{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:58:29Z","timestamp":1793257109056,"version":"4.5.0"},"reference-count":113,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T00:00:00Z","timestamp":1616025600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T00:00:00Z","timestamp":1616025600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010198","name":"Ministerio de Econom\u00eda, Industria y Competitividad, Gobierno de Espa\u00f1a","doi-asserted-by":"publisher","award":["SAF2016-76451R"],"award-info":[{"award-number":["SAF2016-76451R"]}],"id":[{"id":"10.13039\/501100010198","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Aging and age-related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain\u2019s immune response, plays an important role in aged associated degeneration of central nervous system (CNS). There is a need for well characterized animal models that will allow the scientific community to understand and modulate this process.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their senescence resistant control mice (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and determined the appearance of Iba1\n                      <jats:sup>+<\/jats:sup>\n                      clustered cells with aging. To analyze specific constant brain areas, we have performed stereology measurements of Iba1\n                      <jats:sup>+<\/jats:sup>\n                      cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m\/Ch), and analyzed their response to systemic lipopolysaccharide (LPS)-driven inflammation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Aged 10 months old SAMP8 mice present many of the hallmarks of aging-dependent neuroinflammation when compared with their SAMR1 control, i.e., increase of protein aggregates, presence of Iba1\n                      <jats:sup>+<\/jats:sup>\n                      clusters, but not an increase in the number of Iba1\n                      <jats:sup>+<\/jats:sup>\n                      cells. We have further observed an increase of main inflammatory mediator IL-1\u03b2, and an augment of border MHCII\n                      <jats:sup>+<\/jats:sup>\n                      Iba1\n                      <jats:sup>+<\/jats:sup>\n                      cells. Isolated CD45\n                      <jats:sup>+<\/jats:sup>\n                      bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m\/Ch) have been analyzed, showing that there is not a significant increase of CD45\n                      <jats:sup>+<\/jats:sup>\n                      cells from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL-1\u03b2) transcription is enhanced in CD45\n                      <jats:sup>+<\/jats:sup>\n                      BP cells. Furthermore, LPS-driven systemic inflammation produces inflammatory cytokines mainly in border bMyC, sensed to a lesser extent by the BP bMyC, showing that IL-1\u03b2 expression is further augmented in aged SAMP8 compared to control SAMR1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of pro-inflammatory cytokines such as IL-1\u03b2, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-021-02104-3","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T17:02:48Z","timestamp":1616086968000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Senescent accelerated prone 8 (SAMP8) mice as a model of age dependent neuroinflammation"],"prefix":"10.1186","volume":"18","author":[{"given":"Andr\u00e9s","family":"Fern\u00e1ndez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Quintana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Velasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"Moreno-Jimenez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"de Andr\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Gaspar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Liste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00e7al","family":"Vilar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Mira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2750-6135","authenticated-orcid":false,"given":"Eva","family":"Cano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"issue":"3","key":"2104_CR1","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1097\/01.jnen.0000202887.22082.63","volume":"65","author":"JR Conde","year":"2006","unstructured":"Conde JR, Streit WJ. Microglia in the aging brain. J Neuropathol Exp Neurol. 2006;65(3):199\u2013203.","journal-title":"J Neuropathol Exp Neurol"},{"issue":"2","key":"2104_CR2","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1002\/glia.10319","volume":"45","author":"WJ Streit","year":"2004","unstructured":"Streit WJ, Sammons NW, Kuhns AJ, Sparks DL. Dystrophic microglia in the aging human brain. Glia. 2004;45(2):208\u201312.","journal-title":"Glia"},{"issue":"3","key":"2104_CR3","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1038\/77046","volume":"25","author":"CK Lee","year":"2000","unstructured":"Lee CK, Weindruch R, Prolla TA. Gene-expression profile of the ageing brain in mice. Nat Genet. 2000;25(3):294\u20137.","journal-title":"Nat Genet"},{"issue":"6994","key":"2104_CR4","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1038\/nature02661","volume":"429","author":"T Lu","year":"2004","unstructured":"Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, et al. Gene regulation and DNA damage in the ageing human brain. Nature. 2004;429(6994):883\u201391.","journal-title":"Nature"},{"issue":"10","key":"2104_CR5","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1038\/s41593-019-0491-3","volume":"22","author":"M Ximerakis","year":"2019","unstructured":"Ximerakis M, Lipnick SL, Innes BT, Simmons SK, Adiconis X, Dionne D, et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat Neurosci. 2019;22(10):1696\u2013708.","journal-title":"Nat Neurosci"},{"issue":"2","key":"2104_CR6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000134","volume":"17","author":"L Zhan","year":"2019","unstructured":"Zhan L, Krabbe G, Du F, Jones I, Reichert MC, Telpoukhovskaia M, et al. Proximal recolonization by self-renewing microglia re-establishes microglial homeostasis in the adult mouse brain. PLoS Biol. 2019;17(2):e3000134.","journal-title":"PLoS Biol"},{"key":"2104_CR7","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/1750-1326-4-47","volume":"4","author":"TC Frank-Cannon","year":"2009","unstructured":"Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener. 2009;4:47.","journal-title":"Mol Neurodegener"},{"issue":"6301","key":"2104_CR8","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(6301):777\u201383.","journal-title":"Science"},{"issue":"2","key":"2104_CR9","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1002\/glia.1101","volume":"36","author":"WF Hickey","year":"2001","unstructured":"Hickey WF. Basic principles of immunological surveillance of the normal central nervous system. Glia. 2001;36(2):118\u201324.","journal-title":"Glia"},{"issue":"1","key":"2104_CR10","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1084\/jem.20180199","volume":"216","author":"GT Norris","year":"2019","unstructured":"Norris GT, Kipnis J. Immune cells and CNS physiology: microglia and beyond. J Exp Med. 2019;216(1):60\u201370.","journal-title":"J Exp Med"},{"issue":"1-2","key":"2104_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jneuroim.2011.07.002","volume":"238","author":"PJ Khandelwal","year":"2011","unstructured":"Khandelwal PJ, Herman AM, Moussa CE. Inflammation in the early stages of neurodegenerative pathology. J Neuroimmunol. 2011;238(1-2):1\u201311.","journal-title":"J Neuroimmunol"},{"issue":"10","key":"2104_CR12","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1038\/nn.2923","volume":"14","author":"M Prinz","year":"2011","unstructured":"Prinz M, Priller J, Sisodia SS, Ransohoff RM. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci. 2011;14(10):1227\u201335.","journal-title":"Nat Neurosci"},{"key":"2104_CR13","doi-asserted-by":"publisher","first-page":"45","DOI":"10.3389\/fncel.2013.00045","volume":"7","author":"F Ginhoux","year":"2013","unstructured":"Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci. 2013;7:45.","journal-title":"Front Cell Neurosci"},{"issue":"12","key":"2104_CR14","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1038\/nn2014","volume":"10","author":"B Ajami","year":"2007","unstructured":"Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci. 2007;10(12):1538\u201343.","journal-title":"Nat Neurosci"},{"issue":"4","key":"2104_CR15","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/s41593-018-0090-8","volume":"21","author":"Y Huang","year":"2018","unstructured":"Huang Y, Xu Z, Xiong S, Sun F, Qin G, Hu G, et al. Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat Neurosci. 2018;21(4):530\u201340.","journal-title":"Nat Neurosci"},{"issue":"5726","key":"2104_CR16","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1126\/science.1110647","volume":"308","author":"A Nimmerjahn","year":"2005","unstructured":"Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314\u20138.","journal-title":"Science"},{"issue":"1","key":"2104_CR17","doi-asserted-by":"publisher","first-page":"108","DOI":"10.2174\/187152711794488575","volume":"10","author":"M Olah","year":"2011","unstructured":"Olah M, Biber K, Vinet J, Boddeke HW. Microglia phenotype diversity. CNS Neurol Disord Drug Targets. 2011;10(1):108\u201318.","journal-title":"CNS Neurol Disord Drug Targets"},{"issue":"4","key":"2104_CR18","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1111\/acel.12210","volume":"13","author":"R Baron","year":"2014","unstructured":"Baron R, Babcock AA, Nemirovsky A, Finsen B, Monsonego A. Accelerated microglial pathology is associated with Abeta plaques in mouse models of Alzheimer\u2019s disease. Aging Cell. 2014;13(4):584\u201395.","journal-title":"Aging Cell"},{"issue":"4","key":"2104_CR19","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1002\/glia.20468","volume":"55","author":"A Sierra","year":"2007","unstructured":"Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia. 2007;55(4):412\u201324.","journal-title":"Glia"},{"issue":"4","key":"2104_CR20","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1111\/neup.12373","volume":"37","author":"I Akiguchi","year":"2017","unstructured":"Akiguchi I, Pallas M, Budka H, Akiyama H, Ueno M, Han J, et al. SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda\u2019s legacy and future directions. Neuropathology. 2017;37(4):293\u2013305.","journal-title":"Neuropathology"},{"issue":"8","key":"2104_CR21","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.2174\/138161212799315795","volume":"18","author":"JE Morley","year":"2012","unstructured":"Morley JE, Farr SA, Kumar VB, Armbrecht HJ. The SAMP8 mouse: a model to develop therapeutic interventions for Alzheimer\u2019s disease. Curr Pharm Des. 2012;18(8):1123\u201330.","journal-title":"Curr Pharm Des"},{"issue":"4","key":"2104_CR22","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/nrneurol.2010.17","volume":"6","author":"VH Perry","year":"2010","unstructured":"Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol. 2010;6(4):193\u2013201.","journal-title":"Nat Rev Neurol"},{"issue":"4","key":"2104_CR23","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/emm.2006.40","volume":"38","author":"YS Kim","year":"2006","unstructured":"Kim YS, Joh TH. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson\u2019s disease. Exp Mol Med. 2006;38(4):333\u201347.","journal-title":"Exp Mol Med"},{"issue":"6","key":"2104_CR24","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2018.3597","volume":"1","author":"Q Tao","year":"2018","unstructured":"Tao Q, Ang TFA, DeCarli C, Auerbach SH, Devine S, Stein TD, et al. Association of chronic low-grade inflammation with risk of Alzheimer disease in ApoE4 carriers. JAMA Netw Open. 2018;1(6):e183597.","journal-title":"JAMA Netw Open"},{"issue":"40","key":"2104_CR25","doi-asserted-by":"publisher","first-page":"14436","DOI":"10.1523\/JNEUROSCI.3836-11.2011","volume":"31","author":"JC Carroll","year":"2011","unstructured":"Carroll JC, Iba M, Bangasser DA, Valentino RJ, James MJ, Brunden KR, et al. Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J Neurosci. 2011;31(40):14436\u201349.","journal-title":"J Neurosci"},{"issue":"3","key":"2104_CR26","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1016\/j.nbd.2009.12.016","volume":"37","author":"TT Tran","year":"2010","unstructured":"Tran TT, Srivareerat M, Alkadhi KA. Chronic psychosocial stress triggers cognitive impairment in a novel at-risk model of Alzheimer\u2019s disease. Neurobiol Dis. 2010;37(3):756\u201363.","journal-title":"Neurobiol Dis"},{"issue":"10","key":"2104_CR27","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41583-018-0054-8","volume":"19","author":"J Gotz","year":"2018","unstructured":"Gotz J, Bodea LG, Goedert M. Rodent models for Alzheimer disease. Nat Rev Neurosci. 2018;19(10):583\u201398.","journal-title":"Nat Rev Neurosci"},{"issue":"1-2","key":"2104_CR28","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1023\/A:1015207429786","volume":"3","author":"JE Morley","year":"2002","unstructured":"Morley JE. The SAMP8 mouse: a model of Alzheimer disease? Biogerontology. 2002;3(1-2):57\u201360.","journal-title":"Biogerontology"},{"issue":"4","key":"2104_CR29","doi-asserted-by":"publisher","first-page":"615","DOI":"10.3233\/JAD-2008-15408","volume":"15","author":"M Pallas","year":"2008","unstructured":"Pallas M, Camins A, Smith MA, Perry G, Lee HG, Casadesus G. From aging to Alzheimer\u2019s disease: unveiling \u201cthe switch\u201d with the senescence-accelerated mouse model (SAMP8). J Alzheimers Dis. 2008;15(4):615\u201324.","journal-title":"J Alzheimers Dis"},{"issue":"4","key":"2104_CR30","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1007\/s11064-009-9922-y","volume":"34","author":"T Takeda","year":"2009","unstructured":"Takeda T. Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice. Neurochem Res. 2009;34(4):639\u201359.","journal-title":"Neurochem Res"},{"issue":"1-2","key":"2104_CR31","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/S0531-5565(96)00061-7","volume":"32","author":"M Miyamoto","year":"1997","unstructured":"Miyamoto M. Characteristics of age-related behavioral changes in senescence-accelerated mouse SAMP8 and SAMP10. Exp Gerontol. 1997;32(1-2):139\u201348.","journal-title":"Exp Gerontol"},{"issue":"5","key":"2104_CR32","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1097\/00005072-198909000-00008","volume":"48","author":"H Yagi","year":"1989","unstructured":"Yagi H, Irino M, Matsushita T, Katoh S, Umezawa M, Tsuboyama T, et al. Spontaneous spongy degeneration of the brain stem in SAM-P\/8 mice, a newly developed memory-deficient strain. J Neuropathol Exp Neurol. 1989;48(5):577\u201390.","journal-title":"J Neuropathol Exp Neurol"},{"issue":"1-2","key":"2104_CR33","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/S0531-5565(96)00063-0","volume":"32","author":"T Kawamata","year":"1997","unstructured":"Kawamata T, Akiguchi I, Yagi H, Irino M, Sugiyama H, Akiyama H, et al. Neuropathological studies on strains of senescence-accelerated mice (SAM) with age-related deficits in learning and memory. Exp Gerontol. 1997;32(1-2):161\u20139.","journal-title":"Exp Gerontol"},{"issue":"2","key":"2104_CR34","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/S0197-4580(99)00006-8","volume":"20","author":"Y Nomura","year":"1999","unstructured":"Nomura Y, Okuma Y. Age-related defects in lifespan and learning ability in SAMP8 mice. Neurobiol Aging. 1999;20(2):111\u20135.","journal-title":"Neurobiol Aging"},{"issue":"2","key":"2104_CR35","doi-asserted-by":"publisher","first-page":"B61","DOI":"10.1093\/gerona\/57.2.B61","volume":"57","author":"EL Spangler","year":"2002","unstructured":"Spangler EL, Patel N, Speer D, Hyman M, Hengemihle J, Markowska A, et al. Passive avoidance and complex maze learning in the senescence accelerated mouse (SAM): age and strain comparisons of SAM P8 and R1. J Gerontol A Biol Sci Med Sci. 2002;57(2):B61\u20138.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"11","key":"2104_CR36","doi-asserted-by":"publisher","first-page":"2623","DOI":"10.1016\/j.neurobiolaging.2013.05.011","volume":"34","author":"M Diaz-Moreno","year":"2013","unstructured":"Diaz-Moreno M, Hortiguela R, Goncalves A, Garcia-Carpio I, Manich G, Garcia-Bermudez E, et al. Abeta increases neural stem cell activity in senescence-accelerated SAMP8 mice. Neurobiol Aging. 2013;34(11):2623\u201338.","journal-title":"Neurobiol Aging"},{"issue":"45","key":"2104_CR37","doi-asserted-by":"publisher","first-page":"11625","DOI":"10.1073\/pnas.1813205115","volume":"115","author":"M Diaz-Moreno","year":"2018","unstructured":"Diaz-Moreno M, Armenteros T, Gradari S, Hortiguela R, Garcia-Corzo L, Fontan-Lozano A, et al. Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology. Proc Natl Acad Sci U S A. 2018;115(45):11625\u201330.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2104_CR38","first-page":"165021","volume":"2012","author":"RE Mrak","year":"2012","unstructured":"Mrak RE. Microglia in Alzheimer brain: a neuropathological perspective. Int J Alzheimers Dis. 2012;2012:165021.","journal-title":"Int J Alzheimers Dis"},{"key":"2104_CR39","doi-asserted-by":"publisher","first-page":"260925","DOI":"10.1155\/2013\/260925","volume":"2013","author":"A Fuster-Matanzo","year":"2013","unstructured":"Fuster-Matanzo A, Llorens-Martin M, Hernandez F, Avila J. Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches. Mediators Inflamm. 2013;2013:260925.","journal-title":"Mediators Inflamm"},{"issue":"4","key":"2104_CR40","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1007\/s11357-012-9448-0","volume":"35","author":"B Bayram","year":"2013","unstructured":"Bayram B, Nikolai S, Huebbe P, Ozcelik B, Grimm S, Grune T, et al. Biomarkers of oxidative stress, antioxidant defence and inflammation are altered in the senescence-accelerated mouse prone 8. Age (Dordr ). 2013;35(4):1205\u201317.","journal-title":"Age (Dordr )"},{"key":"2104_CR41","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.exger.2016.03.014","volume":"80","author":"C Grinan-Ferre","year":"2016","unstructured":"Grinan-Ferre C, Palomera-Avalos V, Puigoriol-Illamola D, Camins A, Porquet D, Pla V, et al. Behaviour and cognitive changes correlated with hippocampal neuroinflammaging and neuronal markers in female SAMP8, a model of accelerated senescence. Exp Gerontol. 2016;80:57\u201369.","journal-title":"Exp Gerontol"},{"issue":"1","key":"2104_CR42","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/S0006-8993(00)02883-3","volume":"885","author":"KK Tha","year":"2000","unstructured":"Tha KK, Okuma Y, Miyazaki H, Murayama T, Uehara T, Hatakeyama R, et al. Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res. 2000;885(1):25\u201331.","journal-title":"Brain Res"},{"key":"2104_CR43","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1742-2094-5-7","volume":"5","author":"SS Shaftel","year":"2008","unstructured":"Shaftel SS, Griffin WS, O\u2019Banion MK. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation. 2008;5:7.","journal-title":"J Neuroinflammation"},{"issue":"1-2","key":"2104_CR44","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/S0165-5728(98)00217-3","volume":"93","author":"SM Ye","year":"1999","unstructured":"Ye SM, Johnson RW. Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol. 1999;93(1-2):139\u201348.","journal-title":"J Neuroimmunol"},{"issue":"6","key":"2104_CR45","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/nrn3880","volume":"16","author":"FL Heppner","year":"2015","unstructured":"Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16(6):358\u201372.","journal-title":"Nat Rev Neurosci"},{"issue":"1","key":"2104_CR46","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1038\/npp.2016.185","volume":"42","author":"A Niraula","year":"2017","unstructured":"Niraula A, Sheridan JF, Godbout JP. Microglia priming with aging and stress. Neuropsychopharmacology. 2017;42(1):318\u201333.","journal-title":"Neuropsychopharmacology"},{"issue":"5","key":"2104_CR47","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1007\/s00281-013-0382-8","volume":"35","author":"VH Perry","year":"2013","unstructured":"Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol. 2013;35(5):601\u201312.","journal-title":"Semin Immunopathol"},{"issue":"4","key":"2104_CR48","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.it.2019.02.001","volume":"40","author":"JJ Neher","year":"2019","unstructured":"Neher JJ, Cunningham C. Priming microglia for innate immune memory in the brain. Trends Immunol. 2019;40(4):358\u201374.","journal-title":"Trends Immunol"},{"issue":"6","key":"2104_CR49","doi-asserted-by":"publisher","first-page":"3916","DOI":"10.4049\/jimmunol.173.6.3916","volume":"173","author":"JK Olson","year":"2004","unstructured":"Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173(6):3916\u201324.","journal-title":"J Immunol"},{"issue":"4","key":"2104_CR50","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1007\/s12031-014-0442-0","volume":"55","author":"J Wang","year":"2015","unstructured":"Wang J, Zhao D, Pan B, Fu Y, Shi F, Kouadir M, et al. Toll-like receptor 2 deficiency shifts PrP106-126-induced microglial activation from a neurotoxic to a neuroprotective phenotype. J Mol Neurosci. 2015;55(4):880\u201390.","journal-title":"J Mol Neurosci"},{"issue":"4","key":"2104_CR51","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.biopsych.2008.07.024","volume":"65","author":"C Cunningham","year":"2009","unstructured":"Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RM, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry. 2009;65(4):304\u201312.","journal-title":"Biol Psychiatry"},{"issue":"31","key":"2104_CR52","doi-asserted-by":"publisher","first-page":"21584","DOI":"10.1074\/jbc.M114.583518","volume":"289","author":"MC Morris","year":"2014","unstructured":"Morris MC, Gilliam EA, Button J, Li L. Dynamic modulation of innate immune response by varying dosages of lipopolysaccharide (LPS) in human monocytic cells. J Biol Chem. 2014;289(31):21584\u201390.","journal-title":"J Biol Chem"},{"issue":"1","key":"2104_CR53","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s13195-018-0352-4","volume":"10","author":"F Bartolome","year":"2018","unstructured":"Bartolome F, de la Cueva M, Pascual C, Antequera D, Fernandez T, Gil C, et al. Amyloid beta-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition. Alzheimers Res Ther. 2018;10(1):24.","journal-title":"Alzheimers Res Ther"},{"key":"2104_CR54","unstructured":"Paxinos G, Franklin K. Mouse brain in stereotaxic coordinates. 5th edici\u00f3n. Academic Press. Elsevier; 2012. ISBN: 9780128161593."},{"issue":"12","key":"2104_CR55","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1002\/glia.22889","volume":"63","author":"E Quintana","year":"2015","unstructured":"Quintana E, Fernandez A, Velasco P, de Andr\u00e9s B, Liste I, Sancho D, et al. DNGR-1(+) dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain. Glia. 2015;63(12):2231\u201348.","journal-title":"Glia"},{"issue":"3","key":"2104_CR56","first-page":"151","volume":"39","author":"B Catalin","year":"2013","unstructured":"Catalin B, Mitran S, Albu C, Iancau M. Comparative aspects of microglia reaction in white and gray matter. Curr Health Sci J. 2013;39(3):151\u20134.","journal-title":"Curr Health Sci J"},{"issue":"3","key":"2104_CR57","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1242\/dev.099655","volume":"141","author":"T Ferreira","year":"2014","unstructured":"Ferreira T, Ou Y, Li S, Giniger E, van Meyel DJ. Dendrite architecture organized by transcriptional control of the F-actin nucleator Spire. Development. 2014;141(3):650\u201360.","journal-title":"Development"},{"issue":"2","key":"2104_CR58","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.jneumeth.2006.05.030","volume":"158","author":"D Ristanovic","year":"2006","unstructured":"Ristanovic D, Milosevic NT, Stulic V. Application of modified Sholl analysis to neuronal dendritic arborization of the cat spinal cord. J Neurosci Methods. 2006;158(2):212\u20138.","journal-title":"J Neurosci Methods"},{"issue":"1","key":"2104_CR59","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1002\/(SICI)1098-1136(199801)22:1<72::AID-GLIA7>3.0.CO;2-A","volume":"22","author":"MJ Carson","year":"1998","unstructured":"Carson MJ, Reilly CR, Sutcliffe JG, Lo D. Mature microglia resemble immature antigen-presenting cells. Glia. 1998;22(1):72\u201385.","journal-title":"Glia"},{"issue":"4","key":"2104_CR60","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(-Delta Delta C(T)) Method. Methods. 2001;25(4):402\u20138.","journal-title":"Methods"},{"key":"2104_CR61","doi-asserted-by":"publisher","first-page":"41807","DOI":"10.1038\/srep41807","volume":"7","author":"E Auge","year":"2017","unstructured":"Auge E, Cabezon I, Pelegri C, Vilaplana J. New perspectives on corpora amylacea in the human brain. Sci Rep. 2017;7:41807.","journal-title":"Sci Rep"},{"issue":"2","key":"2104_CR62","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1007\/BF00685973","volume":"72","author":"H Akiyama","year":"1986","unstructured":"Akiyama H, Kameyama M, Akiguchi I, Sugiyama H, Kawamata T, Fukuyama H, et al. Periodic acid-Schiff (PAS)-positive, granular structures increase in the brain of senescence accelerated mouse (SAM). Acta Neuropathol. 1986;72(2):124\u20139.","journal-title":"Acta Neuropathol"},{"key":"2104_CR63","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.arr.2016.03.001","volume":"27","author":"G Manich","year":"2016","unstructured":"Manich G, Cabezon I, Auge E, Pelegri C, Vilaplana J. Periodic acid-Schiff granules in the brain of aged mice: from amyloid aggregates to degenerative structures containing neo-epitopes. Ageing Res Rev. 2016;27:42\u201355.","journal-title":"Ageing Res Rev"},{"issue":"6","key":"2104_CR64","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1007\/BF00318576","volume":"90","author":"S Nakamura","year":"1995","unstructured":"Nakamura S, Akiguchi I, Seriu N, Ohnishi K, Takemura M, Ueno M, et al. Monoamine oxidase-B-positive granular structures in the hippocampus of aged senescence-accelerated mouse (SAMP8). Acta Neuropathol. 1995;90(6):626\u201332.","journal-title":"Acta Neuropathol"},{"issue":"9","key":"2104_CR65","doi-asserted-by":"publisher","first-page":"2057","DOI":"10.1016\/0306-4522(82)90120-8","volume":"7","author":"J Schoenen","year":"1982","unstructured":"Schoenen J. The dendritic organization of the human spinal cord: the dorsal horn. Neuroscience. 1982;7(9):2057\u201387.","journal-title":"Neuroscience"},{"key":"2104_CR66","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.jneumeth.2014.01.016","volume":"226","author":"LM Garcia-Segura","year":"2014","unstructured":"Garcia-Segura LM, Perez-Marquez J. A new mathematical function to evaluate neuronal morphology using the Sholl analysis. J Neurosci Methods. 2014;226:103\u20139.","journal-title":"J Neurosci Methods"},{"issue":"4","key":"2104_CR67","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1002\/glia.22287","volume":"60","author":"ME Tremblay","year":"2012","unstructured":"Tremblay ME, Zettel ML, Ison JR, Allen PD, Majewska AK. Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia. 2012;60(4):541\u201358.","journal-title":"Glia"},{"issue":"1","key":"2104_CR68","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/j.1440-1789.2010.01126.x","volume":"31","author":"S Hasegawa-Ishii","year":"2011","unstructured":"Hasegawa-Ishii S, Takei S, Chiba Y, Furukawa A, Umegaki H, Iguchi A, et al. Morphological impairments in microglia precede age-related neuronal degeneration in senescence-accelerated mice. Neuropathology. 2011;31(1):20\u20138.","journal-title":"Neuropathology"},{"issue":"6","key":"2104_CR69","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1111\/bpa.12717","volume":"29","author":"PJ Paasila","year":"2019","unstructured":"Paasila PJ, Davies DS, Kril JJ, Goldsbury C, Sutherland GT. The relationship between the morphological subtypes of microglia and Alzheimer\u2019s disease neuropathology. Brain Pathol. 2019;29(6):726\u201340.","journal-title":"Brain Pathol"},{"issue":"2","key":"2104_CR70","doi-asserted-by":"publisher","first-page":"129","DOI":"10.4161\/epi.5.2.11080","volume":"5","author":"LJ Mah","year":"2010","unstructured":"Mah LJ, El-Osta A, Karagiannis TC. GammaH2AX as a molecular marker of aging and disease. Epigenetics. 2010;5(2):129\u201336.","journal-title":"Epigenetics"},{"issue":"24","key":"2104_CR71","doi-asserted-by":"publisher","first-page":"4112","DOI":"10.4161\/cc.8.24.10215","volume":"8","author":"TV Pospelova","year":"2009","unstructured":"Pospelova TV, Demidenko ZN, Bukreeva EI, Pospelov VA, Gudkov AV, Blagosklonny MV. Pseudo-DNA damage response in senescent cells. Cell Cycle. 2009;8(24):4112\u20138.","journal-title":"Cell Cycle"},{"issue":"1","key":"2104_CR72","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.3390\/ijms15011554","volume":"15","author":"S Barral","year":"2014","unstructured":"Barral S, Beltramo R, Salio C, Aimar P, Lossi L, Merighi A. Phosphorylation of histone H2AX in the mouse brain from development to senescence. Int J Mol Sci. 2014;15(1):1554\u201373.","journal-title":"Int J Mol Sci"},{"issue":"4","key":"2104_CR73","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/s11357-008-9050-7","volume":"30","author":"NH Myung","year":"2008","unstructured":"Myung NH, Zhu X, Kruman II, Castellani RJ, Petersen RB, Siedlak SL, et al. Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes. Age (Dordr ). 2008;30(4):209\u201315.","journal-title":"Age (Dordr )"},{"issue":"1","key":"2104_CR74","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s40478-019-0723-5","volume":"7","author":"NM Shanbhag","year":"2019","unstructured":"Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, et al. Early neuronal accumulation of DNA double strand breaks in Alzheimer\u2019s disease. Acta Neuropathol Commun. 2019;7(1):77.","journal-title":"Acta Neuropathol Commun"},{"issue":"1","key":"2104_CR75","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/j.1365-2990.2009.01030.x","volume":"36","author":"JE Simpson","year":"2010","unstructured":"Simpson JE, Ince PG, Haynes LJ, Theaker R, Gelsthorpe C, Baxter L, et al. Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol. 2010;36(1):25\u201340.","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"3","key":"2104_CR76","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/S0896-6273(02)00794-8","volume":"35","author":"T Wyss-Coray","year":"2002","unstructured":"Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 2002;35(3):419\u201332.","journal-title":"Neuron"},{"issue":"5","key":"2104_CR77","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1016\/j.bbi.2011.11.006","volume":"26","author":"AD Hart","year":"2012","unstructured":"Hart AD, Wyttenbach A, Perry VH, Teeling JL. Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav Immun. 2012;26(5):754\u201365.","journal-title":"Brain Behav Immun"},{"issue":"1","key":"2104_CR78","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1002\/(SICI)1097-0029(19981001)43:1<59::AID-JEMT9>3.0.CO;2-X","volume":"43","author":"T Kawamata","year":"1998","unstructured":"Kawamata T, Akiguchi I, Maeda K, Tanaka C, Higuchi K, Hosokawa M, et al. Age-related changes in the brains of senescence-accelerated mice (SAM): association with glial and endothelial reactions. Microsc Res Tech. 1998;43(1):59\u201367.","journal-title":"Microsc Res Tech"},{"issue":"11","key":"2104_CR79","doi-asserted-by":"publisher","first-page":"4106","DOI":"10.1128\/MCB.20.11.4106-4114.2000","volume":"20","author":"S Jung","year":"2000","unstructured":"Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol. 2000;20(11):4106\u201314.","journal-title":"Mol Cell Biol"},{"issue":"9","key":"2104_CR80","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/nri3265","volume":"12","author":"RM Ransohoff","year":"2012","unstructured":"Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012;12(9):623\u201335.","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"2104_CR81","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1084\/jem.177.1.57","volume":"177","author":"JL Baron","year":"1993","unstructured":"Baron JL, Madri JA, Ruddle NH, Hashim G, Janeway CA Jr. Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med. 1993;177(1):57\u201368.","journal-title":"J Exp Med"},{"key":"2104_CR82","first-page":"447","volume":"8","author":"ES Wohleb","year":"2014","unstructured":"Wohleb ES, McKim DB, Sheridan JF, Godbout JP. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front Neurosci. 2014;8:447.","journal-title":"Front Neurosci"},{"issue":"9","key":"2104_CR83","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1016\/j.celrep.2016.10.052","volume":"17","author":"RL Bowman","year":"2016","unstructured":"Bowman RL, Klemm F, Akkari L, Pyonteck SM, Sevenich L, Quail DF, et al. Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep. 2016;17(9):2445\u201359.","journal-title":"Cell Rep"},{"issue":"1","key":"2104_CR84","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.neuron.2009.08.039","volume":"64","author":"KM Lucin","year":"2009","unstructured":"Lucin KM, Wyss-Coray T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron. 2009;64(1):110\u201322.","journal-title":"Neuron"},{"issue":"34","key":"2104_CR85","doi-asserted-by":"publisher","first-page":"11706","DOI":"10.1523\/JNEUROSCI.0730-12.2012","volume":"32","author":"Z Chen","year":"2012","unstructured":"Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, Yin X, et al. Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci. 2012;32(34):11706\u201315.","journal-title":"J Neurosci"},{"issue":"1","key":"2104_CR86","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1038\/s41598-018-20643-3","volume":"8","author":"E Furube","year":"2018","unstructured":"Furube E, Kawai S, Inagaki H, Takagi S, Miyata S. Brain region-dependent heterogeneity and dose-dependent difference in transient microglia population increase during lipopolysaccharide-induced inflammation. Sci Rep. 2018;8(1):2203.","journal-title":"Sci Rep"},{"issue":"2","key":"2104_CR87","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/nrn1032","volume":"4","author":"VH Perry","year":"2003","unstructured":"Perry VH, Newman TA, Cunningham C. The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci. 2003;4(2):103\u201312.","journal-title":"Nat Rev Neurosci"},{"key":"2104_CR88","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1750-1326-7-56","volume":"7","author":"B Wolozin","year":"2012","unstructured":"Wolozin B. Regulated protein aggregation: stress granules and neurodegeneration. Mol Neurodegener. 2012;7:56.","journal-title":"Mol Neurodegener"},{"issue":"1","key":"2104_CR89","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/S0006-8993(02)03475-3","volume":"956","author":"PR Mouton","year":"2002","unstructured":"Mouton PR, Long JM, Lei DL, Howard V, Jucker M, Calhoun ME, et al. Age and gender effects on microglia and astrocyte numbers in brains of mice. Brain Res. 2002;956(1):30\u20135.","journal-title":"Brain Res"},{"issue":"4","key":"2104_CR90","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1007\/s11011-010-9224-8","volume":"25","author":"M Adachi","year":"2010","unstructured":"Adachi M, Abe M, Sasaki T, Kato H, Kasahara J, Araki T. Role of inducible or neuronal nitric oxide synthase in neurogenesis of the dentate gyrus in aged mice. Metab Brain Dis. 2010;25(4):419\u201324.","journal-title":"Metab Brain Dis"},{"issue":"4","key":"2104_CR91","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.mad.2007.01.005","volume":"128","author":"N Hayakawa","year":"2007","unstructured":"Hayakawa N, Kato H, Araki T. Age-related changes of astorocytes, oligodendrocytes and microglia in the mouse hippocampal CA1 sector. Mech Ageing Dev. 2007;128(4):311\u20136.","journal-title":"Mech Ageing Dev"},{"key":"2104_CR92","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/1742-2094-8-138","volume":"8","author":"HD Vanguilder","year":"2011","unstructured":"Vanguilder HD, Bixler GV, Brucklacher RM, Farley JA, Yan H, Warrington JP, et al. Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. J Neuroinflammation. 2011;8:138.","journal-title":"J Neuroinflammation"},{"key":"2104_CR93","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.brainres.2010.05.043","volume":"1345","author":"J Liu","year":"2010","unstructured":"Liu J, Wang MW, Gu P, Ma QY, Wang YY, Geng Y, et al. Microglial activation and age-related dopaminergic neurodegeneration in MPTP-treated SAMP8 mice. Brain Res. 2010;1345:213\u201320.","journal-title":"Brain Res"},{"issue":"10","key":"2104_CR94","doi-asserted-by":"publisher","first-page":"3063","DOI":"10.1002\/(SICI)1521-4141(199910)29:10<3063::AID-IMMU3063>3.0.CO;2-G","volume":"29","author":"MK Matyszak","year":"1999","unstructured":"Matyszak MK, Denis-Donini S, Citterio S, Longhi R, Granucci F, Ricciardi-Castagnoli P. Microglia induce myelin basic protein-specific T cell anergy or T cell activation, according to their state of activation. Eur J Immunol. 1999;29(10):3063\u201376.","journal-title":"Eur J Immunol"},{"issue":"5","key":"2104_CR95","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/j.neurobiolaging.2005.03.013","volume":"27","author":"MG Frank","year":"2006","unstructured":"Frank MG, Barrientos RM, Biedenkapp JC, Rudy JW, Watkins LR, Maier SF. mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging. 2006;27(5):717\u201322.","journal-title":"Neurobiol Aging"},{"issue":"1-2","key":"2104_CR96","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.jneuroim.2010.05.022","volume":"226","author":"MG Frank","year":"2010","unstructured":"Frank MG, Barrientos RM, Watkins LR, Maier SF. Aging sensitizes rapidly isolated hippocampal microglia to LPS ex vivo. J Neuroimmunol. 2010;226(1-2):181\u20134.","journal-title":"J Neuroimmunol"},{"issue":"1","key":"2104_CR97","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/glia.440070111","volume":"7","author":"VH Perry","year":"1993","unstructured":"Perry VH, Matyszak MK, Fearn S. Altered antigen expression of microglia in the aged rodent CNS. Glia. 1993;7(1):60\u20137.","journal-title":"Glia"},{"issue":"5","key":"2104_CR98","first-page":"414","volume":"2","author":"A Shimada","year":"2011","unstructured":"Shimada A, Hasegawa-Ishii S. Senescence-accelerated mice (SAMs) as a model for brain aging and immunosenescence. Aging Dis. 2011;2(5):414\u201335.","journal-title":"Aging Dis"},{"key":"2104_CR99","doi-asserted-by":"crossref","unstructured":"Erickson MA, Banks WA. Age-associated changes in the immune system and blood brain barrier functions. Int J Mol Sci. 2019;20(7):1632-59.","DOI":"10.3390\/ijms20071632"},{"key":"2104_CR100","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/978-1-62703-520-0_3","volume":"1041","author":"JK Lee","year":"2013","unstructured":"Lee JK, Tansey MG. Microglia isolation from adult mouse brain. Methods Mol Biol. 2013;1041:17\u201323.","journal-title":"Methods Mol Biol"},{"issue":"16","key":"2104_CR101","doi-asserted-by":"publisher","first-page":"7438","DOI":"10.1073\/pnas.88.16.7438","volume":"88","author":"JD Sedgwick","year":"1991","unstructured":"Sedgwick JD, Schwender S, Imrich H, Dorries R, Butcher GW, ter Meulen V. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci U S A. 1991;88(16):7438\u201342.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2104_CR102","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.jneumeth.2015.03.021","volume":"247","author":"L Legroux","year":"2015","unstructured":"Legroux L, Pittet CL, Beauseigle D, Deblois G, Prat A, Arbour N. An optimized method to process mouse CNS to simultaneously analyze neural cells and leukocytes by flow cytometry. J Neurosci Methods. 2015;247:23\u201331.","journal-title":"J Neurosci Methods"},{"key":"2104_CR103","first-page":"53658","volume":"108","author":"C Posel","year":"2016","unstructured":"Posel C, Moller K, Boltze J, Wagner DC, Weise G. Isolation and flow cytometric analysis of immune cells from the ischemic mouse brain. J Vis Exp. 2016;108:53658.","journal-title":"J Vis Exp"},{"issue":"5","key":"2104_CR104","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1021\/tx500046k","volume":"27","author":"V Singh","year":"2014","unstructured":"Singh V, Mitra S, Sharma AK, Gera R, Ghosh D. Isolation and characterization of microglia from adult mouse brain: selected applications for ex vivo evaluation of immunotoxicological alterations following in vivo xenobiotic exposure. Chem Res Toxicol. 2014;27(5):895\u2013903.","journal-title":"Chem Res Toxicol"},{"issue":"4","key":"2104_CR105","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1038\/nprot.2006.327","volume":"1","author":"AE Cardona","year":"2006","unstructured":"Cardona AE, Huang D, Sasse ME, Ransohoff RM. Isolation of murine microglial cells for RNA analysis or flow cytometry. Nat Protoc. 2006;1(4):1947\u201351.","journal-title":"Nat Protoc"},{"issue":"9","key":"2104_CR106","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/j.mad.2007.07.002","volume":"128","author":"C Pelegri","year":"2007","unstructured":"Pelegri C, Canudas AM, del Valle J, Casadesus G, Smith MA, Camins A, et al. Increased permeability of blood-brain barrier on the hippocampus of a murine model of senescence. Mech Ageing Dev. 2007;128(9):522\u20138.","journal-title":"Mech Ageing Dev"},{"issue":"3","key":"2104_CR107","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1002\/jemt.1088","volume":"53","author":"M Ueno","year":"2001","unstructured":"Ueno M, Sakamoto H, Kanenishi K, Onodera M, Akiguchi I, Hosokawa M. Ultrastructural and permeability features of microvessels in the periventricular area of senescence-accelerated mice (SAM). Microsc Res Tech. 2001;53(3):232\u20138.","journal-title":"Microsc Res Tech"},{"issue":"12","key":"2104_CR108","doi-asserted-by":"publisher","first-page":"B601","DOI":"10.1093\/gerona\/55.12.B601","volume":"55","author":"WA Banks","year":"2000","unstructured":"Banks WA, Farr SA, Morley JE. Permeability of the blood-brain barrier to albumin and insulin in the young and aged SAMP8 mouse. J Gerontol A Biol Sci Med Sci. 2000;55(12):B601\u20136.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"2","key":"2104_CR109","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/nri2015","volume":"7","author":"VH Perry","year":"2007","unstructured":"Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7(2):161\u20137.","journal-title":"Nat Rev Immunol"},{"issue":"3","key":"2104_CR110","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1007\/s00401-010-0722-x","volume":"120","author":"VH Perry","year":"2010","unstructured":"Perry VH. Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol. 2010;120(3):277\u201386.","journal-title":"Acta Neuropathol"},{"issue":"3","key":"2104_CR111","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/S0306-4522(02)00048-9","volume":"112","author":"MG Proescholdt","year":"2002","unstructured":"Proescholdt MG, Chakravarty S, Foster JA, Foti SB, Briley EM, Herkenham M. Intracerebroventricular but not intravenous interleukin-1beta induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neuroscience. 2002;112(3):731\u201349.","journal-title":"Neuroscience"},{"issue":"1-2","key":"2104_CR112","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.jneuroim.2005.07.009","volume":"168","author":"A Depino","year":"2005","unstructured":"Depino A, Ferrari C, Pott Godoy MC, Tarelli R, Pitossi FJ. Differential effects of interleukin-1beta on neurotoxicity, cytokine induction and glial reaction in specific brain regions. J Neuroimmunol. 2005;168(1-2):96\u2013110.","journal-title":"J Neuroimmunol"},{"key":"2104_CR113","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.neuro.2019.10.006","volume":"76","author":"S Hasegawa-Ishii","year":"2020","unstructured":"Hasegawa-Ishii S, Inaba M, Shimada A. Widespread time-dependent changes in tissue cytokine concentrations in brain regions during the acute phase of endotoxemia in mice. Neurotoxicology. 2020;76:67\u201374.","journal-title":"Neurotoxicology"}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-021-02104-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12974-021-02104-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-021-02104-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T13:09:34Z","timestamp":1616159374000},"score":1,"resource":{"primary":{"URL":"https:\/\/jneuroinflammation.biomedcentral.com\/articles\/10.1186\/s12974-021-02104-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,18]]},"references-count":113,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2104"],"URL":"https:\/\/doi.org\/10.1186\/s12974-021-02104-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-72160\/v1","asserted-by":"object"}]},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,18]]},"assertion":[{"value":"3 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was carried out in accordance with EU and National Animal Care guidelines (directive 2010\/63\/EU and RD 53\/2013). All the procedures were approved by the Institutional Review Board at the ISCIII and the \u201cConsejer\u00eda de Medio Ambiente del la Comunidad de Madrid\u201d (PROEX179\/14).","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":"Authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"75"}}