Lo MW, Woodruff TM. Complement: Bridging the innate and adaptive immune systems in sterile inflammation. J Leukoc Biol. 2020.
Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. New insights into the immune functions of complement. Nat Rev Immunol. 2019;19(8):503–16.
Article CAS PubMed PubMed Central Google Scholar
Velazquez P, Cribbs DH, Poulos TL, Tenner AJ. Aspartate residue 7 in amyloid beta-protein is critical for classical complement pathway activation: implications for Alzheimer’s disease pathogenesis. Nat Med. 1997;3(1):77–9.
Article CAS PubMed Google Scholar
Shen Y, Lue L, Yang L, Roher A, Kuo Y, Strohmeyer R, et al. Complement activation by neurofibrillary tangles in Alzheimer’s disease. Neurosci Lett. 2001;305(3):165–8.
Article CAS PubMed Google Scholar
Tenner AJ, Stevens B, Woodruff TM. New tricks for an ancient system: Physiological and pathological roles of complement in the CNS. Mol Immunol. 2018;102:3–13.
Article CAS PubMed PubMed Central Google Scholar
Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013;190(8):3831–8.
Article CAS PubMed PubMed Central Google Scholar
Cong Q, Soteros BM, Wollet M, Kim JH, Sia GM. The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development. Nat Neurosci. 2020.
Gialeli C, Gungor B, Blom AM. Novel potential inhibitors of complement system and their roles in complement regulation and beyond. Mol Immunol. 2018;102:73–83.
Article CAS PubMed Google Scholar
Forneris F, Wu J, Xue X, Ricklin D, Lin Z, Sfyroera G, et al. Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode. EMBO J. 2016;35(10):1133–49.
Article CAS PubMed PubMed Central Google Scholar
Harris CL, Heurich M, Rodriguez de CS, Morgan BP. The complotype: dictating risk for inflammation and infection. Trends Immunol. 2012;33(10):513–21.
Article CAS PubMed PubMed Central Google Scholar
Kemper C, Kohl J. Back to the future - non-canonical functions of complement. Semin Immunol. 2018;37:1–3.
Article PubMed PubMed Central Google Scholar
West EE, Kunz N, Kemper C. Complement and human T cell metabolism: location, location, location. Immunol Rev. 2020;295(1):68–81.
Article CAS PubMed PubMed Central Google Scholar
Perlmutter DH, Colten HR. Molecular immunobiology of complement biosynthesis: a model of single-cell control of effector-inhibitor balance. Annu Rev Immunol. 1986;4:231–51.
Article CAS PubMed Google Scholar
Minutti CM, Jackson-Jones LH, Garcia-Fojeda B, Knipper JA, Sutherland TE, Logan N, et al. Local amplifiers of IL-4Ralpha-mediated macrophage activation promote repair in lung and liver. Science. 2017;356(6342):1076–80.
Article CAS PubMed PubMed Central Google Scholar
Singhrao SK, Neal JW, Rushmere NK, Morgan BP, Gasque P. Differential expression of individual complement regulators in the brain and choroid plexus. Lab Invest. 1999;79(10):1247–59.
CAS PubMed Google Scholar
Fonseca MI, Chu SH, Hernandez MX, Fang MJ, Modarresi L, Selvan P, et al. Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J Neuroinflammation. 2017;14(1):48.
Article PubMed PubMed Central CAS Google Scholar
Wu T, Dejanovic B, Gandham VD, Gogineni A, Edmonds R, Schauer S, et al. Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 2019;28(8):2111–23 e6.
Article CAS PubMed Google Scholar
Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med. 2020;26(1):131–42.
Article CAS PubMed PubMed Central Google Scholar
Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016.
Wang Y, Cella M, Mallinson K, Ulrich Jason D, Young Katherine L, Robinette Michelle L, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell. 2015;160(6):1061–71.
Article CAS PubMed PubMed Central Google Scholar
Srinivasan K, Friedman BA, Larson JL, Lauffer BE, Goldstein LD, Appling LL, et al. Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nat Commun. 2016;7(1):11295.
Article CAS PubMed PubMed Central Google Scholar
Chiu Isaac M, Morimoto Emiko TA, Goodarzi H, Liao Jennifer T, O’Keeffe S, Phatnani Hemali P, et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 2013;4(2):385–401.
Article CAS PubMed PubMed Central Google Scholar
Schäfer MK-H, Schwaeble WJ, Post C, Salvati P, Calabresi M, Sim RB, et al. Complement C1q is dramatically up-regulated in brain microglia in response to transient global cerebral ischemia. J Immunol. 2000;164(10):5446–52.
Article PubMed Google Scholar
Izzy S, Liu Q, Fang Z, Lule S, Wu L, Chung JY, et al. Time-dependent changes in microglia transcriptional networks following traumatic brain injury. Front Cell Neurosci. 2019;13:307.
Article CAS PubMed PubMed Central Google Scholar
Starossom SC, Imitola J, Wang Y, Cao L, Khoury SJ. Subventricular zone microglia transcriptional networks. Brain Behav Immun. 2011;25(5):991–9.
Article CAS PubMed Google Scholar
Hirbec HE, Noristani HN, Perrin FE. Microglia responses in acute and chronic neurological diseases: what microglia-specific transcriptomic studies taught (and did not teach) Us. Front Aging Neurosci. 2017;9:227.
Article CAS Google Scholar
Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D, Dvir-Szternfeld R, et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat Neurosci. 2020;23(6):701–6.
Article CAS PubMed Google Scholar
Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32(18):6391–410.
Article CAS PubMed PubMed Central Google Scholar
Early AN, Gorman AA, Van Eldik LJ, Bachstetter AD, Morganti JM. Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice. J Neuroinflammation. 2020;17(1):115.
Article CAS PubMed PubMed Central Google Scholar
Tassoni A, Farkhondeh V, Itoh Y, Itoh N, Sofroniew MV, Voskuhl RR. The astrocyte transcriptome in EAE optic neuritis shows complement activation and reveals a sex difference in astrocytic C3 expression. Sci Rep. 2019;9(1):10010.
Article PubMed PubMed Central CAS Google Scholar
Shen Y, Li R, McGeer EG, McGeer PL. Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res. 1997;769(2):391–5.
Article CAS PubMed Google Scholar
Sta M, Sylva-Steenland RMR, Casula M, de Jong JMBV, Troost D, Aronica E, et al. Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol Dis. 2011;42(3):211–20.
Article CAS PubMed Google Scholar
Lobsiger CS, Boillée S, Cleveland DW. Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc Natl Acad Sci. 2007;104(18):7319–26.
Article CAS PubMed Google Scholar
Humayun S, Gohar M, Volkening K, Moisse K, Leystra-Lantz C, Mepham J, et al. The complement factor C5a receptor is upregulated in NFL-/- mouse motor neurons. J Neuroimmunol. 2009;210(1-2):52–62.
Article CAS PubMed Google Scholar
Barnum SR, Ames RS, Maycox PR, Hadingham SJ, Meakin J, Harrison D, et al. Expression of the complement C3a and C5a receptors after permanent focal ischemia: An alternative interpretation. Glia. 2002;38(2):169–73.
Article PubMed Google Scholar
Pavlovski D, Thundyil J, Monk PN, Wetsel RA, Taylor SM, Woodruff TM. Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis. FASEB J. 2012;26(9):3680–90.
Article CAS PubMed Google Scholar
Shen Y, Li R, McGeer EG, McGeer PL. Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res. 1997;769:391–5.
Article CAS PubMed Google Scholar
Bialas AR, Stevens B. TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013;16(12):1773–82.
Article CAS PubMed PubMed Central Google Scholar
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):1164–78.
Article CAS PubMed Google Scholar
Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 2019;570(7761):332–7.
Article CAS PubMed PubMed Central Google Scholar
Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, et al. A dramatic increase of C1q protein in the CNS during normal aging. J Neurosci. 2013;33(33):13460–74.
Article CAS PubMed PubMed Central Google Scholar
Chen G, Tan CS, Teh BK, Lu J. Molecular mechanisms for synchronized transcription of three complement C1q subunit genes in dendritic cells and macrophages. J Biol Chem. 2011;286(40):34941–50.
Article CAS PubMed PubMed Central Google Scholar
Zhou J, Fonseca MI, Pisalyaput K, Tenner AJ. Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer’s disease. J Neurochem. 2008;106(5):2080–92.
Article CAS PubMed PubMed Central Google Scholar
Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ. the aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep. 2018;22(1):269–85.
Article CAS PubMed PubMed Central Google Scholar
Clarke LE, Liddelow SA, Chakraborty C, Munch AE, Heiman M, Barres BA. Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci U S A. 2018;115(8):E1896–E905.
Article CAS PubMed PubMed Central Google Scholar
Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D, Dvir-Szternfeld R, et al. Disease-associated astrocytes in Alzheimerʼs disease and aging. Nat Neurosci. 2020.
Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, et al. NFkappaB-activated astroglial release of complement C3 Compromises neuronal morphology and function associated with Alzheimerʼs disease. Neuron. 2015;85(1):101–15.
Article CAS PubMed Google Scholar
Reichwald J, Danner S, Wiederhold KH, Staufenbiel M. Expression of complement system components during aging and amyloid deposition in APP transgenic mice. J Neuroinflammation. 2009;6:35.
Article PubMed PubMed Central CAS Google Scholar
Suk K. Gamma subunit of complement component 8 is an innate immune suppressor in brain. Journal of Immunology. 2020;204(1).
Bensa JC, Reboul A, Colomb MG. Biosynthesis in vitro of complement subcomponents C1q, C1s and C1 inhibitor by resting and stimulated human monocytes. Biochem J. 1983;216:385–92.
Article CAS PubMed PubMed Central Google Scholar
Veerhuis R, Nielsen HM, Tenner AJ. Complement in the brain. Mol Immunol. 2011;48:1592–603.
Article CAS PubMed PubMed Central Google Scholar
Lu JH, Teh BK, Ld W, Wang YN, Tan YS, Lai MC, et al. The classical and regulatory functions of C1q in immunity and autoimmunity. Cell Mol Immunol. 2008;5(1):9–21.
Article CAS PubMed PubMed Central Google Scholar
Thielens NM, Tedesco F, Bohlson SS, Gaboriaud C, Tenner AJ. C1q: A fresh look upon an old molecule. Mol Immunol. 2017;89:73–83.
Article CAS PubMed PubMed Central Google Scholar
Fraser DA, Laust AK, Nelson EL, Tenner AJ. C1q differentially modulates phagocytosis and cytokine responses during ingestion of apoptotic cells by human monocytes, macrophages, and dendritic cells. J Immunol. 2009;183(10):6175–85.
Article CAS PubMed PubMed Central Google Scholar
Hulsebus HJ, O’Conner SD, Smith EM, Jie C, Bohlson SS. Complement component C1q programs a pro-efferocytic phenotype while limiting TNFalpha production in primary mouse and human macrophages. Front Immunol. 2016;7:230.
Article PubMed PubMed Central CAS Google Scholar
Fraser DA, Pisalyaput K, Tenner AJ. C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J Neurochem. 2010;112(3):733–43.
Article CAS PubMed Google Scholar
Pisalyaput K, Tenner AJ. Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem. 2008;104(3):696–707.
CAS PubMed Google Scholar
Benoit ME, Hernandez MX, Dinh ML, Benavente F, Vasquez O, Tenner AJ. C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloid-beta neurotoxicity. J Biol Chem. 2013;288(1):654–65.
Article CAS PubMed Google Scholar
Benoit ME, Tenner AJ. Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and MicroRNA expression. J Neurosci. 2011;31(9):3459–69.
Article CAS PubMed PubMed Central Google Scholar
Suzuki K, Elegheert J, Song I, Sasakura H, Senkov O, Matsuda K, et al. A synthetic synaptic organizer protein restores glutamatergic neuronal circuits. Science. 2020;369(6507).
Yuzaki M. The C1q complement family of synaptic organizers: not just complementary. Curr Opin Neurobiol. 2017;45:9–15.
Article CAS PubMed Google Scholar
Chu Y, Jin X, Parada I, Pesic A, Stevens B, Barres B, et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc Natl Acad Sci U S A. 2010;107(17):7975–80.
Article CAS PubMed PubMed Central Google Scholar
Wang C, Yue H, Hu Z, Shen Y, Ma J, Li J, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science. 2020;367(6478):688–94.
Article CAS PubMed Google Scholar
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691–705.
Article CAS PubMed PubMed Central Google Scholar
Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 2016;113(36):10186–91.
Article CAS PubMed PubMed Central Google Scholar
Sekar A, Bialas AR, de RH, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016.
Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352(6286):712–6.
Article CAS PubMed PubMed Central Google Scholar
Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell. 2016;165(4):921–35.
Article CAS PubMed PubMed Central Google Scholar
Vasek MJ, Garber C, Dorsey D, Durrant DM, Bollman B, Soung A, et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature. 2016;534(7608):538–43.
Article CAS PubMed PubMed Central Google Scholar
Vukojicic A, Delestree N, Fletcher EV, Pagiazitis JG, Sankaranarayanan S, Yednock TA, et al. The classical complement pathway mediates microglia-dependent remodeling of spinal motor circuits during development and in SMA. Cell Rep. 2019;29(10):3087–100 e7.
Article CAS PubMed PubMed Central Google Scholar
Dejanovic B, Huntley MA, De Maziere A, Meilandt WJ, Wu T, Srinivasan K, et al. Changes in the Synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron. 2018;100(6):1322–36 e7.
Article CAS PubMed Google Scholar
Linnartz-Gerlach B, Schuy C, Shahraz A, Tenner AJ, Neumann H. Sialylation of neurites inhibits complement-mediated macrophage removal in a human macrophage-neuron Co-Culture System. Glia. 2016;64(1):35–47.
Article PubMed Google Scholar
Linnartz B, Kopatz J, Tenner AJ, Neumann H. Sialic acid on the neuronal glycocalyx prevents complement c1 binding and complement receptor-3-mediated removal by microglia. J Neurosci. 2012;32(3):946–52.
Article CAS PubMed PubMed Central Google Scholar
Gyorffy BA, Kun J, Torok G, Bulyaki E, Borhegyi Z, Gulyassy P, et al. Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning. Proc Natl Acad Sci U S A. 2018;115(24):6303–8.
Article CAS PubMed PubMed Central Google Scholar
Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST, Frouin A, et al. CD47 protects synapses from excess microglia-mediated pruning during development. Neuron. 2018;100(1):120–34 e6.
Article CAS PubMed PubMed Central Google Scholar
Gyorffy BA, Toth V, Torok G, Gulyassy P, Kovacs RA, Vadaszi H, et al. Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimerʼs disease animal model. Cell Mol Life Sci. 2020.
Michailidou I, Willems JG, Kooi EJ, van Eden C, Gold SM, Geurts JJ, et al. Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus. Ann Neurol. 2015;77(6):1007–26.
Article CAS PubMed Google Scholar
Werneburg S, Jung J, Kunjamma RB, Ha SK, Luciano NJ, Willis CM, et al. Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease. Immunity. 2020;52(1):167–82 e7.
Article CAS PubMed Google Scholar
Kiafard Z, Tschernig T, Schweyer S, Bley A, Neumann D, Zwirner J. Use of monoclonal antibodies to assess expression of anaphylatoxin receptors in tubular epithelial cells of human, murine and rat kidneys. Immunobiology. 2007;212(2):129–39.
Article CAS PubMed Google Scholar
Seow V, Lim J, Iyer A, Suen JY, Ariffin JK, Hohenhaus DM, et al. Inflammatory responses induced by lipopolysaccharide are amplified in primary human monocytes but suppressed in macrophages by complement protein C5a. J Immunol. 2013;191(8):4308–16.
Article CAS PubMed Google Scholar
Klos A, Wende E, Wareham KJ, Monk PN. International union of basic and clinical pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol Rev. 2013;65(1):500–43.
Article PubMed CAS Google Scholar
Lee JD, Coulthard LG, Woodruff TM. Complement dysregulation in the central nervous system during development and disease. Semin Immunol. 2019;101340.
Woodruff TM, Nandakumar KS, Tedesco F. Inhibiting the C5-C5a receptor axis. Mol Immunol. 2011;48(14):1631–42.
Article CAS PubMed Google Scholar
Li XX, Lee JD, Kemper C, Woodruff TM. The Complement receptor C5aR2: a powerful modulator of innate and adaptive immunity. J Immunol. 2019;202(12):3339–48.
Article CAS PubMed Google Scholar
Hernandez MX, Namiranian P, Nguyen E, Fonseca MI, Tenner AJ. C5a increases the Injury to primary neurons elicited by fibrillar amyloid beta. ASN Neuro 2017;9(1):1759091416687871.
Hernandez MX, Jiang S, Cole TA, Chu SH, Fonseca MI, Fang MJ, et al. Prevention of C5aR1 signaling delays microglial inflammatory polarization, favors clearance pathways and suppresses cognitive loss. Mol Neurodegener. 2017;12(1):66.
Article PubMed PubMed Central CAS Google Scholar
Coulthard LG, Woodruff TM. Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J Immunol. 2015;194(8):3542–8.
Article CAS PubMed Google Scholar
El Gaamouch F, Audrain M, Lin WJ, Beckmann N, Jiang C, Hariharan S, et al. VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice. Mol Neurodegener. 2020;15(1):4.
Article PubMed PubMed Central CAS Google Scholar
Hajishengallis G, Lambris JD. Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 2010;31(4):154–63.
Article CAS PubMed PubMed Central Google Scholar
Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J. The role of the anaphylatoxins in health and disease. Mol Immunol. 2009;46(14):2753–66.
Article CAS PubMed PubMed Central Google Scholar
Fonseca MI, Zhou J, Botto M, Tenner AJ. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J Neurosci. 2004;24(29):6457–65.
Article CAS PubMed PubMed Central Google Scholar
Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017;9(392):eaaf6295.
Article PubMed PubMed Central Google Scholar
Hernandez MX, Jiang S, Cole TA, Chu S-H, Fonseca MI, Fang MJ, et al. Prevention of C5aR1 signaling delays microglial inflammatory polarization, favors clearance pathways and suppresses cognitive loss. Molecular Neurodegeneration. 2017;12(1):66.
Article PubMed PubMed Central CAS Google Scholar
Fonseca MI, Ager RR, Chu SH, Yazan O, Sanderson SD, LaFerla FM, et al. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer’s disease. J Immunol. 2009;183(2):1375–83.
Article CAS PubMed PubMed Central Google Scholar
Lobsiger CS, Boillée S, Pozniak C, Khan AM, McAlonis-Downes M, Lewcock JW, et al. C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice. Proc Natl Acad Sci. 2013;110(46):E4385–E92.
Article CAS PubMed Google Scholar
Wang HA, Lee JD, Lee KM, Woodruff TM, Noakes PG. Complement C5a-C5aR1 signalling drives skeletal muscle macrophage recruitment in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. Skeletal Muscle. 2017;7(1):10.
Article PubMed PubMed Central CAS Google Scholar
Woodruff TM, Costantini KJ, Crane JW, Atkin JD, Monk PN, Taylor SM, et al. The complement factor C5a Contributes to pathology in a rat model of amyotrophic lateral sclerosis. J Immunol. 2008;181(12):8727–34.
Article CAS PubMed Google Scholar
Woodruff TM, Lee JD, Noakes PG. Role for terminal complement activation in amyotrophic lateral sclerosis disease progression. Proc Natl Acad Sci 2014;111(1):E3-E4.
Lee JD, Kumar V, Fung JNT, Ruitenberg MJ, Noakes PG, Woodruff TM. Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. Br J Pharmacol. 2017;174(8):689–99.
Article CAS PubMed PubMed Central Google Scholar
Ten VS, Sosunov SA, Mazer SP, Stark RI, Caspersen C, Sughrue ME, et al. C1q-Deficiency is neuroprotective against hypoxic-ischemic brain injury in neonatal mice. Stroke. 2005;36(10):2244–50.
Article CAS PubMed Google Scholar
Fan G, Li Q, Qian J. C1q contributes to post-stroke angiogenesis via LAIR1-HIF1α-VEGF pathway. Frontiers In Bioscience, Landmark 2019;24:1050-9.
Heydenreich N, Nolte MW, Gob E, Langhauser F, Hofmeister M, Kraft P, et al. C1-inhibitor protects from brain ischemia-reperfusion injury by combined antiinflammatory and antithrombotic mechanisms. Stroke. 2012;43(9):2457–67.
Article CAS PubMed Google Scholar
Cervera A, Planas AM, Justicia C, Urra X, Jensenius JC, Torres F, et al. Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke. PLoS One. 2010;5(2):e8433.
Article PubMed PubMed Central CAS Google Scholar
Clarke AR, Christophe BR, Khahera A, Sim JL, Connolly ES Jr. Therapeutic modulation of the complement cascade in stroke. Front Immunol. 2019;10:1723.
Article CAS PubMed PubMed Central Google Scholar
Elvington A, Atkinson C, Zhu H, Yu J, Takahashi K, Stahl GL, et al. The alternative complement pathway propagates inflammation and injury in murine ischemic stroke. J Immunol. 2012;189(9):4640–7.
Article CAS PubMed PubMed Central Google Scholar
Mocco J, Mack WJ, Ducruet AF, Sosunov SA, Sughrue ME, Hassid BG, et al. Complement component C3 mediates inflammatory injury following focal cerebral ischemia. Circ Res. 2006;99(2):209–17.
Article CAS PubMed Google Scholar
Alawieh A, Langley EF, Tomlinson S. Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice. Sci Transl Med. 2018;10(441):eaao6459.
Article PubMed PubMed Central CAS Google Scholar
Ma Y, Ramachandran A, Ford N, Parada I, Prince DA. Remodeling of dendrites and spines in the C1q knockout model of genetic epilepsy. Epilepsia. 2013;54(7):1232–9.
Article PubMed PubMed Central Google Scholar
Chen M, Arumugam TV, Leanage G, Tieng QM, Yadav A, Ullmann JFP, et al. Disease-modifying effect of intravenous immunoglobulin in an experimental model of epilepsy. Sci Rep. 2017;7(1):40528.
Article CAS PubMed PubMed Central Google Scholar
Buckingham SC, Ramos TN, Barnum SR. Complement C5-deficient mice are protected from seizures in experimental cerebral malaria. Epilepsia. 2014;55(12):e139–e42.
Article PubMed PubMed Central Google Scholar
Benson MJ, Thomas NK, Talwar S, Hodson MP, Lynch JW, Woodruff TM, et al. A novel anticonvulsant mechanism via inhibition of complement receptor C5ar1 in murine epilepsy models. Neurobiol Dis. 2015;76:87–97.
Article CAS PubMed Google Scholar
Benson MJ, Manzanero S, Borges K. The effects of C5aR1 on leukocyte infiltration following pilocarpine-induced status epilepticus. Epilepsia. 2017;58(4):e54–e8.
Article CAS PubMed Google Scholar
Krukowski K, Chou A, Feng X, Tiret B, Paladini MS, Riparip LK, et al. Traumatic brain injury in aged mice induces chronic microglia activation, synapse loss, and complement-dependent memory deficits. Int J Mol Sci. 2018;19(12).
You Z, Yang J, Takahashi K, Yager PH, Kim HH, Qin T, et al. Reduced tissue damage and improved recovery of motor function after traumatic brain injury in mice deficient in complement component C4. J Cereb Blood Flow Metab. 2007;27(12):1954–64.
Article CAS PubMed Google Scholar
Leinhase I, Holers VM, Thurman JM, Harhausen D, Schmidt OI, Pietzcker M, et al. Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation. BMC Neurosci. 2006;7:55.
Article PubMed PubMed Central CAS Google Scholar
Alawieh A, Langley EF, Weber S, Adkins D, Tomlinson S. Identifying the role of complement in triggering neuroinflammation after traumatic brain injury. J Neurosci. 2018;38(10):2519–32.
Article CAS PubMed PubMed Central Google Scholar
Ruseva MM, Ramaglia V, Morgan BP, Harris CL. An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice. Proc Natl Acad Sci U S A. 2015;112(46):14319–24.
Article CAS PubMed PubMed Central Google Scholar
Fluiter K, Opperhuizen AL, Morgan BP, Baas F, Ramaglia V. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. J Immunol. 2014;192(5):2339–48.
Article CAS PubMed Google Scholar
Boos LA, Szalai AJ, Barnum SR. Murine complement C4 is not required for experimental autoimmune encephalomyelitis. Glia. 2005;49(1):158–60.
Article PubMed Google Scholar
Nataf S, Carroll SL, Wetsel RA, Szalai AJ, Barnum SR. Attenuation of experimental autoimmune demyelination in complement-deficient mice. J Immunol. 2000;165(10):5867–73.
Article CAS PubMed Google Scholar
Barnum SR, Szalai AJ. Complement and demyelinating disease: no MAC needed? Brain Res Rev. 2006;52(1):58–68.
Article CAS PubMed Google Scholar
Piddlesden SJ, Storch MK, Hibbs M, Freeman AM, Lassmann H, Morgan BP. Soluble recombinant complement receptor 1 inhibits inflammation and demyelination in antibody-mediated demyelinating experimental allergic encephalomyelitis. J Immunol. 1994;152(11):5477–84.
CAS PubMed Google Scholar
Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol. 2014;25(2):225–31.
Article CAS PubMed Google Scholar
Hajishengallis G, Kajikawa T, Hajishengallis E, Maekawa T, Reis ES, Mastellos DC, et al. Complement-Dependent Mechanisms and Interventions in Periodontal Disease. Front Immunol. 2019;10:406.
Article CAS PubMed PubMed Central Google Scholar
2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 2020.
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016.
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.
Article CAS PubMed Google Scholar
Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement (N Y). 2019;5:272–93.
Article Google Scholar
Vitek MP, Edelmayer, R. M. Translational animal models for Alzheimer’s disease: an Alzheimer’s Association Business Consortium think tank. Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 2020.
Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol. 1999;155(3):853–62.
Article CAS PubMed PubMed Central Google Scholar
Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017;9(392).
Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain. 2016;139(Pt 4):1265-1281.
Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet. 2019;51(3):414–30.
Article CAS PubMed PubMed Central Google Scholar
Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303.
Article CAS PubMed PubMed Central Google Scholar
Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet. 2009;41(10):1094–9.
Article CAS PubMed Google Scholar
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009;41(10):1088–93.
Article CAS PubMed PubMed Central Google Scholar
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368(2):117–27.
Article CAS PubMed Google Scholar
Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci. 2017;20(8):1052–61.
Article CAS PubMed PubMed Central Google Scholar
Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49(9):1373–84.
Article CAS PubMed PubMed Central Google Scholar
Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J Exp Med. 2020;217(9).
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017;169(7):1276–90.e17.
Article CAS Google Scholar
Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, et al. Brain interleukin I and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989;86:7611–5.
Article CAS PubMed PubMed Central Google Scholar
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21(3):383–421.
Article CAS PubMed PubMed Central Google Scholar
Mrak RE, Sheng JG, Griffin WS. Glial cytokines in Alzheimer’s disease: review and pathogenic implications. Hum Pathol. 1995;26:816–23.
Article CAS PubMed PubMed Central Google Scholar
Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med. 2012;2(1):a006346.
Article PubMed PubMed Central Google Scholar
Tejera D, Mercan D, Sanchez-Caro JM, Hanan M, Greenberg D, Soreq H, et al. Systemic inflammation impairs microglial Abeta clearance through NLRP3 inflammasome. EMBO J. 2019:e101064.
Heneka MT, Carson MJ, El KJ, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388–405.
Article CAS PubMed PubMed Central Google Scholar
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):601–12.
Article CAS PubMed PubMed Central Google Scholar
Woodling NS, Andreasson KI. Untangling the web: toxic and protective effects of neuroinflammation and PGE2 signaling in Alzheimer’s disease. ACS Chem Nerosci. 2016;7(4):454–63.
Article CAS Google Scholar
Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, et al. Integrated Systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. 2013;153(3):707–20.
Article CAS PubMed PubMed Central Google Scholar
Hur JY, Frost GR, Wu X, Crump C, Pan SJ, Wong E, et al. The innate immunity protein IFITM3 modulates gamma-secretase in Alzheimer’s disease. In: Nature; 2020.
Google Scholar
Harris CL. Expanding horizons in complement drug discovery: challenges and emerging strategies. Semin Immunopathol. 2018;40(1):125–40.
Article CAS PubMed Google Scholar
Rogers J, Schultz J, Brachova L, Lue LF, Webster S, Bradt B, et al. Complement activation and á-amyloid-mediated neurotoxicity in Alzheimer’s disease. Res Immunol. 1992;143:624–30.
Article CAS PubMed Google Scholar
Jiang H, Burdick D, Glabe CG, Cotman CW, Tenner AJ. beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. J Immunol. 1994;152(10):5050–9.
CAS PubMed Google Scholar
Bradt BM, Kolb WP, Cooper NR. Complement-dependent proinflammatory properties of the Alzheimer’s disease beta-peptide. J Exp Med. 1998;188(3):431–8.
Article CAS PubMed PubMed Central Google Scholar
Afagh A, Cummings BJ, Cribbs DH, Cotman CW, Tenner AJ. Localization and cell association of C1q in Alzheimer’s disease brain. Exp Neurol. 1996;138:22–32.
Article CAS PubMed Google Scholar
Fonseca MI, Chu SH, Berci AM, Benoit ME, Peters DG, Kimura Y, et al. Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer’s disease. J Neuroinflammation. 2011;8(1):4.
Article PubMed PubMed Central Google Scholar
Matsuoka Y, Picciano M, Malester B, LaFrancois J, Zehr C, Daeschner JM, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol. 2001;158(4):1345–54.
Article CAS PubMed PubMed Central Google Scholar
Eikelenboom P, Stam FC. Immunoglobulins and complement factors in senile plaques. Acta Neuropathol. 1982;57:239–42.
Article CAS PubMed Google Scholar
Webster S, Lue LF, Brachova L, Tenner AJ, McGeer PL, Terai K, et al. Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer’s disease. Neurobiol Aging. 1997;18(4):415–21.
Article CAS PubMed Google Scholar
Yang J, Wise L, Fukuchi KI. TLR4 Cross-talk With NLRP3 inflammasome and complement signaling pathways in Alzheimer’s disease. Front Immunol. 2020;11:724.
Article CAS PubMed PubMed Central Google Scholar
Tenner AJ. Complement-mediated events in Alzheimer’s disease: mechanisms and potential therapeutic targets. J Immunol. 2020;204(2):306–15.
Article CAS PubMed Google Scholar
Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, et al. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflammation. 2012;9(1):179.
Article CAS PubMed PubMed Central Google Scholar
Shi Q, Colodner KJ, Matousek SB, Merry K, Hong S, Kenison JE, et al. Complement C3-deficient mice fail to display age-related hippocampal decline. J Neurosci. 2015;35(38):13029–42.
Article CAS PubMed PubMed Central Google Scholar
Ryman D, Gao Y, Lamb BT. Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2008;29(8):1190–8.
Article CAS PubMed Google Scholar
Landlinger C, Oberleitner L, Gruber P, Noiges B, Yatsyk K, Santic R, et al. Active immunization against complement factor C5a: a new therapeutic approach for Alzheimer’s disease. J Neuroinflammation. 2015;12:150.
Article PubMed PubMed Central CAS Google Scholar
Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, et al. Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem. 2007;282(33):23818–28.
Article CAS PubMed Google Scholar
Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016;213(5):667–75.
Article CAS PubMed PubMed Central Google Scholar
Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, et al. Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One. 2013;8(4).
Rangaraju S, Dammer EB, Raza SA, Rathakrishnan P, Xiao H, Gao T, et al. Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease. Mol Neurodegener. 2018;13(1):24.
Article PubMed PubMed Central CAS Google Scholar
Litvinchuk A, Wan YW, Swartzlander DB, Chen F, Cole A, Propson NE, et al. Complement C3aR Inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and Alzheimer’s disease. Neuron. 2018.
Woodruff TM, Tenner AJ. A Commentary On: "NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease". A cautionary note regarding C3aR. Front Immunol. 2015;6:220.
Beckmann ND, Lin WJ, Wang M, Cohain AT, Charney AW, Wang P, et al. Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease. Nat Commun. 2020;11(1):3942.
Article CAS PubMed PubMed Central Google Scholar
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9(8):857–65.
Article CAS PubMed PubMed Central Google Scholar
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674–8.
Article CAS PubMed Google Scholar
Sheng JG, Ito K, Skinner RD, Mrak RE, Rovnaghi CR, Van Eldik LJ, et al. In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. Neurobiol Aging. 1996;17:761–6.
Article CAS PubMed PubMed Central Google Scholar
Luciunaite A, McManus RM, Jankunec M, Racz I, Dansokho C, Dalgediene I, et al. Soluble Abeta oligomers and protofibrils induce NLRP3 inflammasome activation in microglia. J Neurochem. 2019:e14945.
Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, et al. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegener. 2016;11:23.
Article PubMed PubMed Central CAS Google Scholar
O’Barr S, Cooper NR. The C5a complement activation peptide increases IL-1beta and IL-6 release from amyloid-beta primed human monocytes: implications for Alzheimer’s disease. J Neuroimmunol. 2000;109(2):87–94.
Article PubMed Google Scholar
Hajishengallis G, Lambris JD. Complement and dysbiosis in periodontal disease. Immunobiology. 2012;217(11):1111–6.
Article CAS PubMed PubMed Central Google Scholar
Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):1456–8.
Article CAS PubMed Google Scholar
Nardin A, Lindorfer MA, Taylor RP. How are immune complexes bound to the primate erythrocyte complement receptor transferred to acceptor phagocytic cells? Mol Immunol. 1999;36(13-14):827–35.
Article CAS PubMed Google Scholar
Keenan BT, Shulman JM, Chibnik LB, Raj T, Tran D, Sabuncu MR, et al. A coding variant in CR1 interacts with APOE-{varepsilon}4 to influence cognitive decline. Hum Mol Genet. 2012.
Klickstein LB, Barbashov SF, Liu T, Jack RM, Nicholson-Weller A. Complement receptor type 1 (CR1, CD35) is a receptor for C1q. Immunity. 1997;7:345–55.
Article CAS PubMed Google Scholar
Dykman TR, Cole JL, Iida K, Atkinson JP. Polymorphism of human erythrocyte C3b/C4b receptor. Proc Natl Acad Sci U S A. 1983;80(6):1698–702.
Article CAS PubMed PubMed Central Google Scholar
Mahmoudi R, Kisserli A, Novella JL, Donvito B, Drame M, Reveil B, et al. Alzheimer’s disease is associated with low density of the long CR1 isoform. Neurobiol Aging. 2015;36(4):1766–12.
Article PubMed CAS Google Scholar
Rogers J, Li R, Mastroeni D, Grover A, Leonard B, Ahern G, et al. Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes. Neurobiol Aging. 2006;27(12):1733–9.
Article CAS PubMed Google Scholar
Crane A, Brubaker WD, Johansson JU, Trigunaite A, Ceballos J, Bradt B, et al. Peripheral complement interactions with amyloid beta peptide in Alzheimer’s disease: 2. Relationship to amyloid beta immunotherapy. Alzheimers Dement. 2018;14(2):243–52.
Article PubMed Google Scholar
Johansson JU, Brubaker WD, Javitz H, Bergen AW, Nishita D, Trigunaite A, et al. Peripheral complement interactions with amyloid beta peptide in Alzheimer’s disease: Polymorphisms, structure, and function of complement receptor 1. In: Alzheimers Dement; 2018.
Google Scholar
Brubaker WD, Crane A, Johansson JU, Yen K, Garfinkel K, Mastroeni D, et al. Peripheral complement interactions with amyloid beta peptide: erythrocyte clearance mechanisms. Alzheimers Dement. 2017;13(12):1397–409.
Article PubMed PubMed Central Google Scholar
Deane R, Sagare A, Zlokovic BV. The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer’s disease. Curr Pharm Des. 2008;14(16):1601-1605.
Taylor RP, Lindorfer MA, Atkinson JP. Clearance of amyloid-beta with bispecific antibody constructs bound to erthrocytes. Alzheimers Dement. 2020;6:e12067.
Google Scholar
Jacobson AC, Weis JH. Comparative functional evolution of human and mouse CR1 and CR2. J Immunol. 2008;181(5):2953–9.
Article CAS PubMed PubMed Central Google Scholar
Li J, Wang JP, Ghiran I, Cerny A, Szalai AJ, Briles DE, et al. Complement receptor 1 expression on mouse erythrocytes mediates clearance of Streptococcus pneumoniae by immune adherence. Infect Immun. 2010;78(7):3129–35.
Article CAS PubMed PubMed Central Google Scholar
Jackson HM, Foley KE, O’Rourke R, Stearns TM, Fatjalla D, Morgan BP, et al. A novel mouse model expressing human forms for complement receptors CR1 and CR2. In: BioRχiv; 2020.
Google Scholar
Trouw LA, Nielsen HM, Minthon L, Londos E, Landberg G, Veerhuis R, et al. C4b-binding protein in Alzheimer’s disease: binding to Abeta1-42 and to dead cells. Mol Immunol. 2008;45(13):3649–60.
Article CAS PubMed Google Scholar
Darley MM, Ramos TN, Wetsel RA, Barnum SR. Deletion of carboxypeptidase N delays onset of experimental cerebral malaria. Parasite Immunol. 2012;34(8-9):444–7.
Article CAS PubMed PubMed Central Google Scholar
Havik B, Le HS, Rietschel M, Lybaek H, Djurovic S, Mattheisen M, et al. The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biol Psychiatry. 2011;70(1):35–42.
Article CAS PubMed Google Scholar
Tu Z, Cohen M, Bu H, Lin F. Tissue distribution and functional analysis of Sushi domain-containing protein 4. Am J Pathol. 2010;176(5):2378–84.
Article CAS PubMed PubMed Central Google Scholar
Sia GM, Clem RL, Huganir RL. The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice. Science. 2013;342(6161):987–91.
Article CAS PubMed PubMed Central Google Scholar
Goetzl EJ, Schwartz JB, Abner EL, Jicha GA, Kapogiannis D. High complement levels in astrocyte-derived exosomes of Alzheimer disease. Ann Neurol. 2018;83(3):544–52.
Article CAS PubMed PubMed Central Google Scholar
Bhargava P, Nogueras-Ortiz C, Kim S, Delgado-Peraza F, Calabresi PA, Kapogiannis D. Synaptic and complement markers in extracellular vesicles in multiple sclerosis. Mult Scler 2020:1352458520924590.
Chen M, Xia W. Proteomic profiling of plasma and brain tissue from Alzheimer’s disease patients reveals candidate network of plasma biomarkers. J Alzheimers Dis. 2020;76(1):349–68.
Article CAS PubMed PubMed Central Google Scholar
Széplaki G, Szegedi R, Hirschberg K, Gombos T, Varga L, Karádi I, et al. Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes. Atherosclerosis. 2009;204(1):315–20.
Article PubMed CAS Google Scholar
Kopczynska M, Zelek WM, Vespa S, Touchard S, Wardle M, Loveless S, et al. Complement system biomarkers in epilepsy. Seizure. 2018;60:1–7.
Article PubMed Google Scholar
Goetzl EJ, Yaffe K, Peltz CB, Ledreux A, Gorgens K, Davidson B, et al. Traumatic brain injury increases plasma astrocyte-derived exosome levels of neurotoxic complement proteins. FASEB J. 2020;34(2):3359–66.
Article CAS PubMed Google Scholar
Ingram G, Hakobyan S, Hirst CL, Harris CL, Loveless S, Mitchell JP, et al. Systemic complement profiling in multiple sclerosis as a biomarker of disease state. Mult Scler. 2012;18(10):1401–11.
Article CAS PubMed PubMed Central Google Scholar
Zelek WM, Fathalla D, Morgan A, Touchard S, Loveless S, Tallantyre E, et al. Cerebrospinal fluid complement system biomarkers in demyelinating disease. Mult Scler. 2019:1352458519887905.
Mantovani S, Gordon R, Macmaw JK, Pfluger CMM, Henderson RD, Noakes PG, et al. Elevation of the terminal complement activation products C5a and C5b-9 in ALS patient blood. J Neuroimmunol. 2014;276(1):213–8.
Article CAS PubMed Google Scholar
Mocco J, Wilson DA, Komotar RJ, Sughrue ME, Coates K, Sacco RL, et al. Alterations in plasma complement levels after human ischemic stroke. Neurosurgery. 2006;59(1):28–33.
Article CAS PubMed Google Scholar
Başaran N, Hincal F, Kansu E, Cǧer A. Humoral and cellular immune parameters in untreated and phenytoin- or carbamazepine-treated epileptic patients. Int J Immunopharmacol. 1994;16(12):1071–7.
Article PubMed Google Scholar
Burk AM, Martin M, Flierl MA, Rittirsch D, Helm M, Lampl L, et al. Early complementopathy after multiple injuries in humans. Shock. 2012;37(4):348–54.
Article PubMed PubMed Central Google Scholar
Hakobyan S, Harding K, Aiyaz M, Hye A, Dobson R, Baird A, et al. Complement biomarkers as predictors of disease progression in Alzheimer’s disease. J Alzheimers Dis. 2016;54(2):707–16.
Article CAS PubMed Google Scholar
Pedersen ED, Waje-Andreassen U, Vedeler CA, Aamodt G, Mollnes TE. Systemic complement activation following human acute ischaemic stroke. Clin Exp Immunol. 2004;137(1):117–22.
Article CAS PubMed PubMed Central Google Scholar
Morgan AR, Touchard S, Leckey C, O’Hagan C, Nevado-Holgado AJ, Consortium N, et al. Inflammatory biomarkers in Alzheimer’s disease plasma. Alzheimers Dement. 2019;15(6):776–87.
Article PubMed PubMed Central Google Scholar
Krance SH, Wu CY, Zou Y, Mao H, Toufighi S, He X, et al. The complement cascade in Alzheimer’s disease: a systematic review and meta-analysis. Mol Psychiatry. 2019.
Jongbloed W, van Dijk KD, Mulder SD, van de Berg WD, Blankenstein MA, van der Flier W, et al. Clusterin levels in plasma predict cognitive decline and progression to Alzheimer’s Disease. J Alzheimers Dis. 2015;46(4):1103–10.
Article CAS PubMed Google Scholar
Thambisetty M, Simmons A, Velayudhan L, Hye A, Campbell J, Zhang Y, et al. Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Arch Gen Psychiatry. 2010;67(7):739–48.
Article PubMed PubMed Central Google Scholar
Morgan AR, Touchard S, O’Hagan C, Sims R, Majounie E, Escott-Price V, et al. The correlation between inflammatory biomarkers and polygenic risk score in Alzheimer’s disease. J Alzheimers Dis. 2017;56(1):25–36.
Article CAS PubMed Google Scholar
Longinetti E, Fang F. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol. 2019;32(5):771–6.
Article CAS PubMed PubMed Central Google Scholar
Deora V, Lee JD, Albornoz EA, McAlary L, Jagaraj CJ, Robertson AAB, et al. The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia. 2020;68(2):407–21.
Article PubMed Google Scholar
Kjældgaard A-L, Pilely K, Olsen KS, Pedersen SW, Lauritsen AØ, Møller K, et al. Amyotrophic lateral sclerosis: the complement and inflammatory hypothesis. Mol Immunol. 2018;102:14–25.
Article PubMed CAS Google Scholar
Humayun S, Gohar M, Volkening K, Moisse K, Leystra-Lantz C, Mepham J, et al. The complement factor C5a receptor is upregulated in NFL-/- mouse motor neurons. J Neuroimmunol. 2009.
Lee JD, Levin SC, Willis EF, Li R, Woodruff TM, Noakes PG. Complement components are upregulated and correlate with disease progression in the TDP-43(Q331K) mouse model of amyotrophic lateral sclerosis. J Neuroinflammation. 2018;15(1):171.
Article PubMed PubMed Central CAS Google Scholar
Lee JD, Kamaruzaman NA, Fung JNT, Taylor SM, Turner BJ, Atkin JD, et al. Dysregulation of the complement cascade in the hSOD1G93Atransgenic mouse model of amyotrophic lateral sclerosis. J Neuroinflammation. 2013;10(1):119.
Article PubMed PubMed Central CAS Google Scholar
Cowled P, Fitridge R. Pathophysiology of Reperfusion Injury. In: Fitridge R, Thompson M, editors. Mechanisms of vascular disease: a reference book for vascular specialists. Adelaide (AU): University of Adelaide Press© The Contributors 2011.; 2011.
Chen S-F, Pan M-X, Tang J-C, Cheng J, Zhao D, Zhang Y, et al. Arginine is neuroprotective through suppressing HIF-1α/LDHA-mediated inflammatory response after cerebral ischemia/reperfusion injury. Mol Brain. 2020;13(1):63.
Article CAS PubMed PubMed Central Google Scholar
Stokowska A, Atkins AL, Morán J, Pekny T, Bulmer L, Pascoe MC, et al. Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia. Brain. 2016;140(2):353–69.
Article PubMed Google Scholar
Ducruet AF, Zacharia BE, Sosunov SA, Gigante PR, Yeh ML, Gorski JW, et al. Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke. PLoS One. 2012;7(6):e38664.
Article CAS PubMed PubMed Central Google Scholar
Li J, Diao B, Guo S, Huang X, Yang C, Feng Z, et al. VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism. Nat Commun. 2017;8(1):1322.
Article PubMed PubMed Central CAS Google Scholar
Lyu Q, Pang X, Zhang Z, Wei Y, Hong J, Chen H. Microglial V-set and immunoglobulin domain-containing 4 protects against ischemic stroke in mice by suppressing TLR4-regulated inflammatory response. Biochem Biophys Res Commun. 2020;522(3):560–7.
Article CAS PubMed Google Scholar
Mack WJ, Sughrue ME, Ducruet AF, Mocco J, Sosunov SA, Hassid BG, et al. Temporal pattern of C1q deposition after transient focal cerebral ischemia. J Neurosci Res. 2006;83(5):883–9.
Article CAS PubMed Google Scholar
De Simoni MG, Rossi E, Storini C, Pizzimenti S, Echart C, Bergamaschini L. The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q. Am J Pathol. 2004;164(5):1857–63.
Article PubMed PubMed Central Google Scholar
Ahmad S, Bhatia K, Kindelin A, Ducruet AF. The role of complement C3a receptor in stroke. Neuromolecular Med. 2019;21(4):467–73.
Article CAS PubMed Google Scholar
Van Beek J, Bernaudin M, Petit E, Gasque P, Nouvelot A, MacKenzie ET, et al. Expression of receptors for complement anaphylatoxins C3a and C5a following permanent focal cerebral ischemia in the mouse. Exp Neurol. 2000;161(1):373–82.
Article PubMed CAS Google Scholar
Rynkowski MA, Kim GH, Garrett MC, Zacharia BE, Otten ML, Sosunov SA, et al. C3a receptor antagonist attenuates brain injury after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2009;29(1):98–107.
Article CAS PubMed Google Scholar
Ahmad S, Kindelin A, Khan SA, Ahmed M, Hoda MN, Bhatia K, et al. C3a Receptor inhibition protects brain endothelial cells against oxygen-glucose deprivation/reperfusion. Exp Neurobiol. 2019;28(2):216–28.
Article PubMed PubMed Central Google Scholar
Shinjyo N, de Pablo Y, Pekny M, Pekna M. Complement Peptide C3a Promotes astrocyte survival in response to ischemic stress. Mol Neurobiol. 2016;53(5):3076–87.
Article CAS PubMed Google Scholar
Meisler MH, O’Brien JE, Sharkey LM. Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. J Physiol 2010;588(Pt 11):1841-1848.
Ravizza T, Vezzani A. Pharmacological targeting of brain inflammation in epilepsy: therapeutic perspectives from experimental and clinical studies. Epilepsia Open. 2018;3(Suppl Suppl 2):133–42.
Article PubMed PubMed Central Google Scholar
Aronica E, Boer K, van Vliet EA, Redeker S, Baayen JC, Spliet WG, et al. Complement activation in experimental and human temporal lobe epilepsy. Neurobiol Dis. 2007;26(3):497–511.
Article CAS PubMed Google Scholar
Dachet F, Bagla S, Keren-Aviram G, Morton A, Balan K, Saadat L, et al. Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering. Brain. 2015;138(2):356–70.
Article PubMed Google Scholar
Wyatt SK, Witt T, Barbaro NM, Cohen-Gadol AA, Brewster AL. Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy. Exp Neurol. 2017;295:184–93.
Article CAS PubMed Google Scholar
Schartz ND, Wyatt-Johnson SK, Price LR, Colin SA, Brewster AL. Status epilepticus triggers long-lasting activation of complement C1q-C3 signaling in the hippocampus that correlates with seizure frequency in experimental epilepsy. Neurobiol Dis. 2018;109:163–73.
Article CAS PubMed Google Scholar
Schartz ND, Herr SA, Madsen L, Butts SJ, Torres C, Mendez LB, et al. Spatiotemporal profile of Map2 and microglial changes in the hippocampal CA1 region following pilocarpine-induced status epilepticus. Sci Rep. 2016;6:24988.
Article CAS PubMed PubMed Central Google Scholar
Kharatishvili I, Shan ZY, She DT, Foong S, Kurniawan ND, Reutens DC. MRI changes and complement activation correlate with epileptogenicity in a mouse model of temporal lobe epilepsy. Brain Struct Funct. 2014;219(2):683–706.
Article CAS PubMed Google Scholar
Durandy A, Kaveri SV, Kuijpers TW, Basta M, Miescher S, Ravetch JV, et al. Intravenous immunoglobulins – understanding properties and mechanisms. Clin Exp Immunol. 2009;158(s1):2–13.
Article CAS PubMed PubMed Central Google Scholar
Xiong Z-Q, Qian W, Suzuki K, McNamara JO. Formation of complement membrane attack complex in mammalian cerebral cortex evokes seizures and neurodegeneration. J Neurosci. 2003;23(3):955–60.
Article CAS PubMed PubMed Central Google Scholar
McGinn MJ, Povlishock JT. Pathophysiology of traumatic brain injury. Neurosurg Clin N Am. 2016;27(4):397–407.
Article PubMed Google Scholar
Kulbe JR, Geddes JW. Current status of fluid biomarkers in mild traumatic brain injury. Experimental neurology. 2016;275 Pt 3(0 3):334-52.
Hammad A, Westacott L, Zaben M. The role of the complement system in traumatic brain injury: a review. J Neuroinflammation. 2018;15(1):24.
Article PubMed PubMed Central CAS Google Scholar
Anada RP, Wong KT, Jayapalan JJ, Hashim OH, Ganesan D. Panel of serum protein biomarkers to grade the severity of traumatic brain injury. Electrophoresis. 2018;39(18):2308–15.
Article CAS PubMed Google Scholar
Manek R, Moghieb A, Yang Z, Kumar D, Kobessiy F, Sarkis GA, et al. Protein biomarkers and neuroproteomics characterization of microvesicles/exosomes from human cerebrospinal fluid following traumatic brain injury. Mol Neurobiol. 2018;55(7):6112–28.
Article CAS PubMed Google Scholar
Bellander BM, Singhrao SK, Ohlsson M, Mattsson P, Svensson M. Complement activation in the human brain after traumatic head injury. J Neurotrauma. 2001;18(12):1295–311.
Article CAS PubMed Google Scholar
Bellander BM, von Holst H, Fredman P, Svensson M. Activation of the complement cascade and increase of clusterin in the brain following a cortical contusion in the adult rat. J Neurosurg. 1996;85(3):468–75.
Article CAS PubMed Google Scholar
Witcher KG, Bray CE, Dziabis JE, McKim DB, Benner BN, Rowe RK, et al. Traumatic brain injury-induced neuronal damage in the somatosensory cortex causes formation of rod-shaped microglia that promote astrogliosis and persistent neuroinflammation. Glia. 2018;66(12):2719–36.
Article PubMed PubMed Central Google Scholar
Stahel PF, Flierl MA, Morgan BP, Persigehl I, Stoll C, Conrad C, et al. Absence of the complement regulatory molecule CD59a leads to exacerbated neuropathology after traumatic brain injury in mice. J Neuroinflammation. 2009;6:2.
Article PubMed PubMed Central CAS Google Scholar
Stahel PF, Morganti-Kossmann MC, Perez D, Redaelli C, Gloor B, Trentz O, et al. Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) Correlate with blood–brain barrier dysfunction in patients with traumatic brain injury. J Neurotrauma. 2001;18(8):773–81.
Article CAS PubMed Google Scholar
Rahpeymai Y, Hietala MA, Wilhelmsson U, Fotheringham A, Davies I, Nilsson AK, et al. Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 2006;25(6):1364–74.
Article CAS PubMed PubMed Central Google Scholar
Ingram G, Hakobyan S, Robertson NP, Morgan BP. Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol. 2009;155.
Weiner HL. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J Neurol. 2008;255(1):3–11.
Article CAS PubMed Google Scholar
Hu X, Holers VM, Thurman JM, Schoeb TR, Ramos TN, Barnum SR. Therapeutic inhibition of the alternative complement pathway attenuates chronic EAE. Mol Immunol. 2013;54(3):302–8.
Article CAS PubMed PubMed Central Google Scholar
Dutta R, Chang A, Doud MK, Kidd GJ, Ribaudo MV, Young EA, et al. Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol. 2011;69(3):445–54.
Article CAS PubMed PubMed Central Google Scholar
Jürgens T, Jafari M, Kreutzfeldt M, Bahn E, Brück W, Kerschensteiner M, et al. Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis. Brain. 2016;139(Pt 1):39-46.
Vilariño-Güell C, Zimprich A, Martinelli-Boneschi F, Herculano B, Wang Z, Matesanz F, et al. Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease. PLoS Genet. 2019;15(6):e1008180.
Article PubMed PubMed Central CAS Google Scholar
Ingram G, Loveless S, Howell OW, Hakobyan S, Dancey B, Harris CL, et al. Complement activation in multiple sclerosis plaques: an immunohistochemical analysis. Acta Neuropathol Commun. 2014;2(1):53.
Article PubMed PubMed Central Google Scholar
Watkins LM, Neal JW, Loveless S, Michailidou I, Ramaglia V, Rees MI, et al. Complement is activated in progressive multiple sclerosis cortical grey matter lesions. J Neuroinflammation. 2016;13(1):161.
Article PubMed PubMed Central CAS Google Scholar
Bellizzi MJ, Geathers JS, Allan KC, Gelbard HA. Platelet-Activating factor receptors mediate excitatory postsynaptic hippocampal injury in experimental autoimmune encephalomyelitis. J Neurosci. 2016;36(4):1336–46.
Article CAS PubMed PubMed Central Google Scholar
Hammond JW, Bellizzi MJ, Ware C, Qiu WQ, Saminathan P, Li H, et al. Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis. Brain Behav Immun. 2020;87:739–50.
Article CAS PubMed Google Scholar
Michailidou I, Jongejan A, Vreijling JP, Georgakopoulou T, de Wissel MB, Wolterman RA, et al. Systemic inhibition of the membrane attack complex impedes neuroinflammation in chronic relapsing experimental autoimmune encephalomyelitis. Acta Neuropathol Commun. 2018;6(1):36.
Article PubMed PubMed Central CAS Google Scholar
Zelek WM, Xie L, Morgan BP, Harris CL. Compendium of current complement therapeutics. Mol Immunol. 2019;114:341–52.
Article CAS PubMed Google Scholar
Carpanini SM, Torvell M, Morgan BP. Therapeutic inhibition of the complement system in diseases of the central nervous system. Front Immunol. 2019;10:362.
Article CAS PubMed PubMed Central Google Scholar
Sahin F, Ozkan MC, Mete NG, Yilmaz M, Oruc N, Gurgun A, et al. Multidisciplinary clinical management of paroxysmal nocturnal hemoglobinuria. AmJBlood Res. 2015;5(1):1–9.
CAS Google Scholar
Giamarellos-Bourboulis EJ, Argyropoulou M, Kanni T, Spyridopoulos T, Otto I, Zenker O, et al. Clinical efficacy of complement C5a inhibition by IFX-1 in hidradenitis suppurativa: an open-label single-arm trial in patients not eligible for adalimumab. Br J Dermatol. 2020;183(1):176–8.
Article CAS PubMed Google Scholar
Jayne DR, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, et al. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. J Am Soc Nephrol. 2017.
Vergunst CE, Gerlag DM, Dinant H, Schulz L, Vinkenoog M, Smeets TJ, et al. Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation. Rheumatology(Oxford). 2007;46(12):1773–8.
Article CAS PubMed Google Scholar
Kumar V, Lee JD, Clark RJ, Noakes PG, Taylor SM, Woodruff TM. Preclinical pharmacokinetics of complement C5a receptor antagonists PMX53 and PMX205 in mice. ACS Omega. 2020;5(5):2345–54.
Article CAS PubMed PubMed Central Google Scholar
Schnatbaum K, Locardi E, Scharn D, Richter U, Hawlisch H, Knolle J, et al. Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivo activity. Bioorg Med Chem Lett. 2006;16(19):5088–92.
Article CAS PubMed Google Scholar
Liu H, Kim HR, Deepak R, Wang L, Chung KY, Fan H, et al. Orthosteric and allosteric action of the C5a receptor antagonists. Nat Struct Mol Biol. 2018;25(6):472–81.
Article CAS PubMed Google Scholar
Li XX, Lee JD, Massey NL, Guan C, Robertson AAB, Clark RJ, et al. Pharmacological characterisation of small molecule C5aR1 inhibitors in human cells reveals biased activities for signalling and function. Biochem Pharmacol. 2020;114156.
Monk PN, Scola AM, Madala P, Fairlie DP. Function, structure and therapeutic potential of complement C5a receptors. Br J Pharmacol. 2007;152:429–48.
Article CAS PubMed PubMed Central Google Scholar
Farkas I, Takahashi M, Fukuda A, Yamamoto N, Akatsu H, Baranyi L, et al. Complement C5a receptor-mediated signaling may be involved in neurodegeneration in Alzheimer’s disease. J Immunol. 2003;170(11):5764–71.
Article CAS PubMed Google Scholar
Page 2
Microglia | C1q, C3, CR4, C3aR [16, 17] | CR4, C1q [22] | C1q [23] | ND | CR4, C1inh, C1s, C3, C4 [24] | C3, CD40, CR4, CR3 [25, 26] |
Astrocytes | C4, C3, C1inh, clusterin [17, 21, 27] | ND | C4, C1rb, C1ra, C1s, C1inh [28] | ND | C1q [29] | C3, C1inh, CR4, C3, C4, C1q [30] |
Neurons | C1q, C2, C3, C4, C5, C6, C7, C8, C9 [31] | C1q, C4, C3 [32], C1q, C5aR1; CD55 is downregulated [33, 34] | C5, C5aR [35, 36] | ND | ND | ND |
Oligodendrocytes | C4 [18] | ND | ND | ND | ND | ND |
- Italics=human tissue, ND not determined