mero,&nbsp;Dillon McKenna,&nbsp;Chitra Venugopal,&nbsp;Kevin R. Brown,&nbsp;Hong Han,&nbsp;Sheila Singh,&nbsp;Jason Moffat","doi":"10.1007/s00401-024-02831-w","DOIUrl":"10.1007/s00401-024-02831-w","url":null,"abstract":"<div><p>Cancer-intrinsic immune evasion mechanisms and pleiotropy are a barrier to cancer immunotherapy. This is apparent in certain highly fatal cancers, including high-grade gliomas and glioblastomas (GBM). In this study, we evaluated two murine syngeneic glioma models (GL261 and CT2A) as preclinical models for human GBM using functional genetic screens, single-cell transcriptomics and machine learning approaches. Through CRISPR genome-wide co-culture killing screens with various immune cells (cytotoxic T cells, natural killer cells, and macrophages), we identified three key cancer-intrinsic evasion mechanisms: NFκB signaling, autophagy/endosome machinery, and chromatin remodeling. Additional fitness screens identified dependencies in murine gliomas that partially recapitulated those seen in human GBM (e.g., UFMylation). Our single-cell analyses showed that different glioma models exhibited distinct immune infiltration patterns and recapitulated key immune gene programs observed in human GBM, including hypoxia, interferon, and TNF signaling. Moreover, in vivo orthotopic tumor engraftment was associated with phenotypic shifts and changes in proliferative capacity, with murine tumors recapitulating the intratumoral heterogeneity observed in human GBM, exhibiting propensities for developmental- and mesenchymal-like phenotypes. Notably, we observed common transcription factors and cofactors shared with human GBM, including developmental (<i>Nfia</i> and <i>Tcf4</i>), mesenchymal (<i>Prrx1</i> and <i>Wwtr1</i>), as well as cycling-associated genes (<i>Bub3</i>, <i>Cenpa</i>, <i>Bard1</i>, <i>Brca1</i>, and <i>Mis18bp1</i>). Perturbation of these genes led to reciprocal phenotypic shifts suggesting intrinsic feedback mechanisms that balance in vivo cellular states. Finally, we used a machine-learning approach to identify two distinct immune evasion gene programs, one of which represents a clinically-relevant phenotype and delineates a subpopulation of stem-like glioma cells that predict response to immune checkpoint inhibition in human patients. This comprehensive characterization helps bridge the gap between murine glioma models and human GBM, providing valuable insights for future therapeutic development.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02831-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714639","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}