{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T11:54:53Z","timestamp":1792756493421,"version":"4.5.0"},"reference-count":91,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T00:00:00Z","timestamp":1588809600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T00:00:00Z","timestamp":1588809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Prion diseases and prion-like disorders, including Alzheimer\u2019s disease and Parkinson\u2019s disease, are characterized by gliosis and accumulation of misfolded aggregated host proteins. Ablating microglia in prion-infected brain by treatment with the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, PLX5622, increased accumulation of misfolded prion protein and decreased survival time.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To better understand the role of glia during neurodegeneration, we used RNA-seq technology, network analysis, and hierarchical cluster analysis to compare gene expression in brains of prion-infected versus mock-inoculated mice. Comparisons were also made between PLX5622-treated prion-infected mice and untreated prion-infected mice to assess mechanisms involved in disease acceleration in the absence of microglia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>RNA-seq and network analysis suggested that microglia responded to prion infection through activation of integrin CD11c\/18 and did not adopt the expression signature associated with other neurodegenerative disease models. Instead, microglia acquired an alternative molecular signature late in the disease process. Furthermore, astrocytes expressed a signature pattern of genes which appeared to be specific for prion diseases. Comparisons were also made with prion-infected mice treated with PLX5622 to assess the impact of microglia ablation on astrocyte gene expression during prion infection. In the presence of microglia, a unique mix of transcripts associated with A1- and A2-reactive astrocytes was increased in brains of prion-infected mice. After ablation of microglia, this reactive astrocyte expression pattern was enhanced. Thus, after prion infection, microglia appeared to decrease the overall A1\/A2-astrocyte responses which might contribute to increased survival after infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>RNA-seq analysis indicated dysregulation of over 300 biological processes within the CNS during prion disease. Distinctive microglia- and astrocyte-associated expression signatures were identified during prion infection. Furthermore, astrogliosis and the unique astrocyte-associated expression signature were independent of microglial influences. Astrogliosis and the unique astrocyte-associated gene expression pattern were increased when microglia were ablated. Our findings emphasize the potential existence of alternative pathways for activating the A1\/A2 paradigm in astrocytes during neurodegenerative disease.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13041-020-00610-8","type":"journal-article","created":{"date-parts":[[2020,5,7]],"date-time":"2020-05-07T12:02:57Z","timestamp":1588852977000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["RNA-seq and network analysis reveal unique glial gene expression signatures during prion infection"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4329-1488","authenticated-orcid":false,"given":"James A.","family":"Carroll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent","family":"Race","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Striebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Chesebro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,7]]},"reference":[{"key":"610_CR1","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1146\/annurev-neuro-071714-033828","volume":"38","author":"LC Walker","year":"2015","unstructured":"Walker LC, Jucker M. Neurodegenerative diseases: expanding the prion concept. Annu Rev Neurosci. 2015;38:87\u2013103.","journal-title":"Annu Rev Neurosci"},{"key":"610_CR2","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1146\/annurev.neuro.26.010302.081142","volume":"26","author":"B Caughey","year":"2003","unstructured":"Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003;26:267\u201398.","journal-title":"Annu Rev Neurosci"},{"key":"610_CR3","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1146\/annurev-micro-092412-155735","volume":"67","author":"A Kraus","year":"2013","unstructured":"Kraus A, Groveman BR, Caughey B. Prions and the potential transmissibility of protein misfolding diseases. Annu Rev Microbiol. 2013;67:543\u201364.","journal-title":"Annu Rev Microbiol"},{"key":"610_CR4","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1126\/science.1675487","volume":"252","author":"SB Prusiner","year":"1991","unstructured":"Prusiner SB. Molecular biology of prion diseases. Science. 1991;252:1515\u201322.","journal-title":"Science."},{"key":"610_CR5","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1146\/annurev.biochem.78.082907.145410","volume":"78","author":"B Caughey","year":"2009","unstructured":"Caughey B, Baron GS, Chesebro B, Jeffrey M. Getting a grip on prions: oligomers, amyloids, and pathological membrane interactions. Annu Rev Biochem. 2009;78:177\u2013204.","journal-title":"Annu Rev Biochem"},{"key":"610_CR6","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1006\/exnr.1997.6424","volume":"144","author":"A Williams","year":"1997","unstructured":"Williams A, Lucassen PJ, Ritchie D, Bruce M. PrP deposition, microglial activation, and neuronal apoptosis in murine scrapie. Exp Neurol. 1997;144:433\u20138.","journal-title":"Exp Neurol"},{"key":"610_CR7","doi-asserted-by":"publisher","first-page":"3459","DOI":"10.1099\/vir.0.80110-0","volume":"85","author":"S Booth","year":"2004","unstructured":"Booth S, Bowman C, Baumgartner R, Sorensen G, Robertson C, Coulthart M, et al. Identification of central nervous system genes involved in the host response to the scrapie agent during preclinical and clinical infection. J Gen Virol. 2004;85:3459\u201371.","journal-title":"J Gen Virol"},{"key":"610_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nm.4269","volume":"23","author":"YC Wong","year":"2017","unstructured":"Wong YC, Krainc D. alpha-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med. 2017;23:1\u201313.","journal-title":"Nat Med"},{"key":"610_CR9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/1742-2094-9-47","volume":"9","author":"N Zilka","year":"2012","unstructured":"Zilka N, Kazmerova Z, Jadhav S, Neradil P, Madari A, Obetkova D, et al. Who fans the flames of Alzheimer\u2019s disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways. J Neuroinflammation. 2012;9:47.","journal-title":"J Neuroinflammation"},{"key":"610_CR10","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/s00401-009-0499-y","volume":"118","author":"N Zilka","year":"2009","unstructured":"Zilka N, Korenova M, Novak M. Misfolded tau protein and disease modifying pathways in transgenic rodent models of human tauopathies. Acta Neuropathol. 2009;118:71\u201386.","journal-title":"Acta Neuropathol"},{"key":"610_CR11","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1126\/science.aag2590","volume":"353","author":"RM Ransohoff","year":"2016","unstructured":"Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353:777\u201383.","journal-title":"Science."},{"key":"610_CR12","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1111\/imm.12233","volume":"142","author":"S Amor","year":"2014","unstructured":"Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, et al. Inflammation in neurodegenerative diseases--an update. Immunology. 2014;142:151\u201366.","journal-title":"Immunology."},{"key":"610_CR13","doi-asserted-by":"publisher","first-page":"e00549","DOI":"10.1128\/JVI.00549-18","volume":"92","author":"JA Carroll","year":"2018","unstructured":"Carroll JA, Race B, Williams K, Striebel J, Chesebro B. Microglia are critical in host defense against prion disease. J Virol. 2018;92:e00549.","journal-title":"J Virol"},{"key":"610_CR14","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.immuni.2017.08.008","volume":"47","author":"S Krasemann","year":"2017","unstructured":"Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47:566\u201381 e9.","journal-title":"Immunity."},{"key":"610_CR15","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/j.immuni.2017.06.006","volume":"46","author":"SA Liddelow","year":"2017","unstructured":"Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46:957\u201367.","journal-title":"Immunity."},{"key":"610_CR16","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature21029","volume":"541","author":"SA Liddelow","year":"2017","unstructured":"Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481\u20137.","journal-title":"Nature."},{"key":"610_CR17","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/s41593-019-0367-6","volume":"22","author":"SA Liddelow","year":"2019","unstructured":"Liddelow SA, Sofroniew MV. Astrocytes usurp neurons as a disease focus. Nat Neurosci. 2019;22:512\u20133.","journal-title":"Nat Neurosci"},{"key":"610_CR18","doi-asserted-by":"publisher","first-page":"6391","DOI":"10.1523\/JNEUROSCI.6221-11.2012","volume":"32","author":"JL Zamanian","year":"2012","unstructured":"Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32:6391\u2013410.","journal-title":"J Neurosci"},{"key":"610_CR19","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s40478-019-0735-1","volume":"7","author":"K Hartmann","year":"2019","unstructured":"Hartmann K, Sepulveda-Falla D, Rose IVL, Madore C, Muth C, Matschke J, et al. Complement 3(+)-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia. Acta Neuropathol Commun. 2019;7:83.","journal-title":"Acta Neuropathol Commun"},{"key":"610_CR20","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.neuron.2014.02.040","volume":"82","author":"MR Elmore","year":"2014","unstructured":"Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014;82:380\u201397.","journal-title":"Neuron."},{"key":"610_CR21","doi-asserted-by":"publisher","first-page":"e0122912","DOI":"10.1371\/journal.pone.0122912","volume":"10","author":"MR Elmore","year":"2015","unstructured":"Elmore MR, Lee RJ, West BL, Green KN. Characterizing newly repopulated microglia in the adult mouse: impacts on animal behavior, cell morphology, and neuroinflammation. PLoS One. 2015;10:e0122912.","journal-title":"PLoS One"},{"key":"610_CR22","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1186\/s12974-015-0366-9","volume":"12","author":"NN Dagher","year":"2015","unstructured":"Dagher NN, Najafi AR, Kayala KM, Elmore MR, White TE, Medeiros R, et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J Neuroinflammation. 2015;12:139.","journal-title":"J Neuroinflammation"},{"key":"610_CR23","doi-asserted-by":"publisher","first-page":"10","DOI":"10.14806\/ej.17.1.200","volume":"17","author":"M Martin","year":"2011","unstructured":"Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. Embnet J. 2011;17:10\u20132.","journal-title":"Embnet J"},{"key":"610_CR24","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","volume":"12","author":"D Kim","year":"2015","unstructured":"Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12:357\u201360.","journal-title":"Nat Methods"},{"key":"610_CR25","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/nbt.3122","volume":"33","author":"M Pertea","year":"2015","unstructured":"Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 2015;33:290\u20135.","journal-title":"Nat Biotechnol"},{"key":"610_CR26","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/nbt.3172","volume":"33","author":"AC Frazee","year":"2015","unstructured":"Frazee AC, Pertea G, Jaffe AE, Langmead B, Salzberg SL, Leek JT. Ballgown bridges the gap between transcriptome assembly and expression analysis. Nat Biotechnol. 2015;33:243\u20136.","journal-title":"Nat Biotechnol"},{"key":"610_CR27","doi-asserted-by":"publisher","first-page":"W147","DOI":"10.1093\/nar\/gkw419","volume":"44","author":"S Babicki","year":"2016","unstructured":"Babicki S, Arndt D, Marcu A, Liang Y, Grant JR, Maciejewski A, et al. Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res. 2016;44:W147\u201353.","journal-title":"Nucleic Acids Res"},{"key":"610_CR28","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","volume":"47","author":"D Szklarczyk","year":"2019","unstructured":"Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607\u2013D13.","journal-title":"Nucleic Acids Res"},{"key":"610_CR29","doi-asserted-by":"publisher","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","volume":"34","author":"Y Zhang","year":"2014","unstructured":"Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929\u201347.","journal-title":"J Neurosci"},{"key":"610_CR30","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(\u2212Delta Delta C(T)) method. Methods. 2001;25:402\u20138.","journal-title":"Methods."},{"key":"610_CR31","doi-asserted-by":"publisher","first-page":"10340","DOI":"10.1128\/JVI.00865-07","volume":"81","author":"L Kercher","year":"2007","unstructured":"Kercher L, Favara C, Striebel JF, LaCasse R, Chesebro B. Prion protein expression differences in microglia and astroglia influence scrapie-induced neurodegeneration in the retina and brain of transgenic mice. J Virol. 2007;81:10340\u201351.","journal-title":"J Virol"},{"key":"610_CR32","doi-asserted-by":"publisher","first-page":"R14","DOI":"10.1186\/gb-2010-11-2-r14","volume":"11","author":"MD Young","year":"2010","unstructured":"Young MD, Wakefield MJ, Smyth GK, Oshlack A. Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol. 2010;11:R14.","journal-title":"Genome Biol"},{"key":"610_CR33","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.neuron.2006.01.033","volume":"49","author":"U Schulte","year":"2006","unstructured":"Schulte U, Thumfart JO, Klocker N, Sailer CA, Bildl W, Biniossek M, et al. The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron. 2006;49:697\u2013706.","journal-title":"Neuron."},{"key":"610_CR34","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/S0092-8674(00)81736-5","volume":"94","author":"S Butz","year":"1998","unstructured":"Butz S, Okamoto M, Sudhof TC. A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell. 1998;94:773\u201382.","journal-title":"Cell."},{"key":"610_CR35","doi-asserted-by":"publisher","first-page":"3003","DOI":"10.1128\/JVI.02613-15","volume":"90","author":"JE Vincenti","year":"2015","unstructured":"Vincenti JE, Murphy L, Grabert K, McColl BW, Cancellotti E, Freeman TC, et al. Defining the microglia response during the time course of chronic neurodegeneration. J Virol. 2015;90:3003\u201317.","journal-title":"J Virol"},{"key":"610_CR36","doi-asserted-by":"publisher","first-page":"3230","DOI":"10.1172\/JCI90605","volume":"127","author":"A Aguzzi","year":"2017","unstructured":"Aguzzi A, Zhu C. Microglia in prion diseases. J Clin Invest. 2017;127:3230\u20139.","journal-title":"J Clin Invest"},{"key":"610_CR37","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1046\/j.1471-4159.1995.65010010.x","volume":"65","author":"N Schaeren-Wiemers","year":"1995","unstructured":"Schaeren-Wiemers N, Schaefer C, Valenzuela DM, Yancopoulos GD, Schwab ME. Identification of new oligodendrocyte- and myelin-specific genes by a differential screening approach. J Neurochem. 1995;65:10\u201322.","journal-title":"J Neurochem"},{"key":"610_CR38","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1002\/jnr.490420316","volume":"42","author":"T Kim","year":"1995","unstructured":"Kim T, Fiedler K, Madison DL, Krueger WH, Pfeiffer SE. Cloning and characterization of MVP17: a developmentally regulated myelin protein in oligodendrocytes. J Neurosci Res. 1995;42:413\u201322.","journal-title":"J Neurosci Res"},{"key":"610_CR39","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/S0301-0082(99)00039-8","volume":"60","author":"M Frank","year":"2000","unstructured":"Frank M. MAL, a proteolipid in glycosphingolipid enriched domains: functional implications in myelin and beyond. Prog Neurobiol. 2000;60:531\u201344.","journal-title":"Prog Neurobiol"},{"key":"610_CR40","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.semcdb.2017.11.025","volume":"85","author":"A Erdei","year":"2019","unstructured":"Erdei A, Lukacsi S, Macsik-Valent B, Nagy-Balo Z, Kurucz I, Bajtay Z. Non-identical twins: different faces of CR3 and CR4 in myeloid and lymphoid cells of mice and men. Semin Cell Dev Biol. 2019;85:110\u201321.","journal-title":"Semin Cell Dev Biol"},{"key":"610_CR41","doi-asserted-by":"publisher","first-page":"5928","DOI":"10.4049\/jimmunol.164.11.5928","volume":"164","author":"R Garnotel","year":"2000","unstructured":"Garnotel R, Rittie L, Poitevin S, Monboisse JC, Nguyen P, Potron G, et al. Human blood monocytes interact with type I collagen through alpha x beta 2 integrin (CD11c-CD18, gp150-95). J Immunol. 2000;164:5928\u201334.","journal-title":"J Immunol"},{"key":"610_CR42","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/978-1-4419-8632-0_41","volume":"419","author":"M Vaughan","year":"1997","unstructured":"Vaughan M, Moss J. Activation of toxin ADP-ribosyltransferases by the family of ADP-ribosylation factors. Adv Exp Med Biol. 1997;419:315\u201320.","journal-title":"Adv Exp Med Biol"},{"key":"610_CR43","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1023\/A:1006993000870","volume":"193","author":"J Moss","year":"1999","unstructured":"Moss J, Vaughan M. Activation of toxin ADP-ribosyltransferases by eukaryotic ADP-ribosylation factors. Mol Cell Biochem. 1999;193:153\u20137.","journal-title":"Mol Cell Biochem"},{"key":"610_CR44","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1007\/s12035-009-8076-x","volume":"40","author":"SI Tomarev","year":"2009","unstructured":"Tomarev SI, Nakaya N. Olfactomedin domain-containing proteins: possible mechanisms of action and functions in normal development and pathology. Mol Neurobiol. 2009;40:122\u201338.","journal-title":"Mol Neurobiol"},{"key":"610_CR45","doi-asserted-by":"publisher","first-page":"e1005551","DOI":"10.1371\/journal.ppat.1005551","volume":"12","author":"JA Carroll","year":"2016","unstructured":"Carroll JA, Striebel JF, Rangel A, Woods T, Phillips K, Peterson KE, et al. Prion strain differences in accumulation of PrPSc on neurons and glia are associated with similar expression profiles of neuroinflammatory genes: comparison of three prion strains. PLoS Pathog. 2016;12:e1005551.","journal-title":"PLoS Pathog"},{"key":"610_CR46","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/1742-2094-11-70","volume":"11","author":"LB Christensen","year":"2014","unstructured":"Christensen LB, Woods TA, Carmody AB, Caughey B, Peterson KE. Age-related differences in neuroinflammatory responses associated with a distinct profile of regulatory markers on neonatal microglia. J Neuroinflammation. 2014;11:70.","journal-title":"J Neuroinflammation"},{"key":"610_CR47","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1038\/nn.3599","volume":"17","author":"O Butovsky","year":"2014","unstructured":"Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17:131\u201343.","journal-title":"Nat Neurosci"},{"key":"610_CR48","doi-asserted-by":"publisher","first-page":"E2987","DOI":"10.1073\/pnas.1320401111","volume":"111","author":"W Kang","year":"2014","unstructured":"Kang W, Balordi F, Su N, Chen L, Fishell G, Hebert JM. Astrocyte activation is suppressed in both normal and injured brain by FGF signaling. Proc Natl Acad Sci U S A. 2014;111:E2987\u201395.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"610_CR49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0306-4522(96)00212-6","volume":"74","author":"S Betmouni","year":"1996","unstructured":"Betmouni S, Perry VH, Gordon JL. Evidence for an early inflammatory response in the central nervous system of mice with scrapie. Neuroscience. 1996;74:1\u20135.","journal-title":"Neuroscience."},{"key":"610_CR50","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1016\/j.neurobiolaging.2006.07.022","volume":"28","author":"CC Stichel","year":"2007","unstructured":"Stichel CC, Luebbert H. Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells. Neurobiol Aging. 2007;28:1507\u201321.","journal-title":"Neurobiol Aging"},{"key":"610_CR51","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1111\/j.1365-2990.2012.01306.x","volume":"39","author":"DM Norden","year":"2013","unstructured":"Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol. 2013;39:19\u201334.","journal-title":"Neuropathol Appl Neurobiol"},{"key":"610_CR52","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s40478-015-0203-5","volume":"3","author":"IR Holtman","year":"2015","unstructured":"Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun. 2015;3:31.","journal-title":"Acta Neuropathol Commun"},{"key":"610_CR53","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S0165-5728(02)00184-4","volume":"129","author":"G Reichmann","year":"2002","unstructured":"Reichmann G, Schroeter M, Jander S, Fischer HG. Dendritic cells and dendritic-like microglia in focal cortical ischemia of the mouse brain. J Neuroimmunol. 2002;129:125\u201332.","journal-title":"J Neuroimmunol"},{"key":"610_CR54","first-page":"1847","volume":"2016","author":"W Kamphuis","year":"1862","unstructured":"Kamphuis W, Kooijman L, Schetters S, Orre M, Hol EM. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer\u2019s disease. Biochim Biophys Acta. 1862;2016:1847\u201360.","journal-title":"Biochim Biophys Acta"},{"key":"610_CR55","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1016\/j.cell.2015.01.049","volume":"160","author":"Y Wang","year":"2015","unstructured":"Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015;160:1061\u201371.","journal-title":"Cell."},{"key":"610_CR56","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1186\/gb-2007-8-5-215","volume":"8","author":"Y Takada","year":"2007","unstructured":"Takada Y, Ye X, Simon S. The integrins. Genome Biol. 2007;8:215.","journal-title":"Genome Biol"},{"key":"610_CR57","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/0014-4827(92)90170-D","volume":"200","author":"GE Davis","year":"1992","unstructured":"Davis GE. The Mac-1 and p150,95 beta 2 integrins bind denatured proteins to mediate leukocyte cell-substrate adhesion. Exp Cell Res. 1992;200:242\u201352.","journal-title":"Exp Cell Res"},{"key":"610_CR58","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.1016\/j.neurobiolaging.2015.02.019","volume":"36","author":"C Zhu","year":"2015","unstructured":"Zhu C, Herrmann US, Li B, Abakumova I, Moos R, Schwarz P, et al. Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains. Neurobiol Aging. 2015;36:1994\u20132003.","journal-title":"Neurobiol Aging"},{"key":"610_CR59","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1212\/WNL.47.2.449","volume":"47","author":"J Tatzelt","year":"1996","unstructured":"Tatzelt J, Maeda N, Pekny M, Yang SL, Betsholtz C, Eliasson C, et al. Scrapie in mice deficient in apolipoprotein E or glial fibrillary acidic protein. Neurology. 1996;47:449\u201353.","journal-title":"Neurology."},{"key":"610_CR60","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/s41591-018-0051-5","volume":"24","author":"SP Yun","year":"2018","unstructured":"Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson\u2019s disease. Nat Med. 2018;24:931\u20138.","journal-title":"Nat Med"},{"key":"610_CR61","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.neuron.2014.11.018","volume":"85","author":"H Lian","year":"2015","unstructured":"Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, et al. NFkappaB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease. Neuron. 2015;85:101\u201315.","journal-title":"Neuron."},{"key":"610_CR62","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/s40478-019-0767-6","volume":"7","author":"J Jin","year":"2019","unstructured":"Jin J, Smith MD, Kersbergen CJ, Kam TI, Viswanathan M, Martin K, et al. Glial pathology and retinal neurotoxicity in the anterior visual pathway in experimental autoimmune encephalomyelitis. Acta Neuropathol Commun. 2019;7:125.","journal-title":"Acta Neuropathol Commun"},{"key":"610_CR63","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1083\/jcb.200406092","volume":"166","author":"N Schaeren-Wiemers","year":"2004","unstructured":"Schaeren-Wiemers N, Bonnet A, Erb M, Erne B, Bartsch U, Kern F, et al. The raft-associated protein MAL is required for maintenance of proper axon--glia interactions in the central nervous system. J Cell Biol. 2004;166:731\u201342.","journal-title":"J Cell Biol"},{"key":"610_CR64","doi-asserted-by":"publisher","first-page":"13280","DOI":"10.1073\/pnas.93.23.13280","volume":"93","author":"A Bosio","year":"1996","unstructured":"Bosio A, Binczek E, Stoffel W. Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebroside synthesis. Proc Natl Acad Sci U S A. 1996;93:13280\u20135.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"610_CR65","volume-title":"Essentials of glycobiology","author":"RL Schnaar","year":"2009","unstructured":"Schnaar RL, Suzuki A, Stanley P. Glycosphingolipids. In: Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Etzler ME, editors. Essentials of glycobiology. New York: Cold Spring Harbor; 2009."},{"key":"610_CR66","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1523\/JNEUROSCI.4317-05.2006","volume":"26","author":"D Brockschnieder","year":"2006","unstructured":"Brockschnieder D, Sabanay H, Riethmacher D, Peles E. Ermin, a myelinating oligodendrocyte-specific protein that regulates cell morphology. J Neurosci. 2006;26:757\u201362.","journal-title":"J Neurosci"},{"key":"610_CR67","doi-asserted-by":"publisher","first-page":"11527","DOI":"10.1073\/pnas.0500952102","volume":"102","author":"B Zhang","year":"2005","unstructured":"Zhang B, Cao Q, Guo A, Chu H, Chan YG, Buschdorf JP, et al. Juxtanodin: an oligodendroglial protein that promotes cellular arborization and 2\u2032,3\u2032-cyclic nucleotide-3\u2032-phosphodiesterase trafficking. Proc Natl Acad Sci U S A. 2005;102:11527\u201332.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"610_CR68","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1111\/j.1750-3639.1998.tb00175.x","volume":"8","author":"A Dorandeu","year":"1998","unstructured":"Dorandeu A, Wingertsmann L, Chretien F, Delisle MB, Vital C, Parchi P, et al. Neuronal apoptosis in fatal familial insomnia. Brain Pathol. 1998;8:531\u20137.","journal-title":"Brain Pathol"},{"key":"610_CR69","first-page":"283","volume":"37","author":"D Jesionek-Kupnicka","year":"1999","unstructured":"Jesionek-Kupnicka D, Buczynski J, Kordek R, Liberski PP. Neuronal loss and apoptosis in experimental Creutzfeldt-Jakob disease in mice. Folia Neuropathol. 1999;37:283\u20136.","journal-title":"Folia Neuropathol"},{"key":"610_CR70","doi-asserted-by":"crossref","first-page":"13","DOI":"10.55782\/ane-2001-1379","volume":"61","author":"D Jesionek-Kupnicka","year":"2001","unstructured":"Jesionek-Kupnicka D, Kordek R, Buczynski J, Liberski PP. Apoptosis in relation to neuronal loss in experimental Creutzfeldt-Jakob disease in mice. Acta Neurobiol Exp (Wars). 2001;61:13\u20139.","journal-title":"Acta Neurobiol Exp (Wars)"},{"key":"610_CR71","doi-asserted-by":"publisher","first-page":"e5","DOI":"10.1017\/erm.2016.8","volume":"18","author":"P Saa","year":"2016","unstructured":"Saa P, Harris DA, Cervenakova L. Mechanisms of prion-induced neurodegeneration. Expert Rev Mol Med. 2016;18:e5.","journal-title":"Expert Rev Mol Med"},{"key":"610_CR72","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1042\/bj20021918","volume":"373","author":"M Pignatelli","year":"2003","unstructured":"Pignatelli M, Luna-Medina R, Perez-Rendon A, Santos A, Perez-Castillo A. The transcription factor early growth response factor-1 (EGR-1) promotes apoptosis of neuroblastoma cells. Biochem J. 2003;373:739\u201346.","journal-title":"Biochem J"},{"key":"610_CR73","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1083\/jcb.127.6.1717","volume":"127","author":"S Estus","year":"1994","unstructured":"Estus S, Zaks WJ, Freeman RS, Gruda M, Bravo R, Johnson EM Jr. Altered gene expression in neurons during programmed cell death: identification of c-Jun as necessary for neuronal apoptosis. J Cell Biol. 1994;127:1717\u201327.","journal-title":"J Cell Biol"},{"key":"610_CR74","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1093\/emboj\/16.7.1695","volume":"16","author":"E Bossy-Wetzel","year":"1997","unstructured":"Bossy-Wetzel E, Bakiri L, Yaniv M. Induction of apoptosis by the transcription factor c-Jun. EMBO J. 1997;16:1695\u2013709.","journal-title":"EMBO J"},{"key":"610_CR75","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1242\/jcs.002063","volume":"120","author":"L Coultas","year":"2007","unstructured":"Coultas L, Terzano S, Thomas T, Voss A, Reid K, Stanley EG, et al. Hrk\/DP5 contributes to the apoptosis of select neuronal populations but is dispensable for haematopoietic cell apoptosis. J Cell Sci. 2007;120:2044\u201352.","journal-title":"J Cell Sci"},{"key":"610_CR76","doi-asserted-by":"publisher","first-page":"30901","DOI":"10.1074\/jbc.M608694200","volume":"282","author":"C Ma","year":"2007","unstructured":"Ma C, Ying C, Yuan Z, Song B, Li D, Liu Y, et al. dp5\/HRK is a c-Jun target gene and required for apoptosis induced by potassium deprivation in cerebellar granule neurons. J Biol Chem. 2007;282:30901\u20139.","journal-title":"J Biol Chem"},{"key":"610_CR77","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1093\/emboj\/16.7.1686","volume":"16","author":"N Inohara","year":"1997","unstructured":"Inohara N, Ding L, Chen S, Nunez G. Harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J. 1997;16:1686\u201394.","journal-title":"EMBO J"},{"key":"610_CR78","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s13041-020-0551-3","volume":"13","author":"TK Kim","year":"2020","unstructured":"Kim TK, Lee I, Cho JH, Canine B, Keller A, Price ND, et al. Core transcriptional regulatory circuits in prion diseases. Mol Brain. 2020;13:10.","journal-title":"Mol Brain"},{"key":"610_CR79","doi-asserted-by":"publisher","first-page":"2311","DOI":"10.1111\/j.1460-9568.2005.04080.x","volume":"21","author":"J Carimalo","year":"2005","unstructured":"Carimalo J, Cronier S, Petit G, Peyrin JM, Boukhtouche F, Arbez N, et al. Activation of the JNK-c-Jun pathway during the early phase of neuronal apoptosis induced by PrP106-126 and prion infection. Eur J Neurosci. 2005;21:2311\u20139.","journal-title":"Eur J Neurosci"},{"key":"610_CR80","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1515\/BC.2007.064","volume":"388","author":"V Stoka","year":"2007","unstructured":"Stoka V, Turk V, Turk B. Lysosomal cysteine cathepsins: signaling pathways in apoptosis. Biol Chem. 2007;388:555\u201360.","journal-title":"Biol Chem"},{"key":"610_CR81","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/0896-6273(95)90324-0","volume":"14","author":"AM Cataldo","year":"1995","unstructured":"Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, et al. Gene expression and cellular content of cathepsin D in Alzheimer\u2019s disease brain: evidence for early up-regulation of the endosomal-lysosomal system. Neuron. 1995;14:671\u201380.","journal-title":"Neuron."},{"key":"610_CR82","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0197-4580(03)00034-4","volume":"25","author":"B Boland","year":"2004","unstructured":"Boland B, Campbell V. Abeta-mediated activation of the apoptotic cascade in cultured cortical neurones: a role for cathepsin-L. Neurobiol Aging. 2004;25:83\u201391.","journal-title":"Neurobiol Aging"},{"key":"610_CR83","doi-asserted-by":"publisher","first-page":"3861","DOI":"10.1073\/pnas.87.10.3861","volume":"87","author":"AM Cataldo","year":"1990","unstructured":"Cataldo AM, Nixon RA. Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc Natl Acad Sci U S A. 1990;87:3861\u20135.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"610_CR84","doi-asserted-by":"publisher","first-page":"10998","DOI":"10.1073\/pnas.88.24.10998","volume":"88","author":"AM Cataldo","year":"1991","unstructured":"Cataldo AM, Paskevich PA, Kominami E, Nixon RA. Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci U S A. 1991;88:10998\u20131002.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"610_CR85","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2011.21","volume":"2","author":"S Thellung","year":"2011","unstructured":"Thellung S, Corsaro A, Villa V, Simi A, Vella S, Pagano A, et al. Human PrP90-231-induced cell death is associated with intracellular accumulation of insoluble and protease-resistant macroaggregates and lysosomal dysfunction. Cell Death Dis. 2011;2:e138.","journal-title":"Cell Death Dis"},{"key":"610_CR86","doi-asserted-by":"publisher","first-page":"4894","DOI":"10.1128\/JVI.74.10.4894-4897.2000","volume":"74","author":"K Doh-Ura","year":"2000","unstructured":"Doh-Ura K, Iwaki T, Caughey B. Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J Virol. 2000;74:4894\u20137.","journal-title":"J Virol"},{"key":"610_CR87","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1093\/oxfordjournals.bmb.a072651","volume":"49","author":"B Caughey","year":"1993","unstructured":"Caughey B. Scrapie associated PrP accumulation and its prevention: insights from cell culture. Br Med Bull. 1993;49:860\u201372.","journal-title":"Br Med Bull"},{"key":"610_CR88","doi-asserted-by":"publisher","first-page":"6597","DOI":"10.1128\/JVI.65.12.6597-6603.1991","volume":"65","author":"B Caughey","year":"1991","unstructured":"Caughey B, Raymond GJ, Ernst D, Race RE. N-terminal truncation of the scrapie-associated form of PrP by lysosomal protease(s): implications regarding the site of conversion of PrP to the protease-resistant state. J Virol. 1991;65:6597\u2013603.","journal-title":"J Virol"},{"key":"610_CR89","doi-asserted-by":"publisher","first-page":"5207","DOI":"10.1523\/JNEUROSCI.0653-05.2005","volume":"25","author":"AC Magalhaes","year":"2005","unstructured":"Magalhaes AC, Baron GS, Lee KS, Steele-Mortimer O, Dorward D, Prado MA, et al. Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells. J Neurosci. 2005;25:5207\u201316.","journal-title":"J Neurosci"},{"key":"610_CR90","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/msb.2009.10","volume":"5","author":"D Hwang","year":"2009","unstructured":"Hwang D, Lee IY, Yoo H, Gehlenborg N, Cho JH, Petritis B, et al. A systems approach to prion disease. Mol Syst Biol. 2009;5:252.","journal-title":"Mol Syst Biol"},{"key":"610_CR91","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1111\/bpa.12441","volume":"27","author":"C Muth","year":"2017","unstructured":"Muth C, Schrock K, Madore C, Hartmann K, Fanek Z, Butovsky O, et al. Activation of microglia by retroviral infection correlates with transient clearance of prions from the brain but does not change incubation time. Brain Pathol. 2017;27:590\u2013602.","journal-title":"Brain Pathol"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-020-00610-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13041-020-00610-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-020-00610-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T12:56:20Z","timestamp":1722862580000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularbrain.biomedcentral.com\/articles\/10.1186\/s13041-020-00610-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,7]]},"references-count":91,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["610"],"URL":"https:\/\/doi.org\/10.1186\/s13041-020-00610-8","relation":{},"ISSN":["1756-6606"],"issn-type":[{"value":"1756-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,7]]},"assertion":[{"value":"10 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All mice were housed at the Rocky Mountain Laboratories (RML) in an AAALAC-accredited facility in compliance with guidelines provided by the Guide for the Care and Use of Laboratory Animals (Institute for Laboratory Animal Research Council). Experimentation followed RML Animal Care and Use Committee approved protocol 2016\u2013043-E.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing financial interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"71"}}