Acta Neuropathologica Communications最新文献

{"title":"Molecular profiling of pre- and post-treatment pediatric high-grade astrocytomas reveals acquired increased tumor mutation burden in a subset of recurrences.","authors":"Matthew D Wood, Carol Beadling, Tanaya Neff, Steve Moore, Christina A Harrington, Lissa Baird, Christopher Corless","doi":"10.1186/s40478-023-01644-4","DOIUrl":"10.1186/s40478-023-01644-4","url":null,"abstract":"<p><p>Diffuse gliomas are a heterogeneous category of primary central nervous system tumors. Due to their infiltrative growth precluding complete surgical resection, most diffuse high-grade gliomas are treated with adjuvant chemotherapy and radiation. Recurrent/progressive diffuse gliomas may show genetic differences when compared to the primary tumors, giving insight into their molecular evolution and mechanisms of treatment resistance. In adult-type diffuse gliomas with or without isocitrate dehydrogenase gene mutations, tumor recurrence/progression can be associated with mutations in genes encoding DNA mismatch repair proteins, leading to a dramatic increase in tumor mutation burden. This phenomenon is closely linked to treatment with the DNA alkylating agent temozolomide, a mainstay of adult diffuse glioma chemotherapeutic management. Post-treatment mismatch repair deficiency and acquired high tumor mutation burden is relatively unexplored in pediatric patients who have recurrent high-grade gliomas. Here, we report a molecular and histological analysis of an institutional cohort of eleven pediatric patients with paired initial and recurrent high-grade astrocytoma samples with intervening temozolomide treatment. We identified three cases with evidence for increased tumor mutation burden at recurrence, including two cases of diffuse hemispheric glioma H3 G34-mutant (one previously reported). We also show that molecular analysis by next-generation DNA sequencing and DNA methylation-based profiling enabled an integrated diagnosis per 2021 World Health Organization criteria in 10 of 11 cases (91%). Our findings indicate that increased tumor mutation burden at post-treatment recurrence is relevant in pediatric-type diffuse high-grade gliomas. Diffuse hemispheric glioma H3 G34-mutant may be particularly susceptible to this phenomenon.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"143"},"PeriodicalIF":7.1,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10481558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10180818","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":"Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease.","authors":"Jaemyung Jang, Seungeun Yeo, Soonbong Baek, Hyun Jin Jung, Mi Suk Lee, Seung Hee Choi, Youngshik Choe","doi":"10.1186/s40478-023-01637-3","DOIUrl":"10.1186/s40478-023-01637-3","url":null,"abstract":"<p><p>Dystrophic neurites (DNs) are abnormal axons and dendrites that are swollen or deformed in various neuropathological conditions. In Alzheimer's disease (AD), DNs play a crucial role in impairing neuronal communication and function, and they may also contribute to the accumulation and spread of amyloid beta (Aβ) in the brain of AD patients. However, it is still a challenge to understand the DNs of specific neurons that are vulnerable to Aβ in the pathogenesis of AD. To shed light on the development of radiating DNs, we examined enriched dystrophic hippocampal axons in a mouse model of AD using a three-dimensional rendering of projecting neurons. We employed the anterograde spread of adeno-associated virus (AAV)1 and conducted proteomic analysis of synaptic compartments obtained from hippocampo-septal regions. Our findings revealed that DNs were formed due to synaptic loss at the axon terminals caused by the accumulation of extracellular vesicle (EV). Abnormal EV-mediated transport and exocytosis were identified in association with primary cilia, indicating their involvement in the accumulation of EVs at presynaptic terminals. To further address the regulation of DNs by primary cilia, we conducted knockdown of the Ift88 gene in hippocampal neurons, which impaired EV-mediated secretion of Aβ and promoted accumulation of axonal spheroids. Using single-cell RNA sequencing, we identified the septal projecting hippocampal somatostatin neurons (SOM) as selectively vulnerable to Aβ with primary cilia dysfunction and vesicle accumulation. Our study suggests that DNs in AD are initiated by the ectopic accumulation of EVs at the neuronal axon terminals, which is affected by neuronal primary cilia.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"142"},"PeriodicalIF":7.1,"publicationDate":"2023-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10478284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10159699","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":"Novel histotypes of sporadic Creutzfeldt-Jakob disease linked to 129MV genotype.","authors":"Laura Cracco, Gianfranco Puoti, Antonio Cornacchia, Katie Glisic, Seong-Ki Lee, Zerui Wang, Mark L Cohen, Brian S Appleby, Ignazio Cali","doi":"10.1186/s40478-023-01631-9","DOIUrl":"10.1186/s40478-023-01631-9","url":null,"abstract":"<p><p>The MV1 and MV2 subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) are linked to the heterozygous methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene. MV2 is phenotypically heterogeneous, whereas MV1, due to its low prevalence, is one of the least well characterized subtypes. In this study, we investigated the biochemical properties of PrP^Sc and phenotypic expression of cases diagnosed as sCJD MV1 and MV2. We describe four MV2 histotypes: 2C, with cortical (C) coarse pathology; 2K, with kuru (K) plaque deposits; 2C-K, with co-existing C and K histotypic features; and the novel histotype 2C-PL that mimics 2C in the cerebral cortex and cerebellum, but exhibits plaque-like (PL) PrP deposits in subcortical regions (e.g., basal nuclei, thalamus and midbrain). Histotype prevalence is highest for 2C-K (55%), intermediate for 2C (31%), and lowest for 2C-PL and 2K (7%). Nearly every MV2 case expressed both PrP^Sc types, with T2 being the predominant type (\"MV2-1\"). MV1 cases typically show a rapid disease course (≤ 4 months), and feature the 1C histotype, phenotypically identical to sCJDMM1. Co-existing PrP^Sc types, with T1 significantly exceeding T2 (\"MV1-2\"), are detected in patients diagnosed as MV1 with longer disease courses. We observed four histotypes among MV1-2 cases, including two novel histotypes: 1V, reminiscent of sCJDVV1; 1C-2C, resembling sCJDMM1-2 with predominant MM1 histotypic component; and novel histotypes 1C-2PL and 1C-2K, overall mimicking 1C in the cerebral cortex, but harboring T2 and plaque-like PrP deposits in subcortical regions (1C-2PL), and T2 and kuru plaques in the cerebellum (1C-2K). Lesion profiles of 1C, 1V, and 1C-2C are similar, but differ from 1C-2PL and 1C-2K, as the latter two groups show prominent hippocampal and nigral degeneration. We believe that the novel \"C-PL\" histotypes are distinct entities rather than intermediate forms between \"C\" and \"C-K\" groups, and that 1C-2PL and 1C-2K histotypes may be characterized by different T1 variants of the same size.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"141"},"PeriodicalIF":6.2,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10469800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10157705","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":"Repeat length of C9orf72-associated glycine-alanine polypeptides affects their toxicity.","authors":"Javier Morón-Oset, Lilly Katharina Sophie Fischer, Nathalie Jauré, Pingze Zhang, Annika Julia Jahn, Tessa Supèr, André Pahl, Adrian M Isaacs, Sebastian Grönke, Linda Partridge","doi":"10.1186/s40478-023-01634-6","DOIUrl":"10.1186/s40478-023-01634-6","url":null,"abstract":"<p><p>G₄C₂ hexanucleotide repeat expansions in a non-coding region of the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). G₄C₂ insertion length is variable, and patients can carry up to several thousand repeats. Dipeptide repeat proteins (DPRs) translated from G₄C₂ transcripts are thought to be a main driver of toxicity. Experiments in model organisms with relatively short DPRs have shown that arginine-rich DPRs are most toxic, while polyGlycine-Alanine (GA) DPRs cause only mild toxicity. However, GA is the most abundant DPR in patient brains, and experimental work in animals has generally relied on the use of low numbers of repeats, with DPRs often tagged for in vivo tracking. Whether repeat length or tagging affect the toxicity of GA has not been systematically assessed. Therefore, we generated Drosophila fly lines expressing GA100, GA200 or GA400 specifically in adult neurons. Consistent with previous studies, expression of GA100 and GA200 caused only mild toxicity. In contrast, neuronal expression of GA400 drastically reduced climbing ability and survival of flies, indicating that long GA DPRs can be highly toxic in vivo. This toxicity could be abolished by tagging GA400. Proteomics analysis of fly brains showed a repeat-length-dependent modulation of the brain proteome, with GA400 causing earlier and stronger changes than shorter GA proteins. PolyGA expression up-regulated proteins involved in ER to Golgi trafficking, and down-regulated proteins involved in insulin signalling. Experimental down-regulation of Tango1, a highly conserved regulator of ER-to Golgi transport, partially rescued GA400 toxicity, suggesting that misregulation of this process contributes to polyGA toxicity. Experimentally increasing insulin signaling also rescued GA toxicity. In summary, our data show that long polyGA proteins can be highly toxic in vivo, and that they may therefore contribute to ALS/FTD pathogenesis in patients.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"140"},"PeriodicalIF":7.1,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10151393","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":"A neuropathologic feature of brain aging: multi-lumen vascular profiles.","authors":"Eseosa T Ighodaro, Ryan K Shahidehpour, Adam D Bachstetter, Erin L Abner, Ruth S Nelson, David W Fardo, Andy Y Shih, Roger I Grant, Janna H Neltner, Frederick A Schmitt, Gregory A Jicha, Richard J Kryscio, Donna M Wilcock, Linda J Van Eldik, Peter T Nelson","doi":"10.1186/s40478-023-01638-2","DOIUrl":"10.1186/s40478-023-01638-2","url":null,"abstract":"<p><p>Cerebrovascular pathologies other than frank infarctions are commonly seen in aged brains. Here, we focus on multi-lumen vascular profiles (MVPs), which are characterized by multiple vessel lumens enclosed in a single vascular channel. Little information exists on the prevalence, risk factors, and co-pathologies of MVPs. Therefore, we used samples and data from the University of Kentucky Alzheimer's Disease Research Center (n = 91), the University of Kentucky Pathology Department (n = 31), and the University of Pittsburgh Pathology Department (n = 4) to study MVPs. Age at death was correlated with MVP density in the frontal neocortex, Brodmann Area 9 (r = 0.51; p < 0.0001). Exploratory analyses were performed to evaluate the association between conventional vascular risk factors (e.g., hypertension, diabetes), cardiovascular diseases (e.g., heart attack, arrhythmia), and cerebrovascular disease (e.g., stroke); the only nominal association with MVP density was a self-reported history of brain trauma (Prevalence Ratio = 2.1; 95 CI 1.1-3.9, before correcting for multiple comparisons). No specific associations were detected between neuropathological (e.g., brain arteriolosclerosis) or genetic (e.g., APOE) variables and MVP density. Using a tissue clearing method called SeeDB, we provide 3-dimensional images of MVPs in brain tissue. We conclude that MVPs are an age-related brain pathology and more work is required to identify their clinical-pathological correlation and associated risk factors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"138"},"PeriodicalIF":7.1,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10126934","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":"MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value.","authors":"Henning Leske, Ulrike Camenisch Gross, Silvia Hofer, Marian Christoph Neidert, Sabine Leske, Michael Weller, Dirk Lehnick, Elisabeth Jane Rushing","doi":"10.1186/s40478-023-01622-w","DOIUrl":"10.1186/s40478-023-01622-w","url":null,"abstract":"<p><p>Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O⁶-methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"139"},"PeriodicalIF":7.1,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10126935","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":"Traumatic brain injury induces TDP-43 mislocalization and neurodegenerative effects in tissue distal to the primary injury site in a non-transgenic mouse.","authors":"George R Bjorklund, Jennifer Wong, David Brafman, Robert Bowser, Sarah E Stabenfeldt","doi":"10.1186/s40478-023-01625-7","DOIUrl":"10.1186/s40478-023-01625-7","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) initiates tissue and cellular damage to the brain that is immediately followed by secondary injury sequalae with delayed and continual damage. This secondary damage includes pathological processes that may contribute to chronic neurodegeneration and permanent functional and cognitive deficits. TBI is also associated with an increased risk of developing neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) as indicated by shared pathological features. For example, abnormalities in the TAR DNA-binding Protein 43 (TDP-43) that includes cytoplasmic mislocalization, cytosolic aggregation, and an increase in phosphorylation and ubiquitination are seen in up to 50% of FTD cases, up to 70% of AD cases, and is considered a hallmark pathology of ALS occurring in > 97% of cases. Yet the prevalence of TDP-43 pathology post-TBI has yet to be fully characterized. Here, we employed a non-transgenic murine controlled cortical injury model of TBI and observed injury-induced hallmark TDP-43 pathologies in brain and spinal cord tissue distal to the primary injury site and did not include the focally damaged tissue within the primary cortical injury site. Analysis revealed a temporal-dependent and significant increase in neuronal TDP-43 mislocalization in the cortical forebrain rostral to and distant from the primary injury site up to 180 days post injury (DPI). TDP-43 mislocalization was also detected in neurons located in the ventral horns of the cervical spinal cord following a TBI. Moreover, a cortical layer-dependent affect was identified, increasing from superficial to deeper cortical layers over time from 7 DPI up to 180 DPI. Lastly, RNAseq analysis confirmed an injury-induced misregulation of several key biological processes implicated in neurons that increased over time. Collectively, this study demonstrates a connection between a single moderate TBI event and chronic neurodegenerative processes that are not limited to the primary injury site and broadly distributed throughout the cortex and corticospinal tract.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"137"},"PeriodicalIF":7.1,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10117236","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":"Diagnostic accuracy of a minimal immunohistochemical panel in at/rt molecular subtyping, correlated to dna-methylation profiling.","authors":"Arnault Tauziède-Espariat, Julien Masliah-Planchon, Mamy Andrianteranagna, Philipp Sievers, Felix Sahm, Andreas von Deimling, Lauren Hasty, Olivier Delattre, Kévin Beccaria, Alice Métais, Fabrice Chrétien, Pascale Varlet, Franck Bourdeaut","doi":"10.1186/s40478-023-01630-w","DOIUrl":"10.1186/s40478-023-01630-w","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"136"},"PeriodicalIF":7.1,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10499827","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":"Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer's disease pathology in the 5xFAD mouse.","authors":"Simone M Crivelli, Zainuddin Quadri, Hemendra J Vekaria, Zhihui Zhu, Priyanka Tripathi, Ahmed Elsherbini, Liping Zhang, Patrick G Sullivan, Erhard Bieberich","doi":"10.1186/s40478-023-01633-7","DOIUrl":"10.1186/s40478-023-01633-7","url":null,"abstract":"<p><p>In Alzheimer's disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. Here, we show that Aβ-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine (C1q, TNF-α, IL-1α) release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. These EVs impeded the capacity of neurons to respond to energy demand. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia, prompting us to test the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. Brain derived-EVs from 5xFAD mice treated with Imipramine contained reduced levels of the astrocytic marker GFAP, ceramide, and Aβ and did not impair mitochondrial respiration when compared to EVs derived from untreated 5xFAD brain. Consistently, Imipramine-treated 5xFAD mice showed reduced AD pathology. Our study identifies A-SMase inhibitors as potential AD therapy by preventing cyotokine-elicited secretion of mitotoxic EVs from astrocytes.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"135"},"PeriodicalIF":6.2,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10481771","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":"Selective neuroimmune modulation by type I interferon drives neuropathology and neurologic dysfunction following traumatic brain injury.","authors":"Brittany P Todd, Zili Luo, Noah Gilkes, Michael S Chimenti, Zeru Peterson, Madison R Mix, John T Harty, Thomas Nickl-Jockschat, Polly J Ferguson, Alexander G Bassuk, Elizabeth A Newell","doi":"10.1186/s40478-023-01635-5","DOIUrl":"10.1186/s40478-023-01635-5","url":null,"abstract":"<p><p>Accumulating evidence suggests that type I interferon (IFN-I) signaling is a key contributor to immune cell-mediated neuropathology in neurodegenerative diseases. Recently, we demonstrated a robust upregulation of type I interferon-stimulated genes in microglia and astrocytes following experimental traumatic brain injury (TBI). The specific molecular and cellular mechanisms by which IFN-I signaling impacts the neuroimmune response and neuropathology following TBI remains unknown. Using the lateral fluid percussion injury model (FPI) in adult male mice, we demonstrated that IFN α/β receptor (IFNAR) deficiency resulted in selective and sustained blockade of type I interferon-stimulated genes following TBI as well as decreased microgliosis and monocyte infiltration. Molecular alteration of reactive microglia also occurred with diminished expression of genes needed for MHC class I antigen processing and presentation following TBI. This was associated with decreased accumulation of cytotoxic T cells in the brain. The IFNAR-dependent modulation of the neuroimmune response was accompanied by protection from secondary neuronal death, white matter disruption, and neurobehavioral dysfunction. These data support further efforts to leverage the IFN-I pathway for novel, targeted therapy of TBI.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"134"},"PeriodicalIF":6.2,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10436463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10145178","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}