1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Immunology
  4. Volume 41, 2023
  5. Article

Annual Review of Immunology

Volume 41, 2023

Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation

Abstract

The complement system is an ancient collection of proteolytic cascades with well-described roles in regulation of innate and adaptive immunity. With the convergence of a revolution in complement-directed clinical therapeutics, the discovery of specific complement-associated targetable pathways in the central nervous system, and the development of integrated multi-omic technologies that have all emerged over the last 15 years, precision therapeutic targeting in Alzheimer disease and other neurodegenerative diseases and processes appears to be within reach. As a sensor of tissue distress, the complement system protects the brain from microbial challenge as well as the accumulation of dead and/or damaged molecules and cells. Additional more recently discovered diverse functions of complement make it of paramount importance to design complement-directed neurotherapeutics such that the beneficial roles in neurodevelopment, adult neural plasticity, and neuroprotective functions of the complement system are retained.

Keyword(s): Alzheimer disease, C1q, complement, microglia, neuroinflammation, synaptic pruning
Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-101921-035639
2023-04-26
2025-03-24
Loading full text...

Full text loading...

/deliver/fulltext/immunol/41/1/annurev-immunol-101921-035639.html?itemId=/content/journals/10.1146/annurev-immunol-101921-035639&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Thielens NM, Tedesco F, Bohlson SS, Gaboriaud C, Tenner AJ. 2017. C1q: a fresh look upon an old molecule. Mol. Immunol. 89:73–83
     [Google Scholar]
  2. 2.
    Hawksworth OA, Li XX, Coulthard LG, Wolvetang EJ, Woodruff TM. 2017. New concepts on the therapeutic control of complement anaphylatoxin receptors. Mol. Immunol. 89:36–43
     [Google Scholar]
  3. 3.
    Peterson SL, Anderson AJ. 2014. Complement and spinal cord injury: traditional and non-traditional aspects of complement cascade function in the injured spinal cord microenvironment. Exp. Neurol. 258:35–47
     [Google Scholar]
  4. 4.
    Velazquez P, Cribbs DH, Poulos TL, Tenner AJ. 1997. Aspartate residue 7 in amyloid beta-protein is critical for classical complement pathway activation: implications for Alzheimer's disease pathogenesis. Nat. Med. 3:77–79
     [Google Scholar]
  5. 5.
    Shen Y, Lue L, Yang L, Roher A, Kuo Y et al. 2001. Complement activation by neurofibrillary tangles in Alzheimer's disease. Neurosci. Lett. 305:165–68
     [Google Scholar]
  6. 6.
    Jiang H, Burdick D, Glabe CG, Cotman CW, Tenner AJ. 1994. beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. J. Immunol. 152:5050–59
     [Google Scholar]
  7. 7.
    Zhang M, Takahashi K, Alicot EM, Vorup-Jensen T, Kessler B et al. 2006. Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury. J. Immunol. 177:4727–34
     [Google Scholar]
  8. 8.
    Nestor J, Arinuma Y, Huerta TS, Kowal C, Nasiri E et al. 2018. Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors. J. Exp. Med. 215:2554–66
     [Google Scholar]
  9. 9.
    Howard JF Jr., Utsugisawa K, Benatar M, Murai H, Barohn RJ et al. 2017. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 16:976–86
     [Google Scholar]
  10. 10.
    Wingerchuk DM, Fujihara K, Palace J, Berthele A, Levy M et al. 2021. Long-term safety and efficacy of eculizumab in aquaporin-4 IgG-positive NMOSD. Ann. Neurol. 89:61088–98
     [Google Scholar]
  11. 11.
    Veerhuis R, Nielsen HM, Tenner AJ. 2011. Complement in the brain. Mol. Immunol. 48:1592–603
     [Google Scholar]
  12. 12.
    Shen Y, Li R, McGeer EG, McGeer PL. 1997. Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res. 769:391–95
     [Google Scholar]
  13. 13.
    Singhrao SK, Neal JW, Rushmere NK, Morgan BP, Gasque P. 1999. Differential expression of individual complement regulators in the brain and choroid plexus. Lab. Investig. 79:1247–59
     [Google Scholar]
  14. 14.
    Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J et al. 2012. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J. Neuroinflamm. 9:179
     [Google Scholar]
  15. 15.
    Carvalho K, Schartz ND, Balderrama-Gutierrez G, Liang HY, Chu SH et al. 2022. Modulation of C5a-C5aR1 signaling alters the dynamics of AD progression. J. Neuroinflamm. 19:178
     [Google Scholar]
  16. 16.
    Boche D, Gordon MN. 2022. Diversity of transcriptomic microglial phenotypes in aging and Alzheimer's disease. Alzheimer's Dement. 18:2360–76
     [Google Scholar]
  17. 17.
    Lee JD, Coulthard LG, Woodruff TM. 2019. Complement dysregulation in the central nervous system during development and disease. Semin. Immunol. 45:101340
     [Google Scholar]
  18. 18.
    Petrisko TJ, Gomez-Arboledas A, Tenner AJ. 2021. Complement as a powerful “influencer” in the brain during development, adulthood and neurological disorders. Adv. Immunol. 152:157–222
     [Google Scholar]
  19. 19.
    Jeanes A, Coulthard LG, Mantovani S, Markham K, Woodruff TM. 2015. Co-ordinated expression of innate immune molecules during mouse neurulation. Mol. Immunol. 68:253–60
     [Google Scholar]
  20. 20.
    Gorelik A, Sapir T, Haffner-Krausz R, Olender T, Woodruff TM, Reiner O. 2017. Developmental activities of the complement pathway in migrating neurons. Nat. Commun. 8:15096
     [Google Scholar]
  21. 21.
    Lee JD, Levin SC, Willis EF, Li R, Woodruff TM, Noakes PG. 2018. Complement components are upregulated and correlate with disease progression in the TDP-43Q331K mouse model of amyotrophic lateral sclerosis. J. Neuroinflamm. 15:171
     [Google Scholar]
  22. 22.
    Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA et al. 2013. A dramatic increase of C1q protein in the CNS during normal aging. J. Neurosci. 33:13460–74
     [Google Scholar]
  23. 23.
    Schartz ND, Tenner AJ. 2020. The good, the bad, and the opportunities of the complement system in neurodegenerative disease. J. Neuroinflamm. 17:354
     [Google Scholar]
  24. 24.
    Fonseca MI, Chu SH, Hernandez MX, Fang MJ, Modarresi L et al. 2017. Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J. Neuroinflamm. 14:48
     [Google Scholar]
  25. 25.
    Deleted in proof
  26. 26.
    Benoit ME, Hernandez MX, Dinh ML, Benavente F, Vasquez O, Tenner AJ. 2013. 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. 288:654–65
     [Google Scholar]
  27. 27.
    Wu T, Dejanovic B, Gandham VD, Gogineni A, Edmonds R et al. 2019. Complement c3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 28:2111–23.e6
     [Google Scholar]
  28. 28.
    Zhou J, Fonseca MI, Pisalyaput K, Tenner AJ. 2008. Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease. J. Neurochem. 106:2080–92
     [Google Scholar]
  29. 29.
    Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D et al. 2020. Disease-associated astrocytes in Alzheimer's disease and aging. Nat. Neurosci. 23:6701–6
     [Google Scholar]
  30. 30.
    Bourel J, Planche V, Dubourdieu N, Oliveira A, Séré A et al. 2021. Complement C3 mediates early hippocampal neurodegeneration and memory impairment in experimental multiple sclerosis. Neurobiol. Dis. 160:105533
     [Google Scholar]
  31. 31.
    Zipfel PF, Skerka C. 2009. Complement regulators and inhibitory proteins. Nat. Rev. Immunol. 9:729–40
     [Google Scholar]
  32. 32.
    Cong Q, Soteros BM, Wollet M, Kim JH, Sia GM. 2020. The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development. Nat. Neurosci. 23:1067–78
     [Google Scholar]
  33. 33.
    Roll P, Rudolf G, Pereira S, Royer B, Scheffer IE et al. 2006. SRPX2 mutations in disorders of language cortex and cognition. Hum. Mol. Genet. 15:1195–207
     [Google Scholar]
  34. 34.
    Gialeli C, Gungor B, Blom AM. 2018. Novel potential inhibitors of complement system and their roles in complement regulation and beyond. Mol. Immunol. 102:73–83
     [Google Scholar]
  35. 35.
    Shinjyo N, Stahlberg A, Dragunow M, Pekny M, Pekna M. 2009. Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem. Cells 27:2824–32
     [Google Scholar]
  36. 36.
    Coulthard LG, Hawksworth OA, Conroy J, Lee JD, Woodruff TM. 2018. Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance. Mol. Immunol. 101:176–81
     [Google Scholar]
  37. 37.
    Rahpeymai Y, Hietala MA, Wilhelmsson U, Fotheringham A, Davies I et al. 2006. Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 25:1364–74
     [Google Scholar]
  38. 38.
    Coulthard LG, Hawksworth OA, Woodruff TM. 2018. Complement: the emerging architect of the developing brain. Trends Neurosci. 41:373–84
     [Google Scholar]
  39. 39.
    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS et al. 2007. The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–78
     [Google Scholar]
  40. 40.
    Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR et al. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705
     [Google Scholar]
  41. 41.
    Shatz CJ. 1990. Competitive interactions between retinal ganglion cells during prenatal development. J. Neurobiol. 21:197–211
     [Google Scholar]
  42. 42.
    Welsh CA, Stephany C, Sapp RW, Stevens B. 2020. Ocular dominance plasticity in binocular primary visual cortex does not require C1q. J. Neurosci. 40:769–83
     [Google Scholar]
  43. 43.
    Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B. 2015. Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol. 36:605–13
     [Google Scholar]
  44. 44.
    Josselyn SA, Köhler S, Frankland PW. 2015. Finding the engram. Nat. Rev. Neurosci. 16:521–34
     [Google Scholar]
  45. 45.
    Wang C, Yue H, Hu Z, Shen Y, Ma J et al. 2020. Microglia mediate forgetting via complement-dependent synaptic elimination. Science 367:688–94
     [Google Scholar]
  46. 46.
    Shi Q, Colodner KJ, Matousek SB, Merry K, Hong S et al. 2015. Complement C3-deficient mice fail to display age-related hippocampal decline. J. Neurosci. 35:13029–42
     [Google Scholar]
  47. 47.
    Chu Y, Jin X, Parada I, Pesic A, Stevens B et al. 2010. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. PNAS 107:7975–80
     [Google Scholar]
  48. 48.
    Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR et al. 2016. Schizophrenia risk from complex variation of complement component 4. Nature 530:177–83
     [Google Scholar]
  49. 49.
    Sia GM, Clem RL, Huganir RL. 2013. The human language–associated gene SRPX2 regulates synapse formation and vocalization in mice. Science 342:987–91
     [Google Scholar]
  50. 50.
    Cong Q, Soteros BM, Huo A, Li Y, Tenner AJ, Sia GM. 2022. C1q and SRPX2 regulate microglia mediated synapse elimination during early development in the visual thalamus but not the visual cortex. Glia 70:451–65
     [Google Scholar]
  51. 51.
    Holmquist E, Okroj M, Nodin B, Jirstrom K, Blom AM. 2013. Sushi domain-containing protein 4 (SUSD4) inhibits complement by disrupting the formation of the classical C3 convertase. FASEB J. 27:2355–66
     [Google Scholar]
  52. 52.
    Zhu H, Meissner LE, Byrnes C, Tuymetova G, Tifft CJ, Proia RL. 2020. The complement regulator Susd4 influences nervous-system function and neuronal morphology in mice. iScience 23:100957
     [Google Scholar]
  53. 53.
    González-Calvo I, Iyer K, Carquin M, Khayachi A, Giuliani FA et al. 2021. Sushi domain-containing protein 4 controls synaptic plasticity and motor learning. eLife 10:e65712
     [Google Scholar]
  54. 54.
    Suzuki K, Elegheert J, Song I, Sasakura H, Senkov O et al. 2020. A synthetic synaptic organizer protein restores glutamatergic neuronal circuits. Science 369:eabb4853
     [Google Scholar]
  55. 55.
    Matsuda K. 2017. Synapse organization and modulation via C1q family proteins and their receptors in the central nervous system. Neurosci. Res. 116:46–53
     [Google Scholar]
  56. 56.
    Yuzaki M. 2017. The C1q complement family of synaptic organizers: not just complementary. Curr. Opin. Neurobiol. 45:9–15
     [Google Scholar]
  57. 57.
    Steen VM, Nepal C, Ersland KM, Holdhus R, Nævdal M et al. 2013. Neuropsychological deficits in mice depleted of the schizophrenia susceptibility gene CSMD1. PLOS ONE 8:e79501
     [Google Scholar]
  58. 58.
    Escudero-Esparza A, Kalchishkova N, Kurbasic E, Jiang WG, Blom AM. 2013. The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I-mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly. FASEB J. 27:5083–93
     [Google Scholar]
  59. 59.
    Mehrotra P, Ravichandran KS. 2022. Drugging the efferocytosis process: concepts and opportunities. Nat. Rev. Drug Discov. 21:8601–20
     [Google Scholar]
  60. 60.
    Galvan MD, Greenlee-Wacker MC, Bohlson SS 2012. C1q and phagocytosis: the perfect complement to a good meal. J. Leukoc. Biol. 92:489–97
     [Google Scholar]
  61. 61.
    Fraser DA, Pisalyaput K, Tenner AJ. 2010. C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J. Neurochem. 112:733–43
     [Google Scholar]
  62. 62.
    Gyorffy BA, Kun J, Torok G, Bulyaki E, Borhegyi Z et al. 2018. Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning. PNAS 115:6303–8
     [Google Scholar]
  63. 63.
    Scott-Hewitt N, Perrucci F, Morini R, Erreni M, Mahoney M et al. 2020. Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia. EMBO J. 39:e105380
     [Google Scholar]
  64. 64.
    Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST et al. 2018. CD47 protects synapses from excess microglia-mediated pruning during development. Neuron 100:120–34.e6
     [Google Scholar]
  65. 65.
    Alzheimer's Assoc 2022. 2022 Alzheimer's disease facts and figures. Alzheimer's Dement. 18:4700–89
     [Google Scholar]
  66. 66.
    Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL et al. 1992. Complement activation by beta-amyloid in Alzheimer disease. PNAS 89:10016–20
     [Google Scholar]
  67. 67.
    Carpanini SM, Harwood JC, Baker E, Torvell M, Gerad Consort., et al. 2021. The impact of complement genes on the risk of late-onset Alzheimer's disease. Genes 12:3443
     [Google Scholar]
  68. 68.
    Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE et al. 2003. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39:409–21
     [Google Scholar]
  69. 69.
    Bensa JC, Reboul A, Colomb MG. 1983. Biosynthesis in vitro of complement subcomponents C1q, C1s and C1 inhibitor by resting and stimulated human monocytes. Biochem. J. 216:385–92
     [Google Scholar]
  70. 70.
    Gao Z, Li M, Ma J, Zhang S. 2014. An amphioxus gC1q protein binds human IgG and initiates the classical pathway: implications for a C1q-mediated complement system in the basal chordate. Eur. J. Immunol. 44:3680–95
     [Google Scholar]
  71. 71.
    Benoit ME, Tenner AJ. 2011. Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression. J. Neurosci. 31:3459–69
     [Google Scholar]
  72. 72.
    Pisalyaput K, Tenner AJ. 2008. Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J. Neurochem. 104:696–707
     [Google Scholar]
  73. 73.
    Fraser DA, Arora M, Bohlson SS, Lozano E, Tenner AJ. 2007. Generation of inhibitory NFκB complexes and phosphorylated cAMP response element-binding protein correlates with the anti-inflammatory activity of complement protein C1q in human monocytes. J. Biol. Chem. 282:7360–67
     [Google Scholar]
  74. 74.
    Benoit ME, Clarke EV, Morgado P, Fraser DA, Tenner AJ. 2012. Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J. Immunol. 188:5682–93
     [Google Scholar]
  75. 75.
    Galiakberova AA, Dashinimaev EB. 2020. Neural stem cells and methods for their generation from induced pluripotent stem cells in vitro. Front. Cell Dev. Biol. 8:815
     [Google Scholar]
  76. 76.
    Benavente F, Piltti KM, Hooshmand MJ, Nava AA, Lakatos A et al. 2020. Novel C1q receptor-mediated signaling controls neural stem cell behavior and neurorepair. eLife 9:e55732
     [Google Scholar]
  77. 77.
    Gyorffy BA, Toth V, Torok G, Gulyassy P, Kovacs RA et al. 2020. Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer's disease animal model. Cell Mol. Life Sci. 77:5243–58
     [Google Scholar]
  78. 78.
    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S et al. 2016. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712–16
     [Google Scholar]
  79. 79.
    Hernandez MX, Jiang S, Cole TA, Chu SH, Fonseca MI et al. 2017. Prevention of C5aR1 signaling delays microglial inflammatory polarization, favors clearance pathways and suppresses cognitive loss. Mol. Neurodegener. 12:66
     [Google Scholar]
  80. 80.
    Pavlovski D, Thundyil J, Monk PN, Wetsel RA, Taylor SM, Woodruff TM. 2012. Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis. FASEB J. 26:3680–90
     [Google Scholar]
  81. 81.
    Fonseca MI, Zhou J, Botto M, Tenner AJ. 2004. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J. Neurosci. 24:6457–65
     [Google Scholar]
  82. 82.
    Yang J, Wise L, Fukuchi KI. 2020. TLR4 cross-talk with NLRP3 inflammasome and complement signaling pathways in Alzheimer's disease. Front. Immunol. 11:724
     [Google Scholar]
  83. 83.
    Shi Q, Chowdhury S, Ma R, Le KX, Hong S et al. 2017. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl. Med. 9:eaaf6295
     [Google Scholar]
  84. 84.
    Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ et al. 2002. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. PNAS 99:10837–42
     [Google Scholar]
  85. 85.
    Selkoe DJ. 2002. Alzheimer's disease is a synaptic failure. Science 298:789–91
     [Google Scholar]
  86. 86.
    Mecca AP, O'Dell RS, Sharp ES, Banks ER, Bartlett HH et al. 2022. Synaptic density and cognitive performance in Alzheimer's disease: a PET imaging study with [11C]UCB-J. Alzheimer's Dement. 18:22527–36
     [Google Scholar]
  87. 87.
    Carpanini SM, Torvell M, Bevan RJ, Byrne RAJ, Daskoulidou N et al. 2022. Terminal complement pathway activation drives synaptic loss in Alzheimer's disease models. Acta Neuropathol. Commun. 10:99
     [Google Scholar]
  88. 88.
    Fatoba O, Itokazu T, Yamashita T. 2022. Complement cascade functions during brain development and neurodegeneration. FEBS J. 289:2085–109
     [Google Scholar]
  89. 89.
    Pozo-Rodrigalvarez A, Ollaranta R, Skoog J, Pekny M, Pekna M. 2021. Hyperactive behavior and altered brain morphology in adult complement C3a receptor deficient mice. Front. Immunol. 12:604812
     [Google Scholar]
  90. 90.
    Spurrier J, Nicholson L, Fang XT, Stoner AJ, Toyonaga T et al. 2022. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Sci. Transl. Med. 14:eabi8593
     [Google Scholar]
  91. 91.
    Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M et al. 2013. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron 79:887–902
     [Google Scholar]
  92. 92.
    Haas LT, Salazar SV, Smith LM, Zhao HR, Cox TO et al. 2017. Silent allosteric modulation of mGluR5 maintains glutamate signaling while rescuing Alzheimer's mouse phenotypes. Cell Rep. 20:76–88
     [Google Scholar]
  93. 93.
    Neff RA, Wang M, Vatansever S, Guo L, Ming C et al. 2021. Molecular subtyping of Alzheimer's disease using RNA sequencing data reveals novel mechanisms and targets. Sci. Adv. 7:eabb5398
     [Google Scholar]
  94. 94.
    Hernandez MX, Namiranian P, Nguyen E, Fonseca MI, Tenner AJ. 2017. C5a increases the injury to primary neurons elicited by fibrillar amyloid beta. ASN Neuro 9:1759091416687871
     [Google Scholar]
  95. 95.
    Fonseca MI, Ager RR, Chu SH, Yazan O, Sanderson SD et al. 2009. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J. Immunol. 183:1375–83
     [Google Scholar]
  96. 96.
    Gomez-Arboledas A, Carvalho K, Balderrama-Gutierrez G, Chu S-H, Liang HY et al. 2022. C5aR1 antagonism alters microglial polarization and mitigates disease progression in a mouse model of Alzheimer's disease. Acta Neuropathol. Commun 10116
     [Google Scholar]
  97. 97.
    Panayiotou E, Fella E, Andreou S, Papacharalambous R, Gerasimou P et al. 2019. C5aR agonist enhances phagocytosis of fibrillar and non-fibrillar Aβ amyloid and preserves memory in a mouse model of familial Alzheimer's disease. PLOS ONE 14:e0225417
     [Google Scholar]
  98. 98.
    Li XX, Lee JD, Kemper C, Woodruff TM. 2019. The complement receptor C5aR2: a powerful modulator of innate and adaptive immunity. J. Immunol. 202:3339–48
     [Google Scholar]
  99. 99.
    Cain SA, Monk PN. 2002. The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg74. J. Biol. Chem. 277:7165–69
     [Google Scholar]
  100. 100.
    Li XX, Clark RJ, Woodruff TM. 2020. C5aR2 activation broadly modulates the signaling and function of primary human macrophages. J. Immunol. 205:1102–12
     [Google Scholar]
  101. 101.
    Vasek MJ, Garber C, Dorsey D, Durrant DM, Bollman B et al. 2016. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534:538–43
     [Google Scholar]
  102. 102.
    Stokowska A, Atkins AL, Moran J, Pekny T, Bulmer L et al. 2017. Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia. Brain 140:353–69
     [Google Scholar]
  103. 103.
    Wei L-L, Ma N, Wu K-Y, Wang J-X, Diao T-Y et al. 2020. Protective role of C3aR (C3a anaphylatoxin receptor) against atherosclerosis in atherosclerosis-prone mice. Arterioscler. Thromb. Vasc. Biol. 40:2070–83
     [Google Scholar]
  104. 104.
    Coulthard LG, Woodruff TM. 2015. Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J. Immunol. 194:3542–48
     [Google Scholar]
  105. 105.
    El Gaamouch F, Audrain M, Lin WJ, Beckmann N, Jiang C et al. 2020. VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice. Mol. Neurodegener. 15:4
     [Google Scholar]
  106. 106.
    Kalant D, Cain SA, Maslowska M, Sniderman AD, Cianflone K, Monk PN. 2003. The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein. J. Biol. Chem. 278:11123–29
     [Google Scholar]
  107. 107.
    Zhou Y, Chen Y, Xu C, Zhang H, Lin C. 2020. TLR4 targeting as a promising therapeutic strategy for Alzheimer disease treatment. Front. Neurosci. 14:602508
     [Google Scholar]
  108. 108.
    Walter S, Letiembre M, Liu Y, Heine H, Penke B et al. 2007. Role of the Toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol. Biochem. 20:947–56
     [Google Scholar]
  109. 109.
    Hajishengallis G, Lambris JD. 2010. Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 31:154–63
     [Google Scholar]
  110. 110.
    Bettcher BM, Tansey MG, Dorothee G, Heneka MT 2021. Peripheral and central immune system crosstalk in Alzheimer disease—a research prospectus. Nat. Rev. Neurol. 17:689–701
     [Google Scholar]
  111. 111.
    Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H et al. 2008. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 111:1840–47
     [Google Scholar]
  112. 112.
    Parker C. 2009. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet 373:759–67
     [Google Scholar]
  113. 113.
    Asavapanumas N, Tradtrantip L, Verkman AS. 2021. Targeting the complement system in neuromyelitis optica spectrum disorder. Expert Opin. Biol. Ther. 21:1073–86
     [Google Scholar]
  114. 114.
    Dhillon S. 2018. Eculizumab: a review in generalized myasthenia gravis. Drugs 78:367–76
     [Google Scholar]
  115. 115.
    Mallah K, Couch C, Alshareef M, Borucki D, Yang X et al. 2021. Complement mediates neuroinflammation and cognitive decline at extended chronic time points after traumatic brain injury. Acta Neuropathol. Commun. 9:72
     [Google Scholar]
  116. 116.
    Alawieh A, Chalhoub RM, Mallah K, Langley EF, York M et al. 2021. Complement drives synaptic degeneration and progressive cognitive decline in the chronic phase after traumatic brain injury. J. Neurosci. 41:1830–43
     [Google Scholar]
  117. 117.
    Alawieh A, Langley EF, Weber S, Adkins D, Tomlinson S. 2018. Identifying the role of complement in triggering neuroinflammation after traumatic brain injury. J. Neurosci. 38:2519–32
     [Google Scholar]
  118. 118.
    Scott G, Hellyer PJ, Ramlackhansingh AF, Brooks DJ, Matthews PM, Sharp DJ. 2015. Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage. J. Neuroinflamm. 12:224
     [Google Scholar]
  119. 119.
    Holden SS, Grandi FC, Aboubakr O, Higashikubo B, Cho FS et al. 2021. Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury. Science 373:eabj2685
     [Google Scholar]
  120. 120.
    Kim YU, Kinoshita T, Molina H, Hourcade D, Seya T et al. 1995. Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein. J. Exp. Med. 181:151–59
     [Google Scholar]
  121. 121.
    Alawieh AM, Langley EF, Feng W, Spiotta AM, Tomlinson S. 2020. Complement-dependent synaptic uptake and cognitive decline after stroke and reperfusion therapy. J. Neurosci. 40:4042–58
     [Google Scholar]
  122. 122.
    Alawieh A, Langley EF, Tomlinson S. 2018. Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice. Sci. Transl. Med. 10:eaao6459
     [Google Scholar]
  123. 123.
    Werneburg S, Jung J, Kunjamma RB, Ha SK, Luciano NJ et al. 2020. Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease. Immunity 52:167–82.e7
     [Google Scholar]
  124. 124.
    Schulz K, Trendelenburg M. 2022. C1q as a target molecule to treat human disease: What do mouse studies teach us?. Front. Immunol. 13:958273
     [Google Scholar]
  125. 125.
    Zelek WM, Morgan BP. 2022. Targeting complement in neurodegeneration: challenges, risks, and strategies. Trends Pharmacol. Sci. 43:615–28
     [Google Scholar]
  126. 126.
    Carpanini SM, Torvell M, Morgan BP. 2019. Therapeutic inhibition of the complement system in diseases of the central nervous system. Front. Immunol. 10:362
     [Google Scholar]
  127. 127.
    Garred P, Tenner AJ, Mollnes TE. 2021. Therapeutic targeting of the complement system: from rare diseases to pandemics. Pharmacol. Rev. 73:792–827
     [Google Scholar]
  128. 128.
    Santra M, Dill KA, de Graff AMR. 2019. Proteostasis collapse is a driver of cell aging and death. PNAS 116:22173–78
     [Google Scholar]
  129. 129.
    Lee JD, Kumar V, Fung JN, Ruitenberg MJ, Noakes PG, Woodruff TM. 2017. Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. Br. J. Pharmacol. 174:689–99
     [Google Scholar]
  130. 130.
    Biggins PJC, Brennan FH, Taylor SM, Woodruff TM, Ruitenberg MJ. 2017. The alternative receptor for complement component 5a, C5aR2, conveys neuroprotection in traumatic spinal cord injury. J. Neurotrauma 34:2075–85
     [Google Scholar]
  131. 131.
    Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A et al. 2016. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353:aad8670
     [Google Scholar]
  132. 132.
    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R et al. 2017. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169:1276–90.e17
     [Google Scholar]
  133. 133.
    Hess C, Schifferli JA. 2003. Immune adherence revisited: novel players in an old game. News Physiol. Sci. 18:104–8
     [Google Scholar]
  134. 134.
    Johansson JU, Brubaker WD, Javitz H, Bergen AW, Nishita D et al. 2018. Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: polymorphisms, structure, and function of complement receptor 1. Alzheimer's Dement. 14:1438–49
     [Google Scholar]
  135. 135.
    Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A et al. 2009. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41:1088–93
     [Google Scholar]
  136. 136.
    Lambert JC, Heath S, Even G, Campion D, Sleegers K et al. 2009. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41:1094–99
     [Google Scholar]
  137. 137.
    Hettmann T, Gillies SD, Kleinschmidt M, Piechotta A, Makioka K et al. 2020. Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer's disease with reduced complement activation. Sci. Rep. 10:3294
     [Google Scholar]
  138. 138.
    Taylor RP, Lindorfer MA, Atkinson JP. 2020. Clearance of amyloid-beta with bispecific antibody constructs bound to erythrocytes. Alzheimer's Dement. 6:e12067
     [Google Scholar]
  139. 139.
    Fonseca MI, Chu S, Pierce AL, Brubaker WD, Hauhart RE et al. 2016. Analysis of the putative role of CR1 in Alzheimer's disease: genetic association, expression and function. PLOS ONE 11:e0149792
     [Google Scholar]
  140. 140.
    Tenner AJ. 2020. Complement-mediated events in Alzheimer's disease: mechanisms and potential therapeutic targets. J. Immunol. 204:306–15
     [Google Scholar]
  141. 141.
    Repik A, Pincus SE, Ghiran I, Nicholson-Weller A, Asher DR et al. 2005. A transgenic mouse model for studying the clearance of blood-borne pathogens via human complement receptor 1 (CR1). Clin. Exp. Immunol. 140:230–40
     [Google Scholar]
  142. 142.
    Jackson HM, Foley KE, O'Rourke R, Stearns TM, Fathalla D et al. 2020. A novel mouse model expressing human forms for complement receptors CR1 and CR2. BMC Genet. 21:101
     [Google Scholar]
  143. 143.
    Mahmoudi R, Kisserli A, Novella JL, Donvito B, Drame M et al. 2015. Alzheimer's disease is associated with low density of the long CR1 isoform. Neurobiol. Aging 36:1766.e5–e12
     [Google Scholar]
  144. 144.
    Merle NS, Singh P, Rahman J, Kemper C. 2020. Integrins meet complement: the evolutionary tip of an iceberg orchestrating metabolism and immunity. Br. J. Pharmacol. 178:142754–70
     [Google Scholar]
  145. 145.
    Kolev M, Kemper C. 2017. Keeping it all going—complement meets metabolism. Front. Immunol. 8: https://doi.org/10.3389/fimmu.2017.00001
    [Google Scholar]
  146. 146.
    Arbore G, West EE, Spolski R, Robertson AAB, Klos A et al. 2016. T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells. Science 352:aad1210
     [Google Scholar]
  147. 147.
    Kolev M, Dimeloe S, Le FG, Navarini A, Arbore G et al. 2015. Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity 42:1033–47
     [Google Scholar]
  148. 148.
    Kunz N, Kemper C. 2021. Complement has brains—do intracellular complement and immunometabolism cooperate in tissue homeostasis and behavior?. Front. Immunol. 12:629986
     [Google Scholar]
  149. 149.
    Niyonzima N, Rahman J, Kunz N, West EE, Freiwald T et al. 2021. Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation. Sci. Immunol. 6:eabf2489
     [Google Scholar]
  150. 150.
    Vlaar APJ, de Bruin S, Busch M, Timmermans S, van Zeggeren IE et al. 2020. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol. 2:12e764–73
     [Google Scholar]
  151. 151.
    Woodruff TM, Shukla AK. 2020. The complement C5a-C5aR1 GPCR axis in COVID-19 therapeutics. Trends Immunol. 41:965–67
     [Google Scholar]
  152. 152.
    De la Obecerra KI, Oosterheert W, van den Bos RM, Xenaki KT, Lorent JH et al. 2022. Multifaceted activities of seven nanobodies against complement C4b. J. Immunol. 208:2207–19
     [Google Scholar]
  153. 153.
    Ullman JC, Arguello A, Getz JA, Bhalla A, Mahon CS et al. 2020. Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice. Sci. Transl. Med. 12:545eaay1163
     [Google Scholar]
  154. 154.
    Wouters Y, Jaspers T, De Strooper B, Dewilde M. 2020. Identification and in vivo characterization of a brain-penetrating nanobody. Fluids Barriers CNS 17:62
     [Google Scholar]
/content/journals/10.1146/annurev-immunol-101921-035639
Loading
Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation
Annual Review of Immunology 41, 431 (2023); https://doi.org/10.1146/annurev-immunol-101921-035639
/content/journals/10.1146/annurev-immunol-101921-035639
/content/journals/10.1146/annurev-immunol-101921-035639
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error