A complement–microglial axis drives synapse loss during virus-induced memory impairment
Open accessAbstract
Over 50% of patients who survive neuroinvasive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae. Although thousands of cases of WNV-mediated memory dysfunction accrue annually, the mechanisms responsible for these impairments are unknown. The classical complement cascade, a key component of innate immune pathogen defence, mediates synaptic pruning by microglia during early postnatal development. Here we show that viral infection of adult hippocampal neurons induces complement-mediated elimination of presynaptic terminals in a murine WNV neuroinvasive disease model. Inoculation of WNV-NS5-E218A, a WNV with a mutant NS5(E218A) protein leads to survival rates and cognitive dysfunction that mirror human WNV neuroinvasive disease. WNV-NS5-E218A-recovered mice (recovery defined as survival after acute infection) display impaired spatial learning and persistence of phagocytic microglia without loss of hippocampal neurons or volume. Hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning show increased expression of genes that drive synaptic remodelling by microglia via complement. C1QA was upregulated and localized to microglia, infected neurons and presynaptic terminals during WNV neuroinvasive disease. Murine and human WNV neuroinvasive disease post-mortem samples exhibit loss of hippocampal CA3 presynaptic terminals, and murine studies revealed microglial engulfment of presynaptic terminals during acute infection and after recovery. Mice with fewer microglia (Il34(-/-) mice with a deficiency in IL-34 production) or deficiency in complement C3 or C3a receptor were protected from WNV-induced synaptic terminal loss. Our study provides a new murine model of WNV-induced spatial memory impairment, and identifies a potential mechanism underlying neurocognitive impairment in patients recovering from WNV neuroinvasive disease.
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Dysregulation of microglial phagocytosis of synapses has been implicated in the pathology of diverse neurological diseases.
“Dysregulation of microglial phagocytosis of synapses has been implicated in the pathology of diverse neurological diseases (Hong et al., 2016; Lui et al., 2016; Vasek et al., 2016), failure to clear myelin debris contributes to CNS regenerative failure (Vargas and Barres, 2007), and problems with microglial uptake and clearance may contribute to aging-associated cognitive decline (Safaiyan et al.,”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Vasek et al., 2016
The paper reports increased engulfment of presynaptic terminals by microglia in West Nile virus-infected mice and links complement- and microglia-dependent synapse loss to spatial-learning defects during recovery (paper text labelled “Abstract”; page unavailable). It supports the claim for this neurological condition, but does not establish that dysregulated microglial synapse phagocytosis is implicated across diverse neurological diseases. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn WNV and ZIKV encephalitis, microglia are orchestrators of spatial-learning impairments seen in the recovery phase after viral neuroinvasion.
“In WNV and Zika virus (ZIKV) encephalitis, microglia have been identified as orchestrators of spatial-learning impairments seen in the recovery phase after viral neuroinvasion [111, 324].”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [324]
The paper reports impaired spatial learning in mice recovering from WNV neuroinvasive disease and implicates microglia in the associated synapse loss (Abstract; page not available). The cited sentence also names ZIKV encephalitis, which this paper does not study. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEnhanced microglia-mediated synaptic engulfment during insult, infection or injury may be protective by preventing excitotoxicity and dampening nonsense signalling from damaged neurons, or by limiting trans-synaptic viral spread or aberrant calcium signalling by infected neurons.
“Nonetheless, enhanced microglia-mediated synaptic engulfment during insult, infection or injury may well be a protective mechanism, for instance by preventing excitotoxicity and dampening nonsense signalling activity from damaged or injured neurons [342] or, in the context of neurotropic infection, by limiting trans-synaptic viral spread or aberrant calcium signalling by infected neurons [324].”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [324]
For the portion attributed to [324], the discussion passage in our copy (indexed under Abstract; page unavailable) proposes that eliminating presynaptic terminals during neurotropic infection may prevent trans-synaptic viral spread or aberrant signalling by infected neurons. It does not specify calcium signalling, so that added detail is unsupported. The excitotoxicity and damaged-neuron portion is attached to [342], not this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredInappropriate removal of hippocampal synapses leads to circuitry dysfunction and spatial-learning deficits in the clinical recovery phase from WNV and ZIKV neuroinvasive disease.
“This is shown by the inappropriate removal of hippocampal synapses leading to circuitry dysfunction and spatial-learning deficits in the clinical recovery phase from WNV and ZIKV neuroinvasive disease [111, 324].”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [324]
The supplied passages (Abstract; page unavailable) report microglial removal of hippocampal presynaptic terminals and impaired spatial learning in mice recovering from WNV infection. They do not address ZIKV or directly demonstrate circuitry dysfunction, and the human WNV synapse samples were from acute disease rather than clinical recovery. (LLM, conf=0.89)
Experimental — accuracy not yet measuredComplement protein C3, via C3a recognized by microglial C3aR, is important in the aberrant engulfment of synapses.
“Both studies show the importance of complement protein C3, the hydrolysed fragment of which, C3a, is recognized by microglial-expressed C3a receptor (C3aR), in the aberrant engulfment of synapses.”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [324]
Housekeeping functions include synaptic remodeling, migration to sites of neuronal death for phagocytosis, and maintenance of myelin homeostasis.
“Physiological housekeeping functions include synaptic remodeling (a function critical for CNS development, homeostasis, and neurodegeneration20–22), migration to sites of neuronal death to phagocytose dead or dying cells23,24 or debris, and maintaining myelin homeostasis25.”
From Microglia in neurodegeneration (2018) · cites this paper as [20]
The complement pathway is implicated in microglia-mediated synapse pruning.
“The complement pathway has been implicated in microglia-mediated synapse pruning (Hong et al., 2016; Vasek et al., 2016).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Vasek et al., 2016
C3aR promotes viral-induced synapse loss and cognitive decline.
“This idea gained further support by a recent report showing a detrimental effect of C3aR in promoting viral-induced synapse loss and cognitive decline (Vasek et al., 2016).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Vasek et al., 2016
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Cites
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890 · see citing works
Statistical significance for genomewide studies
Storey, J. D., & Tibshirani, R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1530509100 · Cited by 9,692 · see citing works
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
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) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089 · see citing works
Self-citationThe Classical Complement Cascade Mediates CNS Synapse Elimination
Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.036 · Cited by 3,313 · see citing works
Self-citationMemory deficits associated with senescence: A neurophysiological and behavioral study in the rat.
Barnes, C. A. (1979) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0077579 · Cited by 2,088 · see citing works
The microglial sensome revealed by direct RNA sequencing
Hickman, S. E., Kingery, N. D., Ohsumi, T. K., Borowsky, M. L., Wang, L.-C., Means, T. K., & El Khoury, J. (2013) · Nature Neuroscience · doi:10.1038/nn.3554 · Cited by 1,511 · see citing works
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
Chung, W.-S., Clarke, L. E., Wang, G. X., Stafford, B. K., Sher, A., Chakraborty, C., Joung, J., Foo, L. C., Thompson, A., Chen, C., et al. (2013) · Nature · doi:10.1038/nature12776 · Cited by 1,377 · see citing works
On the role of the hippocampus in learning and memory in the rat.
Jarrard, L. E. (1993) · Behavioral and Neural Biology · doi:10.1016/0163-1047(93)90664-4 · Cited by 1,125 · see citing works
Wang, Y., Szretter, K. J., Vermi, W., Gilfillan, S., Rossini, C., Cella, M., Barrow, A. D., Diamond, M. S., & Colonna, M. (2012) · Nature Immunology · doi:10.1038/ni.2360 · Cited by 1,011 · see citing works
2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members
Daffis, S., Szretter, K. J., Schriewer, J. M., Li, J., Youn, S., Errett, J. S., Lin, T., Schneller, S. W., Züst, R., Dong, H., et al. (2010) · Nature · doi:10.1038/nature09489 · Cited by 910 · see citing works
Neurologic Manifestations and Outcome of West Nile Virus Infection
Sejvar, J. J. (2003) · JAMA · doi:10.1001/jama.290.4.511 · Cited by 648 · see citing works
Lian, H., Litvinchuk, A., Chiang, A. C.-A., Aithmitti, N., Jankowsky, J. L., & Zheng, H. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.2117-15.2016 · Cited by 597 · see citing works
Samuel, M. A., & Diamond, M. (2005) · Journal of Virology · doi:10.1128/jvi.79.21.13350-13361.2005 · Cited by 430 · see citing works
A Dramatic Increase of C1q Protein in the CNS during Normal Aging
Stephan, A. H., Madison, D. V., Mateos, J. M., Fraser, D. A., Lovelett, E. A., Coutellier, L., Kim, L., Tsai, H.-H., Huang, E. J., Rowitch, D. H., et al. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1333-13.2013 · Cited by 423 · see citing works
Enhanced synaptic connectivity and epilepsy in C1q knockout mice
Chu, Y., Jin, X., Parada, I., Pesic, A., Stevens, B., Barres, B., & Prince, D. A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913449107 · Cited by 364 · see citing works
Self-citationSequestration by IFIT1 Impairs Translation of 2′O-unmethylated Capped RNA
Habjan, M., Hubel, P., Mariano, L. L., Benda, C., Holze, C., Eberl, H. C., Mann, A., Kindler, E., Gil‐Cruz, C., Ziebuhr, J., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003663 · Cited by 213 · see citing works
Long-Term Prognosis for Clinical West Nile Virus Infection
Klee, A. L., Maldin, B., Edwin, B., Poshni, I., Mostashari, F., Fine, A., Layton, M., & Nash, D. (2004) · Emerging Infectious Diseases · doi:10.3201/eid1008.030879 · Cited by 207 · see citing works
Ebenbichler, C. F., Thielens, N. M., Vornhagen, R., Marschang, P., Arlaud, G. J., & Dierich, M. P. (1991) · The Journal of Experimental Medicine · doi:10.1084/jem.174.6.1417 · Cited by 203 · see citing works
Estimated cumulative incidence of West Nile virus infection in US adults, 1999–2010
Petersen, L. R., Carson, P. J., Biggerstaff, B. J., Custer, B., Borchardt, S. M., & Busch, M. P. (2012) · Epidemiology and Infection · doi:10.1017/s0950268812001070 · Cited by 182 · see citing works
Samuel, M. A., Morrey, J. D., & Diamond, M. (2006) · Journal of Virology · doi:10.1128/jvi.02311-06 · Cited by 181 · see citing works
Mehlhop, E., & Diamond, M. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052388 · Cited by 175 · see citing works
Szretter, K. J., Daniels, B. P., Cho, H., Gainey, M. D., Yokoyama, W. M., Gale, M., Virgin, H. W., Klein, R. S., Sen, G. C., & Diamond, M. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002698 · Cited by 168 · see citing works
Self-citationVeerhuis, R., Janssen, I., Groot, C. J. A. D., Muiswinkel, F. L. V., Hack, C. E., & Eikelenboom, P. (1999) · Experimental Neurology · doi:10.1006/exnr.1999.7199 · Cited by 154 · see citing works
Mehlhop, E., Whitby, K., Oliphant, T., Marri, A., Engle, M. J., & Diamond, M. (2005) · Journal of Virology · doi:10.1128/jvi.79.12.7466-7477.2005 · Cited by 154 · see citing works
McCandless, E. E., Zhang, B., Diamond, M., & Klein, R. S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0800898105 · Cited by 151 · see citing works
Self-citationShrestha, B., Zhang, B., Purtha, W. E., Klein, R. S., & Diamond, M. (2008) · Journal of Virology · doi:10.1128/jvi.01118-08 · Cited by 107 · see citing works
Self-citationArmah, H. B., Wang, G., Omalu, B. I., Tesh, R. B., Gyure, K. A., Chute, D. J., Smith, R. D., Dulai, P., Vinters, H. V., Kleinschmidt‐DeMasters, B. K., et al. (2007) · Brain Pathology · doi:10.1111/j.1750-3639.2007.00080.x · Cited by 105 · see citing works
Durrant, D. M., Robinette, M. L., & Klein, R. S. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20121897 · Cited by 78 · see citing works
Self-citationPersistent neuropsychological impairment associated with West Nile virus infection
Sadek, J. R., Pergam, S. A., Harrington, J. A., Echevarria, L. A., Davis, L. E., Goade, D., Harnar, J., Nofchissey, R. A., Sewell, C. M., Ettestad, P., et al. (2009) · Journal of Clinical and Experimental Neuropsychology · doi:10.1080/13803390902881918 · Cited by 72 · see citing works
Clarke, P., Leser, J. S., Bowen, R. A., & Tyler, K. L. (2014) · mBio · doi:10.1128/mbio.00902-14 · Cited by 67 · see citing works
Self-citationClarke, P., Leser, J. S., Quick, E. D., Dionne, K. R., Beckham, J. D., & Tyler, K. L. (2013) · Journal of Virology · doi:10.1128/jvi.02944-13 · Cited by 59 · see citing works
Self-citationMénard, C., Quirion, R., Vigneault, É., Bouchard, S., Ferland, G., Mestikawy, S. E., & Gaudreau, P. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.11.013 · Cited by 41 · see citing works
Sun, T., Vasek, M. J., & Klein, R. S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096442 · Cited by 20 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Microglia and macrophages in brain homeostasis and disease
Li, Q., & Barres, B. A. (2018) · Nature Reviews Immunology · doi:10.1038/nri.2017.125 · Cited by 1,999 · see citing works
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935 · see citing works
Microglia emerge as central players in brain disease
Salter, M. W., & Stevens, B. (2017) · Nature Medicine · doi:10.1038/nm.4397 · Cited by 1,767 · see citing works
Self-citationMicroglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710 · see citing works
Desforges, M., Le Coupanec, A., Dubeau, P., Bourgouin, A., Lajoie, L., Dubé, M., & Talbot, P. J. (2019) · Viruses · doi:10.3390/v12010014 · Cited by 1,048 · see citing works
Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity
Mantovani, A., Dinarello, C. A., Molgora, M., & Garlanda, C. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.012 · Cited by 1,046 · see citing works
Microglia: Immune and non-immune functions
Borst, K., Dumas, A. A., & Prinz, M. (2021) · Immunity · doi:10.1016/j.immuni.2021.09.014 · Cited by 804 · see citing works
Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B., & El Khoury, J. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.010 · Cited by 799 · see citing works
Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction
Weinhard, L., di Bartolomei, G., Bolasco, G., Machado, P., Schieber, N. L., Neniskyte, U., Exiga, M., Vadisiute, A., Raggioli, A., Schertel, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03566-5 · Cited by 790 · see citing works
A single-cell RNA-seq survey of the developmental landscape of the human prefrontal cortex
Zhong, S., Zhang, S., Fan, X., Wu, Q., Yan, L., Dong, J., Zhang, H., Li, L., Sun, L., Pan, N., et al. (2018) · Nature · doi:10.1038/nature25980 · Cited by 689 · see citing works
Bohlen, C. J., Bennett, F. C., Tucker, A. F., Collins, H. Y., Mulinyawe, S. B., & Barres, B. A. (2017) · Neuron · doi:10.1016/j.neuron.2017.04.043 · Cited by 676 · see citing works
The Role of Astrocytes in CNS Inflammation
Giovannoni, F., & Quintana, F. J. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.07.007 · Cited by 651 · see citing works
Neuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638 · see citing works
Tissue macrophages: heterogeneity and functions
Gordon, S., & Plüddemann, A. (2017) · BMC Biology · doi:10.1186/s12915-017-0392-4 · Cited by 601 · see citing works
Dejanovic, B., Huntley, M. A., De Mazière, A., Meilandt, W. J., Wu, T., Srinivasan, K., Jiang, Z., Gandham, V., Friedman, B. A., Ngu, H., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.014 · Cited by 575 · see citing works
Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease
Roy, E. R., Wang, B., Wan, Y.-W., Chiu, G., Cole, A., Yin, Z., Propson, N. E., Xu, Y., Jankowsky, J. L., Liu, Z., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133737 · Cited by 563 · see citing works
Litvinchuk, A., Wan, Y.-W., Swartzlander, D. B., Chen, F., Cole, A., Propson, N. E., Wang, Q., Zhang, B., Liu, Z., & Zheng, H. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.031 · Cited by 523 · see citing works
Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M.-H., Wood, J., O’Dea, M. R., Dutton, S., Shamardani, K., Nwangwu, K., et al. (2022) · Cell · doi:10.1016/j.cell.2022.06.008 · Cited by 521 · see citing works
Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation
Jäkel, S., & Dimou, L. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00024 · Cited by 501 · see citing works
Novel mechanisms and functions of complement
Hajishengallis, G., Reis, E. S., Mastellos, D. C., Ricklin, D., & Lambris, J. D. (2017) · Nature Immunology · doi:10.1038/ni.3858 · Cited by 484 · see citing works
New insights into the immune functions of complement
Reis, E. S., Mastellos, D. C., Hajishengallis, G., & Lambris, J. D. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0168-x · Cited by 474 · see citing works
Wu, T., Dejanovic, B., Gandham, V. D., Gogineni, A., Edmonds, R., Schauer, S., Srinivasan, K., Huntley, M. A., Wang, Y., Wang, T.-M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.060 · Cited by 466 · see citing works
Astrocytes and microglia: In sickness and in health
Vainchtein, I. D., & Molofsky, A. V. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.01.003 · Cited by 450 · see citing works
Werneburg, S., Jung, J., Kunjamma, R. B., Ha, S.-K., Luciano, N. J., Willis, C. M., Gao, G., Biscola, N. P., Havton, L. A., Crocker, S. J., et al. (2020) · Immunity · doi:10.1016/j.immuni.2019.12.004 · Cited by 440 · see citing works
How COVID-19 Affects the Brain
Boldrini, M., Canoll, P., & Klein, R. S. (2021) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2021.0500 · Cited by 433 · see citing works
Self-citationLocal externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
Scott‐Hewitt, N., Perrucci, F., Morini, R., Erreni, M., Mahoney, M., Witkowska, A., Carey, A. E., Faggiani, E., Schuetz, L. T., Mason, S., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020105380 · Cited by 425 · see citing works
Self-citationThe neurobiology of long COVID
Monje, M., & Iwasaki, A. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.006 · Cited by 415 · see citing works
Witcher, K. G., Bray, C. E., Chunchai, T., Zhao, F., O'Neil, S. M., Gordillo, A. J., Campbell, W. A., McKim, D. B., Liu, X., Dziabis, J. E., et al. (2021) · The Journal of Neuroscience · doi:10.1523/jneurosci.2469-20.2020 · Cited by 387 · see citing works
COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital
Thakur, K. T., Miller, E. H., Glendinning, M. D., Al‐Dalahmah, O., Banu, M. A., Boehme, A. K., Boubour, A., Bruce, S. S., Chong, A. M., Claassen, J., et al. (2021) · Brain · doi:10.1093/brain/awab148 · Cited by 385 · see citing works
Self-citationMultifaceted interactions between adaptive immunity and the central nervous system
Kipnis, J. (2016) · Science · doi:10.1126/science.aag2638 · Cited by 376 · see citing works
Yachou, Y., Idrissi, A. E., Belapasov, V., & BenAli, S. A. (2020) · Neurological Sciences · doi:10.1007/s10072-020-04575-3 · Cited by 374 · see citing works
Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition
Pasciuto, E., Burton, O. T., Roca, C. P., Lagou, V., Rajan, W. D., Theys, T., Mancuso, R., Tito, R. Y., Kouser, L., Callaerts-Vegh, Z., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.026 · Cited by 368 · see citing works
A guide to complement biology, pathology and therapeutic opportunity
Mastellos, D. C., Hajishengallis, G., & Lambris, J. D. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00926-1 · Cited by 343 · see citing works
Dejanovic, B., Wu, T., Tsai, M.-C., Graykowski, D., Gandham, V. D., Rose, C. M., Bakalarski, C. E., Ngu, H., Wang, Y., Pandey, S., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00281-1 · Cited by 341 · see citing works
Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain
Fonseca, M. I., Chu, S.-H., Hernandez, M. X., Fang, M. J., Modarresi, L., Selvan, P., MacGregor, G. R., & Tenner, A. J. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0814-9 · Cited by 337 · see citing works
Neuron-glia signaling in synapse elimination
Wilton, D. K., Dissing-Olesen, L., & Stevens, B. (2019) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070918-050306 · Cited by 332 · see citing works
Self-citationThe effects of microglia-associated neuroinflammation on Alzheimer’s disease
Wang, C., Zong, S., Cui, X., Wang, X., Wu, S., Wang, L., Liu, Y., & Lu, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1117172 · Cited by 318 · see citing works
Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling
Gunner, G., Cheadle, L., Johnson, K. M., Ayata, P., Badimon, A., Mondo, E., Nagy, M. A., Liu, L., Bemiller, S. M., Kim, K.-W., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0419-y · Cited by 311 · see citing works
Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders
Neniškytė, U., & Gross, C. T. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.110 · Cited by 309 · see citing works
The identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308 · see citing works
ApoE attenuates unresolvable inflammation by complex formation with activated C1q
Yin, C., Ackermann, S., Ma, Z., Mohanta, S. K., Zhang, C., Li, Y., Nietzsche, S., Westermann, M., Peng, L., Hu, D., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0336-8 · Cited by 305 · see citing works
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology
Lee, S.-H., Meilandt, W. J., Xie, L., Gandham, V. D., Ngu, H., Barck, K. H., Rezzonico, M. G., Imperio, J., Lalehzadeh, G., Huntley, M. A., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.02.010 · Cited by 300 · see citing works
De Schepper, S., Ge, J. Z., Sierksma, A., Crowley, G., Ferreira, L. S. S., Garceau, D., Toomey, C. E., Sokolova, D., Rueda-Carrasco, J., Shin, S.-H., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01257-z · Cited by 295 · see citing works
Microglial phagocytosis of neurons in neurodegeneration, and its regulation
Butler, C. A., Popescu, A. S., Kitchener, E. J. A., Allendorf, D. H., Puigdellívol, M., & Brown, G. C. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15327 · Cited by 293 · see citing works
Bioenergetic regulation of microglia
Ghosh, S., Castillo, E., Frias, E. S., & Swanson, R. A. (2017) · Glia · doi:10.1002/glia.23271 · Cited by 290 · see citing works
The good, the bad, and the opportunities of the complement system in neurodegenerative disease
Schartz, N. D., & Tenner, A. J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-02024-8 · Cited by 283 · see citing works
Complement System in Neural Synapse Elimination in Development and Disease
Présumey, J., Bialas, A. R., & Carroll, M. C. (2017) · Advances in immunology · doi:10.1016/bs.ai.2017.06.004 · Cited by 278 · see citing works
Immune cells and CNS physiology: Microglia and beyond
Norris, G. T., & Kipnis, J. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20180199 · Cited by 274 · see citing works
Garber, C., Soung, A., Vollmer, L. L., Kanmogne, M., Last, A., Brown, J., & Klein, R. S. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0427-y · Cited by 272 · see citing works
Self-citationDeczkowska, A., Matcovitch-Natan, O., Tsitsou-Kampeli, A., Ben-Hamo, S., Dvir-Szternfeld, R., Spinrad, A., Singer, O., David, E., Winter, D. R., Smith, L. K., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00769-0 · Cited by 260 · see citing works
Kopec, A. M., Smith, C. J. W., Ayre, N. R., Sweat, S. C., & Bilbo, S. D. (2018) · Nature Communications · doi:10.1038/s41467-018-06118-z · Cited by 260 · see citing works
C1q: A fresh look upon an old molecule
Thielens, N. M., Tedesco, F., Bohlson, S. S., Gaboriaud, C., & Tenner, A. J. (2017) · Molecular Immunology · doi:10.1016/j.molimm.2017.05.025 · Cited by 237 · see citing works
Hosseini, S., Wilk, E., Michaelsen-Preusse, K., Gerhauser, I., Baumgärtner, W., Geffers, R., Schughart, K., & Korte, M. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.1740-17.2018 · Cited by 236 · see citing works
Targeting Neuroinflammation to Treat Alzheimer’s Disease
Ardura-Fabregat, A., Boddeke, E., Boza‐Serrano, A., Brioschi, S., Castro‐Gomez, S., Ceyzériat, K., Dansokho, C., Dierkes, T., Gelders, G., Heneka, M. T., et al. (2017) · CNS Drugs · doi:10.1007/s40263-017-0483-3 · Cited by 236 · see citing works
Infectious immunity in the central nervous system and brain function
Klein, R. S., Garber, C., & Howard, N. (2017) · Nature Immunology · doi:10.1038/ni.3656 · Cited by 235 · see citing works
Self-citationMicroglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
Zhang, L.-Y., Pan, J., Mamtilahun, M., Zhu, Y., Wang, L., Venkatesh, A., Shi, R., Tu, X.-Q., Jin, K., Wang, Y., et al. (2019) · Theranostics · doi:10.7150/thno.35841 · Cited by 219 · see citing works
Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function
Spiteri, A. G., Wishart, C. L., Pamphlett, R., Locatelli, G., & King, N. J. C. (2022) · Acta Neuropathologica · doi:10.1007/s00401-021-02384-2 · Cited by 216 · see citing works
Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics
Garred, P., Tenner, A. J., & Mollnes, T. E. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000072 · Cited by 215 · see citing works
Peripheral immune system in aging and Alzheimer’s disease
Cao, W., & Zheng, H. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0284-2 · Cited by 214 · see citing works
Microglia in Brain Development, Homeostasis, and Neurodegeneration
Bohlen, C. J., Friedman, B. A., Dejanovic, B., & Sheng, M. (2019) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043515 · Cited by 212 · see citing works
Zika virus replicates in adult human brain tissue and impairs synapses and memory in mice
Figueiredo, C. P., Barros‐Aragão, F. G. Q., Neris, R. L. S., Frost, P. S., Soares, C., Souza, I. N. D. O., Zeidler, J. D., Zamberlan, D. C., de Sousa, V. L., de Souza, A. S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11866-7 · Cited by 211 · see citing works
The Role of Complement in Synaptic Pruning and Neurodegeneration
Gómez-Arboledas, Á., Acharya, M. M., & Tenner, A. J. (2021) · ImmunoTargets and Therapy · doi:10.2147/itt.s305420 · Cited by 204 · see citing works
Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging
Mangold, C. A., Wronowski, B., Du, M., Masser, D. R., Hadad, N., Bixler, G. V., Brucklacher, R. M., Ford, M. M., Sonntag, W. E., & Freeman, W. M. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0920-8 · Cited by 203 · see citing works
Neurons under T Cell Attack Coordinate Phagocyte-Mediated Synaptic Stripping
Di Liberto, G., Pantelyushin, S., Kreutzfeldt, M., Page, N., Musardo, S., Coras, R., Steinbach, K., Vincenti, I., Klimek, B., Lingner, T., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.049 · Cited by 195 · see citing works
Xu, F., Han, L., Wang, Y., Deng, D., Ding, Y., Zhao, S., Zhang, Q., Ma, L., & Chen, X. (2023) · BMC Medicine · doi:10.1186/s12916-022-02705-6 · Cited by 194 · see citing works
Cerebral dysfunctions caused by sepsis during ageing
Manabe, T., & Heneka, M. T. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00643-7 · Cited by 191 · see citing works
The role of microglia in viral encephalitis: a review
Chen, Z., Zhong, D., & Li, G. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1443-2 · Cited by 189 · see citing works
Microglia regulate synaptic development and plasticity
Andoh, M., & Koyama, R. (2021) · Developmental Neurobiology · doi:10.1002/dneu.22814 · Cited by 188 · see citing works
Microglia as Dynamic Cellular Mediators of Brain Function
Wright-Jin, E. C., & Gutmann, D. H. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.08.013 · Cited by 186 · see citing works
Fekete, R., Cserép, C., Lénárt, N., Tóth, K., Orsolits, B., Martinecz, B., Méhes, E., Szabó, B., Németh, V., Gönci, B., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1885-0 · Cited by 184 · see citing works
Forgetting as a form of adaptive engram cell plasticity
Ryan, T. J., & Frankland, P. W. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00548-3 · Cited by 182 · see citing works
How does Zika virus cause microcephaly?Preprint
Wen, Z., Song, H., & Ming, G. (2017) · Genes & Development · doi:10.1101/gad.298216.117 · Cited by 182 · see citing works
Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration
Ding, X., Wang, J., Huang, M., Chen, Z., Liu, J., Zhang, Q., Zhang, C., Xiang, Y., Zen, K., & Li, L. (2021) · Nature Communications · doi:10.1038/s41467-021-22301-1 · Cited by 180 · see citing works
Wilton, D. K., Mastro, K. J., Heller, M. D., Gergits, F. W., Willing, C. R., Fahey, J. B., Frouin, A., Daggett, A., Gu, X., Kim, Y. A., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02566-3 · Cited by 179 · see citing works
Self-citationRIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation
Daniels, B. P., Snyder, A. G., Olsen, T. M., Orozco, S. L., Oguin, T. H., Tait, S. W. G., Martinez, J., Gale, M., Loo, Y., & Oberst, A. (2017) · Cell · doi:10.1016/j.cell.2017.03.011 · Cited by 177 · see citing works
A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding
Li, T., Chiou, B., Gilman, C. K., Luo, R., Koshi, T., Yu, D., Oak, H. C., Giera, S., Johnson‐Venkatesh, E., Muthukumar, A. K., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2019104136 · Cited by 177 · see citing works
Self-citationFontes-Dantas, F. L., Fernandes, G. G., Gutman, E. G., de Lima, E. V., Antonio, L. S., Hämmerle, M. B., Mota-Araujo, H. P., Colodeti, L. C., Araújo, S. M. B., Froz, G. M., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112189 · Cited by 177 · see citing works
Vilalta, A., & Brown, G. C. (2017) · FEBS Journal · doi:10.1111/febs.14323 · Cited by 174 · see citing works
Madore, C., Leyrolle, Q., Morel, L., Rossitto, M., Greenhalgh, A. D., Delpech, J.-C., Martinat, M., Bosch‐Bouju, C., Bourel, J., Rani, B., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19861-z · Cited by 174 · see citing works
Tissue-resident macrophages: guardians of organ homeostasis
Nobs, S. P., & Köpf, M. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.04.007 · Cited by 172 · see citing works
Targeting synapse function and loss for treatment of neurodegenerative diseases
Dejanovic, B., Sheng, M., & Hanson, J. E. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00823-1 · Cited by 168 · see citing works
CB2 Receptor in Microglia: The Guardian of Self-Control
Komorowska‐Müller, J. A., & Schmöle, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010019 · Cited by 167 · see citing works
Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle
Wohlfert, E. A., Blader, I. J., & Wilson, E. H. (2017) · Trends in Parasitology · doi:10.1016/j.pt.2017.04.001 · Cited by 162 · see citing works
Neuroinflammation During RNA Viral Infections
Klein, R. S., Garber, C., Funk, K. E., Salimi, H., Soung, A., Kanmogne, M., Manivasagam, S., Agner, S., & Cain, M. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041417 · Cited by 160 · see citing works
Self-citationT cell engagement of cross-presenting microglia protects the brain from a nasal virus infection
Moseman, E. A., Blanchard, A. C., Nayak, D., & McGavern, D. B. (2020) · Science Immunology · doi:10.1126/sciimmunol.abb1817 · Cited by 157 · see citing works
CSF1R antagonism limits local restimulation of antiviral CD8+ T cells during viral encephalitis
Funk, K. E., & Klein, R. S. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1397-4 · Cited by 156 · see citing works
Self-citationThe twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis
Muñoz-García, J., Cochonneau, D., Télétchéa, S., Moranton, E., Lanoé, D., Brion, R., Lézot, F., Heymann, M., & Heymann, D. (2020) · Theranostics · doi:10.7150/thno.50683 · Cited by 155 · see citing works
Xie, J., Cools, L., Imschoot, G. V., Wonterghem, E. V., Pauwels, M. J., Vlaeminck, I., Witte, C. D., Andaloussi, S. E., Wierda, K. D. B., Groef, L. D., et al. (2023) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12306 · Cited by 154 · see citing works
Microglia-Specific Metabolic Changes in Neurodegeneration
Aldana, B. I. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.03.006 · Cited by 153 · see citing works
Advances in the Potential Biomarkers of Epilepsy
Kobylarek, D., Iwanowski, P. S., Lewandowska, Z., Limphaibool, N., Szafranek, S., Labrzycka, A., & Kozubski, W. P. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00685 · Cited by 153 · see citing works
Zhou, J., Wade, S. D., Graykowski, D., Xiao, M.-F., Zhao, B., Giannini, L. A. A., Hanson, J. E., van Swieten, J. C., Sheng, M., Worley, P. F., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adf0141 · Cited by 152 · see citing works
Kann, O., Almouhanna, F., & Chausse, B. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.10.007 · Cited by 150 · see citing works
Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1
Garber, C., Vasek, M. J., Vollmer, L. L., Sun, T., Jiang, X., & Klein, R. S. (2017) · Nature Immunology · doi:10.1038/s41590-017-0021-y · Cited by 149 · see citing works
Self-citationMicroglia: Key players in neurodevelopment and neuronal plasticity
Sominsky, L., Luca, S. N. D., & Spencer, S. J. (2017) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.11.012 · Cited by 147 · see citing works
Interleukin-34, a comprehensive review
Baghdadi, M., Umeyama, Y., Hama, N., Kobayashi, T., Han, N., Wada, H., & Seino, K.-I. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr1117-457r · Cited by 145 · see citing works
Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration
Henstridge, C. M., Tzioras, M., & Paolicelli, R. C. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00063 · Cited by 145 · see citing works
Chhatbar, C., Detje, C. N., Grabski, E., Borst, K., Spanier, J., Ghita, L., Elliott, D. A., Jordão, M. J. C., Mueller, N., Sutton, J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.09.003 · Cited by 141 · see citing works
Krukowski, K., Chou, A., Feng, X., Tiret, B., Paladini, M. S., Riparip, L., Chaumeil, M. M., Lemere, C. A., & Rosi, S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123753 · Cited by 139 · see citing works
Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia
Stokowska, A., Atkins, A. L., Morán, J., Pekny, T., Bulmer, L., Pascoe, M. C., Barnum, S. R., Wetsel, R. A., Nilsson, J. A., Dragunow, M., et al. (2016) · Brain · doi:10.1093/brain/aww314 · Cited by 134 · see citing works
The immune system and psychiatric disease: a basic science perspective
Bennett, F. C., & Molofsky, A. V. (2019) · Clinical & Experimental Immunology · doi:10.1111/cei.13334 · Cited by 133 · see citing works
- Authors
- Vasek, M. J., Garber, C., Dorsey, D., Durrant, D. M., Bollman, B., Soung, A., Yu, J., Perez-Torres, C., Frouin, A., Wilton, D. K., Funk, K., DeMasters, B. K., Jiang, X., Bowen, J. R., Mennerick, S., Robinson, J. K., Garbow, J. R., Tyler, K. L., Suthar, M. S., Schmidt, R. E., Stevens, B., & Klein, R. S.
- Affiliations
- Washington University in St. Louis (US)
- Boston Children's Hospital (US)
- University of Colorado Anschutz (US)
- Emory University (US)
- Stony Brook University (US)
- Corresponding author
- Klein, Robyn S.
- ORCID
- Venue
- Nature
- Published
- 2016-06-22
- Volume
- 534
- Issue
- 7608
- Pages
- 538-543
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5452615
- OpenAlex
- W2471701648
- Cited by
- 671
- References
- 33
- Citations by year
- 2026: 33 · 2025: 44 · 2024: 70 · 2023: 78 · 2022: 87 · 2021: 110 · 2020: 64 · 2019: 63 · 2018: 57 · 2017: 55 · 2016: 8 · 2013: 1
- FWCI
- 33.42
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (P30CA091842)
- National Institute of Allergy and Infectious Diseases (U19AI083019, R01AI101400, T32AI052066)
- National Institute of Neurological Disorders and Stroke (R01NS052632, F31NS077640)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- West Nile virus, complement system, microglia, synaptic pruning, memory impairment, hippocampus, C1QA, C3a receptor, IL-34, neuroinvasive infection, spatial learning, CA3, neuroinflammation, viral encephalitis, complement C3a
- MeSH terms
- Animals, Complement System Proteins, Complement Activation, Complement Pathway, Classical, Disease Models, Animal, Female, Humans, Male, Memory Disorders, Neuronal Plasticity, Neurons, West Nile Fever, West Nile virus, Microglia, Presynaptic Terminals, Mice, CA3 Region, Hippocampal, Spatial Memory
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