[en] Sepsis-associated encephalopathy (SAE) represents diverse cerebral dysfunctions in response to pathogen-induced systemic inflammation. Peripheral exposure to lipopolysaccharide (LPS), a component of the gram-negative bacterial cell wall, has been extensively used to model systemic inflammation. Our previous studies suggested that LPS led to hippocampal neuron death and synaptic destruction in vivo. However, the underlying roles of activated microglia in these neuronal changes remained unclear. Here, LPS from two different bacterial strains (Salmonella enterica or E. coli) were compared and injected in 14- to 16-month-old mice and evaluated for neuroinflammation and neuronal integrity in the hippocampus at 7 or 63 days post-injection (dpi). LPS injection resulted in persistent neuroinflammation lasting for seven days and a subsequent normalisation by 63 dpi. Of note, increases in proinflammatory cytokines, microglial morphology and microglial mean lysosome volume were more pronounced after E. coli LPS injection than Salmonella LPS at 7 dpi. While inhibitory synaptic puncta density remained normal, excitatory synaptic puncta were locally reduced in the CA3 region of the hippocampus at 63 dpi. Finally, we provide evidence that excitatory synapses coated with complement factor 3 (C3) decreased between 7 dpi and 63 dpi. Although we did not find an increase of synaptic pruning by microglia, it is plausible that microglia recognised and eliminated these C3-tagged synapses between the two time points of investigation. Since a region-specific decline of CA3 synapses has previously been reported during normal ageing, we postulate that systemic inflammation may have accelerated or worsened the CA3 synaptic changes in the ageing brain.
Disciplines :
Neurology
Author, co-author :
Manabe, Tatsuya ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Center, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Rácz, Ildikó; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Center, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Schwartz, Stephanie; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Center, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Oberle, Linda; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Santarelli, Francesco; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Emmrich, Julius V; Department of Neurology and Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Neher, Jonas J; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
HENEKA, Michael ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Center, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
External co-authors :
yes
Language :
English
Title :
Systemic inflammation induced the delayed reduction of excitatory synapses in the CA3 during ageing.
The present study was funded by German Research Council (Deutsche Forschungsgemeinschaft) to J.J.N. (NE 1951/4‐1), J.V.E. (EM 252/2‐1) and M.T.H (HE 3350/11‐1). We would like to thank the Light Microscope Facility at DZNE in Bonn and Microscopy Core Facility at Medical Faculty of the University of Bonn (funded by German Research Council, project number 266686698) for the microscopes and analysis software with their continuous support. Graphical abstract was created using BioRender ( https://biorender.com/ ).
Adams, M. M., Donohue, H. S., Linville, M. C., Iversen, E. A., Newton, I. G., & Brunso-Bechtold, J. K. (2010). Age-related synapse loss in hippocampal CA3 is not reversed by caloric restriction. Neuroscience, 171, 373–382. https://doi.org/10.1016/j.neuroscience.2010.09.022
Arganda-Carreras, I., Fernández-González, R., Muñoz-Barrutia, A., & Ortiz-De-Solorzano, C. (2010). 3D reconstruction of histological sections: Application to mammary gland tissue. Microscopy Research and Technique, 73, 1019–1029. https://doi.org/10.1002/jemt.20829
Bertoglio, D., Verhaeghe, J., Miranda, A., Kertesz, I., Cybulska, K., Korat, Š., Wyffels, L., Stroobants, S., Mrzljak, L., Dominguez, C., Liu, L., Skinbjerg, M., Munoz-Sanjuan, I., & Staelens, S. (2020). Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice. Journal of Cerebral Blood Flow and Metabolism, 40, 1351–1362.
Beyer, M. M. S., Lonnemann, N., Remus, A., Latz, E., Heneka, M. T., & Korte, M. (2020). Enduring changes in neuronal function upon systemic inflammation are NLRP3 inflammasome dependent. Journal of Neuroscience, 40, 5480–5494. https://doi.org/10.1523/JNEUROSCI.0200-20.2020
Bodea, L.-G., Wang, Y., Linnartz-Gerlach, B., Kopatz, J., Sinkkonen, L., Musgrove, R., Kaoma, T., Muller, A., Vallar, L., Di Monte, D. A., Balling, R., & Neumann, H. (2014). Neurodegeneration by activation of the microglial complement-phagosome pathway. Journal of Neuroscience, 34, 8546–8556. https://doi.org/10.1523/JNEUROSCI.5002-13.2014
Broadhead, M. J., Horrocks, M. H., Zhu, F., Muresan, L., Benavides-Piccione, R., DeFelipe, J., Fricker, D., Kopanitsa, M. V., Duncan, R. R., Klenerman, D., Komiyama, N. H., Lee, S. F., & Grant, S. G. N. (2016). PSD95 nanoclusters are postsynaptic building blocks in hippocampus circuits. Scientific Reports, 6, 24626. https://doi.org/10.1038/srep24626
Buras, J. A., Holzmann, B., & Sitkovsky, M. (2005). Animal models of sepsis: Setting the stage. Nature Reviews Drug Discovery, 4, 854–865. https://doi.org/10.1038/nrd1854
Burton, M. D., Rytych, J. L., Freund, G. G., & Johnson, R. W. (2013). Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice. Brain, Behavior, and Immunity, 30, 66–72. https://doi.org/10.1016/j.bbi.2013.01.002
Crane, J. W., Baiquni, G. P., Sullivan, R. K., Lee, J. D., Sah, P., Taylor, S. M., Noakes, P. G., & Woodruff, T. M. (2009). The C5a anaphylatoxin receptor CD88 is expressed in presynaptic terminals of hippocampal mossy fibres. Journal of Neuroinflammation, 6, 34. https://doi.org/10.1186/1742-2094-6-34
Crapser, J. D., Spangenberg, E. E., Barahona, R. A., Arreola, M. A., Hohsfield, L. A., & Green, K. N. (2020). Microglia facilitate loss of perineuronal nets in the Alzheimer’s disease brain. EBioMedicine, 58, 102919. https://doi.org/10.1016/j.ebiom.2020.102919
Cserép, C., Pósfai, B., Lénárt, N., Fekete, R., László, Z. I., Lele, Z., Orsolits, B., Molnár, G., Heindl, S., Schwarcz, A. D., Ujvári, K., Környei, Z., Tóth, K., Szabadits, E., Sperlágh, B., Baranyi, M., Csiba, L., Hortobágyi, T., Maglóczky, Z., … Dénes, Á. (2020). Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science, 367, 528. https://doi.org/10.1126/science.aax6752
Dejanovic, B., Huntley, M. A., De Mazière, A., Meilandt, W. J., Wu, T., Srinivasan, K., Jiang, Z., Gandham, V., Friedman, B. A., Ngu, H., Foreman, O., Carano, R. A. D., Chih, B., Klumperman, J., Bakalarski, C., Hanson, J. E., & Sheng, M. (2018). Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron, 100, 1322–1336.e7.
Deng, X., Wang, Y., Chou, J., & Cadet, J. L. (2001). Methamphetamine causes widespread apoptosis in the mouse brain: Evidence from using an improved TUNEL histochemical method. Molecular Brain Research, 93, 64–69. https://doi.org/10.1016/S0169-328X(01)00184-X
Doube, M., Kłosowski, M. M., Arganda-Carreras, I., Cordelières, F. P., Dougherty, R. P., Jackson, J. S., Schmid, B., Hutchinson, J. R., & Shefelbine, S. J. (2010). BoneJ: Free and extensible bone image analysis in ImageJ. Bone, 47, 1076–1079. https://doi.org/10.1016/j.bone.2010.08.023
Efron, P. A., Mohr, A. M., Moore, F. A., & Moldawer, L. L. (2015). The future of murine sepsis and trauma research models. Journal of Leukocyte Biology, 98, 945–952. https://doi.org/10.1189/jlb.5MR0315-127R
Faul, F., Erdfelder, E., Lang, A.-G., & Buchner, A. (2007). G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39, 175–191. https://doi.org/10.3758/BF03193146
Felts, P. A., Woolston, A.-M., Fernando, H. B., Asquith, S., Gregson, N. A., Mizzi, O. J., & Smith, K. J. (2005). Inflammation and primary demyelination induced by the intraspinal injection of lipopolysaccharide. Brain, 128, 1649–1666. https://doi.org/10.1093/brain/awh516
Franceschi, C., Capri, M., Monti, D., Giunta, S., Olivieri, F., Sevini, F., Panourgia, M. P., Invidia, L., Celani, L., Scurti, M., Cevenini, E., Castellani, G. C., & Salvioli, S. (2007). Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans. Mechanisms of Ageing and Development, 128, 92–105. https://doi.org/10.1016/j.mad.2006.11.016
Fritze, T., Doblhammer, G., Widmann, C. N., & Heneka, M. T. (2021). Time course of dementia following sepsis in German health claims data. Neurology: Neuroimmunology & Neuroinflammation, 8, e911.
Gentile, L. F., Cuenca, A. G., Efron, P. A., Ang, D., Bihorac, A., McKinley, B. A., Moldawer, L. L., & Moore, F. A. (2012). Persistent inflammation and immunosuppression: A common syndrome and new horizon for surgical intensive care. Journal of Trauma and Acute Care Surgery, 72, 1491–1501. https://doi.org/10.1097/TA.0b013e318256e000
Girard, T. D., Thompson, J. L., Pandharipande, P. P., Brummel, N. E., Jackson, J. C., Patel, M. B., Hughes, C. G., Chandrasekhar, R., Pun, B. T., Boehm, L. M., Elstad, M. R., Goodman, R. B., Bernard, G. R., Dittus, R. S., & Ely, E. W. (2018). Clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: A prospective cohort study. Lancet Respiratory Medicine, 6, 213–222. https://doi.org/10.1016/S2213-2600(18)30062-6
Godbout, J. P., Chen, J., Abraham, J., Richwine, A. F., Berg, B. M., Kelley, K. W., & Johnson, R. W. (2005). Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB Journal, 19, 1329–1331.
Gunther, M. L., Morandi, A., Krauskopf, E., Pandharipande, P., Girard, T. D., Jackson, J. C., Thompson, J., Shintani, A. K., Geevarghese, S., Miller, R. R., Canonico, A., Merkle, K., Cannistraci, C. J., Rogers, B. P., Gatenby, J. C., Heckers, S., Gore, J. C., Hopkins, R. O., & Ely, E. W. (2012). The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: The VISIONS cohort magnetic resonance imaging study. Critical Care Medicine, 40, 2022–2032. https://doi.org/10.1097/CCM.0b013e318250acc0
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., Lemere, C. A., Selkoe, D. J., & Stevens, B. (2016). Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, 352, 712–716. https://doi.org/10.1126/science.aad8373
Huff, J. (2015). The Airyscan detector from ZEISS: confocal imaging with improved signal-to-noise ratio and super-resolution. Nature Methods, 12, i–ii.
Inouye, S. K., Robinson, T., Blaum, C., Busby-Whitehead, J., Boustani, M., Chalian, A., Deiner, S., Fick, D., Hutchison, L., Johanning, J., Katlic, M., Kempton, J., Kennedy, M., Kimchi, E., Ko, C., Leung, J., Mattison, M., Mohanty, S., Nana, A., … Richter, H. (2015). Postoperative delirium in older adults: Best practice statement from the american geriatrics society. Journal of the American College of Surgeons, 220, 136–148.e1.
Jacob, A., Hensley, L. K., Safratowich, B. D., Quigg, R. J., & Alexander, J. J. (2007). The role of the complement cascade in endotoxin-induced septic encephalopathy. Laboratory Investigation, 87, 1186–1194. https://doi.org/10.1038/labinvest.3700686
Ji, M.-H., Qiu, L.-L., Tang, H., Ju, L.-S., Sun, X.-R., Zhang, H., Jia, M., Zuo, Z.-Y., Shen, J.-C., & Yang, J.-J. (2015). Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice. Journal of Neuroinflammation, 12, 182. https://doi.org/10.1186/s12974-015-0401-x
Jinno, S., Fleischer, F., Eckel, S., Schmidt, V., & Kosaka, T. (2007). Spatial arrangement of microglia in the mouse hippocampus: a stereological study in comparison with astrocytes. Glia, 55, 1334–1347. https://doi.org/10.1002/glia.20552
Kaukonen, K.-M., Bailey, M., Suzuki, S., Pilcher, D., & Bellomo, R. (2014). Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA, 311, 1308. https://doi.org/10.1001/jama.2014.2637
Kayagaki, N., Wong, M. T., Stowe, I. B., Ramani, S. R., Gonzalez, L. C., Akashi-Takamura, S., Miyake, K., Zhang, J., Lee, W. P., Muszynski, A., Forsberg, L. S., Carlson, R. W., & Dixit, V. M. (2013). Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science, 341, 1246–1249. https://doi.org/10.1126/science.1240248
Keane, L., Antignano, I., Riechers, S.-P., Zollinger, R., Dumas, A. A., Offermann, N., Bernis, M. E., Russ, J., Graelmann, F., McCormick, P. N., Esser, J., Tejera, D., Nagano, A. I., Wang, J., Chelala, C., Biederbick, Y., Halle, A., Salomoni, P., Heneka, M. T., & Capasso, M. (2021). mTOR-dependent translation amplifies microglia priming in aging mice. Journal of Clinical Investigation, 131, 132727. https://doi.org/10.1172/JCI132727
Kondo, S., Kohsaka, S., & Okabe, S. (2011). Long-term changes of spine dynamics and microglia after transient peripheral immune response triggered by LPS in vivo. Molecular Brain, 4, 27. https://doi.org/10.1186/1756-6606-4-27
Lee, J.-H., Kim, J.-Y., Noh, S., Lee, H., Lee, S. Y., Mun, J. Y., Park, H., & Chung, W.-S. (2021). Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature, 590, 612–617. https://doi.org/10.1038/s41586-020-03060-3
Lee, J., Lee, Y., Yuk, D., Choi, D., Ban, S., Oh, K., & Hong, J. (2008). Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. Journal of Neuroinflammation, 5, 37. https://doi.org/10.1186/1742-2094-5-37
Lerouge, I., & Vanderleyden, J. (2002). O-antigen structural variation: mechanisms and possible roles in animal/plant–microbe interactions. FEMS Microbiology Reviews, 26, 17–47. https://doi.org/10.1111/j.1574-6976.2002.tb00597.x
Li, S., Li, B., Zhang, L., Zhang, G., Sun, J., Ji, M., & Yang, J. (2020). A complement-microglial axis driving inhibitory synapse related protein loss might contribute to systemic inflammation-induced cognitive impairment. International Immunopharmacology, 87, 106814. https://doi.org/10.1016/j.intimp.2020.106814
Martin, G. S., Mannino, D. M., Eaton, S., & Moss, M. (2003). The epidemiology of sepsis in the United States from 1979 through 2000. New England Journal of Medicine, 348, 1546–1554. https://doi.org/10.1056/NEJMoa022139
Mei, J., Riedel, N., Grittner, U., Endres, M., Banneke, S., & Emmrich, J. V. (2018). Body temperature measurement in mice during acute illness: implantable temperature transponder versus surface infrared thermometry. Scientific Reports, 8, 3526. https://doi.org/10.1038/s41598-018-22020-6
Miyamoto, A., Wake, H., Ishikawa, A. W., Eto, K., Shibata, K., Murakoshi, H., Koizumi, S., Moorhouse, A. J., Yoshimura, Y., & Nabekura, J. (2016). Microglia contact induces synapse formation in developing somatosensory cortex. Nature Communications, 7, 12540. https://doi.org/10.1038/ncomms12540
Mutterer, J., & Zinck, E. (2013). Quick-and-clean article figures with FigureJ. Journal of Microscopy, 252, 89–91. https://doi.org/10.1111/jmi.12069
Muzambi, R., Bhaskaran, K., Smeeth, L., Brayne, C., Chaturvedi, N., & Warren-Gash, C. (2021). Assessment of common infections and incident dementia using UK primary and secondary care data: a historical cohort study. Lancet Healthy Longevity, 2, e426–e435.
Neher, J. J., & Cunningham, C. (2019). Priming microglia for innate immune memory in the brain. Trends in Immunology, 40, 358–374. https://doi.org/10.1016/j.it.2019.02.001
Netea, M. G., Kullberg, B. J., Joosten, L. A., Sprong, T., Verschueren, I., Boerman, O. C., Amiot, F., van den Berg, W. B., & Van der Meer, J. W. (2001). Lethal Escherichia coli and Salmonella typhimurium endotoxemia is mediated through different pathways. European Journal of Immunology, 31, 2529–2538. https://doi.org/10.1002/1521-4141(200109)31:9<2529:AID-IMMU2529>3.0.CO;2-B
Nguyen, M. D., Julien, J.-P., & Rivest, S. (2002). Innate immunity: The missing link in neuroprotection and neurodegeneration? Nature Reviews Neuroscience, 3, 216–227.
O’Neil, S. M., Witcher, K. G., McKim, D. B., & Godbout, J. P. (2018). Forced turnover of aged microglia induces an intermediate phenotype but does not rebalance CNS environmental cues driving priming to immune challenge. Acta Neuropathologica Communications, 6, 129. https://doi.org/10.1186/s40478-018-0636-8
Ogata, K., & Kosaka, T. (2002). Structural and quantitative analysis of astrocytes in the mouse hippocampus. Neuroscience, 113, 221–233. https://doi.org/10.1016/S0306-4522(02)00041-6
Ormerod, B. K., Hanft, S. J., Asokan, A., Haditsch, U., Lee, S. W., & Palmer, T. D. (2013). PPARγ activation prevents impairments in spatial memory and neurogenesis following transient illness. Brain, Behavior, and Immunity, 29, 28–38. https://doi.org/10.1016/j.bbi.2012.10.017
Prescott, H. C., & Angus, D. C. (2018). Enhancing recovery from sepsis: A review. JAMA, 319, 62–75. https://doi.org/10.1001/jama.2017.17687
Qin, L., Wu, X., Block, M. L., Liu, Y., Breese, G. R., Hong, J.-S., Knapp, D. J., & Crews, F. T. (2007). Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia, 55, 453–462. https://doi.org/10.1002/glia.20467
Robinson, J. L., Molina-Porcel, L., Corrada, M. M., Raible, K., Lee, E. B., Lee, V.- M.-Y., Kawas, C. H., & Trojanowski, J. Q. (2014). Perforant path synaptic loss correlates with cognitive impairment and Alzheimer’s disease in the oldest-old. Brain, 137, 2578–2587. https://doi.org/10.1093/brain/awu190
Rodriguez-Loureiro, I., Latza, V. M., Fragneto, G., & Schneck, E. (2018). Conformation of single and interacting lipopolysaccharide surfaces bearing O-side Chains. Biophysical Journal, 114, 1624–1635. https://doi.org/10.1016/j.bpj.2018.02.014
Rudd, K. E., Johnson, S. C., Agesa, K. M., Shackelford, K. A., Tsoi, D., Kievlan, D. R., Colombara, D. V., Ikuta, K. S., Kissoon, N., Finfer, S., Fleischmann-Struzek, C., Machado, F. R., Reinhart, K. K., Rowan, K., Seymour, C. W., Watson, R. S., West, T. E., Marinho, F., Hay, S. I., … Naghavi, M. (2020). Global, regional, and national sepsis incidence and mortality, 1990–2017: Analysis for the Global Burden of Disease Study. Lancet, 395, 200–211. https://doi.org/10.1016/S0140-6736(19)32989-7
Sandiego, C. M., Gallezot, J.-D., Pittman, B., Nabulsi, N., Lim, K., Lin, S.-F., Matuskey, D., Lee, J.-Y., O’Connor, K. C., Huang, Y., Carson, R. E., Hannestad, J., & Cosgrove, K. P. (2015). Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proceedings of the National Academy of Sciences of the United States of America, 112, 12468–12473. https://doi.org/10.1073/pnas.1511003112
Sauerbeck, A. D., Gangolli, M., Reitz, S. J., Salyards, M. H., Kim, S. H., Hemingway, C., Gratuze, M., Makkapati, T., Kerschensteiner, M., Holtzman, D. M., Brody, D. L., & Kummer, T. T. (2020). SEQUIN multiscale imaging of mammalian central synapses reveals loss of synaptic connectivity resulting from diffuse traumatic brain injury. Neuron, 107, 257–273.e5.
Schafer, D. P., Lehrman, E. K., Heller, C. T., & Stevens, B. (2014). An engulfment assay: A protocol to assess interactions between CNS phagocytes and neurons. Journal of Visualized Experiments, 88, 51482. https://doi.org/10.3791/51482
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012). Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron, 74, 691–705. https://doi.org/10.1016/j.neuron.2012.03.026
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., Tinevez, J.-Y., White, D. J., Hartenstein, V., Eliceiri, K., Tomancak, P., & Cardona, A. (2012). Fiji: An open-source platform for biological-image analysis. Nature Methods, 9, 676–682. https://doi.org/10.1038/nmeth.2019
Semmler, A., Frisch, C., Debeir, T., Ramanathan, M., Okulla, T., Klockgether, T., & Heneka, M. T. (2007). Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Experimental Neurology, 204, 733–740.
Semmler, A., Widmann, C. N., Okulla, T., Urbach, H., Kaiser, M., Widman, G., Mormann, F., Weide, J., Fliessbach, K., Hoeft, A., Jessen, F., Putensen, C., & Heneka, M. T. (2013). Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. Journal of Neurology, Neurosurgery and Psychiatry, 84, 62–69. https://doi.org/10.1136/jnnp-2012-302883
Shi, Q., Colodner, K. J., Matousek, S. B., Merry, K., Hong, S., Kenison, J. E., Frost, J. L., Le, K. X., Li, S., Dodart, J.-C., Caldarone, B. J., Stevens, B., & Lemere, C. A. (2015). Complement C3-deficient mice fail to display age-related hippocampal decline. Journal of Neuroscience, 35, 13029–13042. https://doi.org/10.1523/JNEUROSCI.1698-15.2015
Shoji, H., Takao, K., Hattori, S., & Miyakawa, T. (2016). Age-related changes in behavior in C57BL/6J mice from young adulthood to middle age. Molecular Brain, 9, 11. https://doi.org/10.1186/s13041-016-0191-9
Simen, A. A., Bordner, K. A., Martin, M. P., Moy, L. A., & Barry, L. C. (2011). Cognitive dysfunction with aging and the role of inflammation. Therapeutic Advances in Chronic Disease, 2, 175–195. https://doi.org/10.1177/2040622311399145
Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G. R., Chiche, J.-D., Coopersmith, C. M., Hotchkiss, R. S., Levy, M. M., Marshall, J. C., Martin, G. S., Opal, S. M., Rubenfeld, G. D., van der Poll, T., Vincent, J.-L., & Angus, D. C. (2016). The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA, 315, 801–810. https://doi.org/10.1001/jama.2016.0287
Sofroniew, M. V., & Vinters, H. V. (2010). Astrocytes: biology and pathology. Acta Neuropathologica, 119, 7–35. https://doi.org/10.1007/s00401-009-0619-8
Taveira da Silva, A. M., Kaulbach, H. C., Chuidian, F. S., Lambert, D. R., Suffredini, A. F., & Danner, R. L. (1993). Brief report: shock and multiple-organ dysfunction after self-administration of Salmonella endotoxin. New England Journal of Medicine, 328, 1457–1460. https://doi.org/10.1056/NEJM199305203282005
Tejera, D., Mercan, D., Sanchez-Caro, J. M., Hanan, M., Greenberg, D., Soreq, H., Latz, E., Golenbock, D., & Heneka, M. T. (2019). Systemic inflammation impairs microglial Aβ clearance through NLRP 3 inflammasome. EMBO Journal, 38, e101064.
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991). Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Annals of Neurology, 30, 572–580. https://doi.org/10.1002/ana.410300410
Tremblay, M.-È., Lowery, R. L., & Majewska, A. K. (2010). Microglial interactions with synapses are modulated by visual experience. PLoS Biology, 8, e1000527.
Valero, J., Mastrella, G., Neiva, I., Sánchez, S., & Malva, J. O. (2014). Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory. Frontiers in Neuroscience, 8, 83. https://doi.org/10.3389/fnins.2014.00083
Vallières, N., Berard, J. L., David, S., & Lacroix, S. (2006). Systemic injections of lipopolysaccharide accelerates myelin phagocytosis during Wallerian degeneration in the injured mouse spinal cord. Glia, 53, 103–113. https://doi.org/10.1002/glia.20266
van der Slikke, E. C., An, A. Y., Hancock, R. E. W., & Bouma, H. R. (2020). Exploring the pathophysiology of post-sepsis syndrome to identify therapeutic opportunities. EBioMedicine, 61, 103044. https://doi.org/10.1016/j.ebiom.2020.103044
van Munster, B. C., Korevaar, J. C., Zwinderman, A. H., Levi, M., Wiersinga, W. J., & De Rooij, S. E. (2008). Time-course of cytokines during delirium in elderly patients with hip fractures. Journal of the American Geriatrics Society, 56, 1704–1709. https://doi.org/10.1111/j.1532-5415.2008.01851.x
Veerhuis, R., Nielsen, H. M., & Tenner, A. J. (2011). Complement in the brain. Molecular Immunology, 48, 1592–1603.
Vereker, E., O’Donnell, E., & Lynch, M. A. (2000). The inhibitory effect of interleukin-1beta on long-term potentiation is coupled with increased activity of stress-activated protein kinases. Journal of Neuroscience, 20, 6811–6819.
Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S., & Nabekura, J. (2009). Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. Journal of Neuroscience, 29, 3974–3980. https://doi.org/10.1523/JNEUROSCI.4363-08.2009
Weberpals, M., Hermes, M., Hermann, S., Kummer, M. P., Terwel, D., Semmler, A., Berger, M., Schafers, M., & Heneka, M. T. (2009). NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. Journal of Neuroscience, 29, 14177–14184. https://doi.org/10.1523/JNEUROSCI.3238-09.2009
Weinhard, L., di Bartolomei, G., Bolasco, G., Machado, P., Schieber, N. L., Neniskyte, U., Exiga, M., Vadisiute, A., Raggioli, A., Schertel, A., Schwab, Y., & Gross, C. T. (2018). Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nature Communications, 9, 1228. https://doi.org/10.1038/s41467-018-03566-5
Wendeln, A.-C., Degenhardt, K., Kaurani, L., Gertig, M., Ulas, T., Jain, G., Wagner, J., Häsler, L. M., Wild, K., Skodras, A., Blank, T., Staszewski, O., Datta, M., Centeno, T. P., Capece, V., Islam, M. R., Kerimoglu, C., Staufenbiel, M., Schultze, J. L., … Neher, J. J. (2018). Innate immune memory in the brain shapes neurological disease hallmarks. Nature, 556, 332–338. https://doi.org/10.1038/s41586-018-0023-4
West, M. J., & Gundersen, H. J. G. (1990). Unbiased stereological estimation of the number of neurons in the human hippocampus. Journal of Comparative Neurology, 296, 1–22.
Whitfield, C., Williams, D. M., & Kelly, S. D. (2020). Lipopolysaccharide O-antigens—bacterial glycans made to measure. Journal of Biological Chemistry, 295, 10593–10609.
Widmann, C. N., & Heneka, M. T. (2014). Long-term cerebral consequences of sepsis. Lancet Neurology, 13, 630–636. https://doi.org/10.1016/S1474-4422(14)70017-1
Wijasa, T. S., Sylvester, M., Brocke-Ahmadinejad, N., Schwartz, S., Santarelli, F., Gieselmann, V., Klockgether, T., Brosseron, F., & Heneka, M. T. (2020). Quantitative proteomics of synaptosome S-nitrosylation in Alzheimer’s disease. Journal of Neurochemistry, 152, 710–726.
Yan, C., & Gao, H. (2012). New insights for C5a and C5a receptors in sepsis. Frontiers in Immunology, 3, 368. https://doi.org/10.3389/fimmu.2012.00368
Yende, S., Kellum, J. A., Talisa, V. B., Peck Palmer, O. M., Chang, C.-C., Filbin, M. R., Shapiro, N. I., Hou, P. C., Venkat, A., LoVecchio, F., Hawkins, K., Crouser, E. D., Newman, A. B., & Angus, D. C. (2019). Long-term host immune response trajectories among hospitalized patients with sepsis. JAMA Network Open, 2, e198686. https://doi.org/10.1001/jamanetworkopen.2019.8686
Youm, Y.-H., Grant, R. W., McCabe, L. R., Albarado, D. C., Nguyen, K. Y., Ravussin, A., Pistell, P., Newman, S., Carter, R., Laque, A., Münzberg, H., Rosen, C. J., Ingram, D. K., Salbaum, J. M., & Dixit, V. D. (2013). Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metabolism, 18, 519–532. https://doi.org/10.1016/j.cmet.2013.09.010
Young, K., & Morrison, H. (2018). Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using ImageJ. Journal of Visualized Experiments, 136, e57648. https://doi.org/10.3791/57648
Yu, S., Zuo, L., Wang, F., Chen, Z., Hu, Y., Wang, Y., Wang, X., & Zhang, W. (2014). Potential biomarkers relating pathological proteins, neuroinflammatory factors and free radicals in PD patients with cognitive impairment: A cross-sectional study. BMC Neurology, 14, 113. https://doi.org/10.1186/1471-2377-14-113
Zhang, S., Wang, X., Ai, S., Ouyang, W., Le, Y., & Tong, J. (2017). Sepsis-induced selective loss of NMDA receptors modulates hippocampal neuropathology in surviving septic mice. PLoS One, 12, e0188273. https://doi.org/10.1371/journal.pone.0188273
Zrzavy, T., Höftberger, R., Berger, T., Rauschka, H., Butovsky, O., Weiner, H., & Lassmann, H. (2019). Pro-inflammatory activation of microglia in the brain of patients with sepsis. Neuropathology and Applied Neurobiology, 45, 278–290. https://doi.org/10.1111/nan.12502
