The Role of the Classical Complement Cascade in Synapse Loss During Development and Glaucoma

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 703)

Abstract

Glaucoma is one of the leading causes of vision loss worldwide, yet the signals that initiate the progressive degeneration of optic nerve axons and the selective loss of retinal ganglion neurons (RGCs) remain elusive. Reactive gliosis, release of inflammatory cytokines, and complement upregulation all occur in the early stages of glaucoma in several disease models. Recent work has implicated the classical complement cascade in the elimination of excess synaptic connections in the developing visual system and in early synapse loss associated with glaucoma, suggesting that mechanisms of developmental synapse elimination may be aberrantly re-activated in glaucoma. This review describes current evidence in support of this “synaptic” hypothesis and places complement in the context of other well-described mechanisms of neurodegeneration occurring in the glaucomatous eye.

References

  1. Ahmed F, Brown KM et al (2004) Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure. Invest Ophthalmol Vis Sci 45(4):1247PubMedCrossRefGoogle Scholar
  2. Alexander JJ, Anderson AJ et al (2008) The complement cascade: Yin-Yang in neuroinflammation-neuro-protection and-degeneration. J Neurochem 107(5):1169PubMedCrossRefGoogle Scholar
  3. Allen NJ, Barres BA (2009) NeuroscienceGlia – more than just brain glue. Nature 457(7230):675–677PubMedCrossRefGoogle Scholar
  4. Alward WLM, Fingert JH et al (1998) Clinical features associated with mutations in the ­chromosome 1 open-angle glaucoma gene (GLC1A). N Engl J Med 338(15):1022PubMedCrossRefGoogle Scholar
  5. Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60(3):430–440PubMedCrossRefGoogle Scholar
  6. Berkelaar M, Clarke DB et al (1994) Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats. J Neurosci 14(7):4368PubMedGoogle Scholar
  7. Bolton MML, Eroglu C (2009) Look who is weaving the neural web: glial control of synapse formation. Curr Opin Neurobiol 19(5):491–497PubMedCrossRefGoogle Scholar
  8. Bosco A, Inman DM et al (2008) Reduced retina microglial activation and improved optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci 49(4):1437PubMedCrossRefGoogle Scholar
  9. Buckingham BP, Inman DM et al (2008) Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma. J Neurosci 28(11):2735PubMedCrossRefGoogle Scholar
  10. Büchi ER, Suivaizdis I et al (1991) Pressure-induced retinal ischemia in rats: an experimental model for quantitative study. Ophthalmologica 203(3):138PubMedCrossRefGoogle Scholar
  11. Bull ND, Irvine KA et al (2009) Transplanted oligodendrocyte precursor cells reduce neurodegeneration in a model of glaucoma. Invest Ophthalmol Vis Sci 50(9):4244PubMedCrossRefGoogle Scholar
  12. Cahoy JD, Emery B et al (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264PubMedCrossRefGoogle Scholar
  13. Carroll MC (2004) The complement system in regulation of adaptive immunity. Nat Immunol 5:981–986PubMedCrossRefGoogle Scholar
  14. Chang B, Smith RS et al (2001) Haploinsufficient Bmp 4 ocular phenotypes include anterior ­segment dysgenesis with elevated intraocular pressure. BMC Genet 2(1):18PubMedCrossRefGoogle Scholar
  15. Chaudhary P, Ahmed F et al (1998) MK801 – a neuroprotectant in rat hypertensive eyes. Brain Res 792(1):154–158PubMedCrossRefGoogle Scholar
  16. Chauhan BC, LeVatte TL et al (2004) Model of endothelin-1-induced chronic optic neuropathy in rat. Invest Ophthalmol Vis Sci 45(1):144–152PubMedCrossRefGoogle Scholar
  17. Chiu IM, Chen A et al (2008) T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci U S A 105(46):17913PubMedCrossRefGoogle Scholar
  18. Chiu IM, Phatnani H et al (2009) Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc Natl Acad Sci U S A 106(49):20960PubMedCrossRefGoogle Scholar
  19. Christopherson KS, Ullian EM et al (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120(3):421–433PubMedCrossRefGoogle Scholar
  20. Dalmau I, Finsen B et al (1998) Development of microglia in the postnatal rat hippocampus. Hippocampus 8(5):458–74PubMedCrossRefGoogle Scholar
  21. Daniel S, Ming L-B et al (2009) The morphology and spatial arrangement of astrocytes in the optic nerve head of the mouse. J Comp Neurol 516(1):spc1CrossRefGoogle Scholar
  22. Dreyer EB, Zurakowski D et al (1996) Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol 114(3):299PubMedCrossRefGoogle Scholar
  23. Duncan RO, Sample PA et al (2007) Retinotopic organization of primary visual cortex in glaucoma: comparing fMRI measurements of cortical function with visual field loss. Prog Retin Eye Res 26(1):38–56PubMedCrossRefGoogle Scholar
  24. Fan BJ, Leung YF et al (2004) Genetic and environmental risk factors for primary open-angle glaucoma. Chin Med J 117(5):706–710PubMedGoogle Scholar
  25. Fiske BK, Brunjes PC (2000) Microglial activation in the developing rat olfactory bulb. Neuroscience 96(4):807–15PubMedCrossRefGoogle Scholar
  26. Fu Q, Li X et al (2009) Synaptic degeneration of retinal ganglion cells in a rat ocular hypertension glaucoma model. Cell Mol Neurobiol 29(4):575–581PubMedCrossRefGoogle Scholar
  27. Griffiths M, Neal JW et al (2007) Innate immunity and protective neuroinflammation: new emphasis on the role of neuroimmune regulatory proteins. Int Rev Neurobiol 82:29–55PubMedCrossRefGoogle Scholar
  28. Grozdanic SD, Betts DM et al (2003) Laser-induced mouse model of chronic ocular hypertension. Invest Ophthalmol Vis Sci 44(10):4337PubMedCrossRefGoogle Scholar
  29. Guo L, Salt TE et al (2007) Targeting amyloid- in glaucoma treatment. Proc Natl Acad Sci U S A 104(33):13444PubMedCrossRefGoogle Scholar
  30. Hageman GS, Anderson DH et al (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102(20):7227PubMedCrossRefGoogle Scholar
  31. Harada T, Harada C et al (2007) The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma. J Clin Invest 117(7):1763–1770PubMedCrossRefGoogle Scholar
  32. Haydon PG (2001) Glia: listening and talking to the synapse. Nat Rev Neurosci 2(3):185–193PubMedCrossRefGoogle Scholar
  33. Hirsch EC, Breidert T et al (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:214–228PubMedCrossRefGoogle Scholar
  34. Howell GR, Libby RT et al (2007a) Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol 179(7):1523PubMedCrossRefGoogle Scholar
  35. Howell GR, Libby RT et al (2007b) Absence of glaucoma in DBA/2 J mice homozygous for wild-type versions of Gpnmb and Tyrp 1. BMC Genet 8(1):45PubMedCrossRefGoogle Scholar
  36. Howell GR, Libby RT et al (2008) Mouse genetic models: an ideal system for understanding glaucomatous neurodegeneration and neuroprotection. Prog Brain Res 173:303PubMedCrossRefGoogle Scholar
  37. Hua JY, Smith SJ (2004) Neural activity and the dynamics of central nervous system development. Nat Neurosci 7(4):327–332PubMedCrossRefGoogle Scholar
  38. Huang W, Fileta JB et al (2005) Calcineurin cleavage is triggered by elevated intraocular pressure, and calcineurin inhibition blocks retinal ganglion cell death in experimental glaucoma. Proc Natl Acad Sci U S A 102(34):12242–12247PubMedCrossRefGoogle Scholar
  39. Huberman AD, Feller MB et al (2008) Mechanisms underlying development of visual maps and receptive fields. Annu Rev Neurosci 31:479–509PubMedCrossRefGoogle Scholar
  40. Imamura K, Onoe H et al (2009) Molecular imaging reveals unique degenerative changes in experimental glaucoma. Neuroreport 20(2):139PubMedCrossRefGoogle Scholar
  41. Janzer RC, Raff MC (1987) Astrocytes induce blood–brain barrier properties in endothelial cells. Nature 325(6101):253–257PubMedCrossRefGoogle Scholar
  42. Jennings C (1994) Death of a synapse. Nature 372(6506):498–499PubMedCrossRefGoogle Scholar
  43. Johnson EC, Deppmeier LMH et al (2000) Chronology of optic nerve head and retinal responses to elevated intraocular pressure. Invest Ophthalmol Vis Sci 41(2):431–442PubMedGoogle Scholar
  44. Johnson TV, Tomarev SI (2010) Rodent models of glaucoma. Brain Research Bulletin 81:349–58PubMedCrossRefGoogle Scholar
  45. Kanamori A, Nakamura M et al (2005) Long-term glial reactivity in rat retinas ipsilateral and contralateral to experimental glaucoma. Exp Eye Res 81(1):48–56PubMedCrossRefGoogle Scholar
  46. Katz LC, Shatz CJ (1996) Synaptic activity and the construction of cortical circuits. Science 274(5290):1133PubMedCrossRefGoogle Scholar
  47. Kim CY, Kuehn MH et al (2005) Comparative analysis of optic nerve head gene expression changes in human glaucoma and in rodent models of ocular hypertension. Invest Ophthalmol Vis Sci 46(5):44Google Scholar
  48. Kuehn MH, Kim CY et al (2008) Disruption of the complement cascade delays retinal ganglion cell death following retinal ischemia-reperfusion. Exp Eye Res 87(2):89–95PubMedCrossRefGoogle Scholar
  49. Kuehn MH, Kim CY et al (2006) Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res 83(3):620–628PubMedCrossRefGoogle Scholar
  50. Lam D, Jim J et al (2009) Astrocyte and microglial activation in the lateral geniculate nucleus and visual cortex of glaucomatous and optic nerve transected primates. Molecular Vision 15:2217–29PubMedGoogle Scholar
  51. Leon S, Yin Y et al (2000) Lens injury stimulates axon regeneration in the mature rat optic nerve. J Neurosci 20(12):4615PubMedGoogle Scholar
  52. Levkovitch-Verbin H, Harris-Cerruti C et al (2000) RGC death in mice after optic nerve crush injury: oxidative stress and neuroprotection. Invest Ophthalmol Vis Sci 41(13):4169PubMedGoogle Scholar
  53. Levkovitch-Verbin H, Kalev-Landoy M et al (2006) Minocycline delays death of retinal ganglion cells in experimental glaucoma and after optic nerve transection. Arch Ophthalmol 124(4):520PubMedCrossRefGoogle Scholar
  54. Libby RT, Anderson MG et al (2005a) Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. Vis Neurosci 22(05):637–648PubMedCrossRefGoogle Scholar
  55. Libby RT, Gould DB et al (2005) Complex genetics of glaucoma susceptibility. Annual Review of Genomics and Human Genetics 6:15–44PubMedCrossRefGoogle Scholar
  56. Libby RT, Smith RS et al (2003) Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 299(5612):1578PubMedCrossRefGoogle Scholar
  57. Lobsiger CS, Boillée S et al (2007) Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc Natl Acad Sci U S A 104(18):7319PubMedCrossRefGoogle Scholar
  58. Lynch MA (2009) The multifaceted profile of activated microglia. Mol Neurobiol 40(2):139–156PubMedCrossRefGoogle Scholar
  59. Mabuchi F, Lindsey JD et al (2004) Optic nerve damage in mice with a targeted type I collagen mutation. Invest Ophthalmol Vis Sci 45(6):1841PubMedCrossRefGoogle Scholar
  60. Maier M, Peng Y et al (2008) Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 28(25):6333PubMedCrossRefGoogle Scholar
  61. Maslinska D, Laure-Kamionowska M et al (1998) Morphological forms and localization of microglial cells in the developing human cerebellum. Folia Neuropathol 36(3):145–51PubMedGoogle Scholar
  62. Mauch DH, Nagler K et al (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294(5545):1354PubMedCrossRefGoogle Scholar
  63. McKinnon SJ (2003) Glaucoma: ocular Alzheimer’s disease. Front Biosci 8:s1140–s1156PubMedCrossRefGoogle Scholar
  64. McKinnon SJ, Lehman DM et al (2002) Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension. Invest Ophthalmol Vis Sci 43(4):1077PubMedGoogle Scholar
  65. Morrison, JC, Moore CG et al (1997). A rat model of chronic pressure-induced optic nerve damage. Experimental Eye Research 64(1):85–96PubMedCrossRefGoogle Scholar
  66. Milligan CE, Cunningham TJ et al (1991) Differential immunochemical markers reveal the normal distribution of brain macrophages and microglia in the developing rat brain. J Comp Neurol 314(1):125–35PubMedCrossRefGoogle Scholar
  67. Nagy L, Hannema A et al (1999) Acquired C1 inhibitor deficiency associated with systemic lupus erythematosus, secondary antiphospholipid syndrome and IgM monoclonal paraproteinaemia. Clin Rheumatol 18(1):56–58PubMedCrossRefGoogle Scholar
  68. Nakano M, Knowlton AA et al (1996) Tumor necrosis factor-alpha-induced expression of heat shock protein 72 in adult feline cardiac myocytes. Am J Physiol Heart Circ Physiol 270(4):H1231Google Scholar
  69. Nakazawa T, Nakazawa C et al (2006) Tumor Necrosis Factor-{alpha} mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci 26(49):12633–12641PubMedCrossRefGoogle Scholar
  70. Naskar R, Vorwerk CK et al (2000) Concurrent downregulation of a glutamate transporter and receptor in glaucoma. Invest Ophthalmol Vis Sci 41(7):1940PubMedGoogle Scholar
  71. Neufeld AH (1999) Microglia in the optic nerve head and the region of parapapillary chorioretinal atrophy in glaucoma. Arch Ophthalmol 117(8):1050–1056PubMedCrossRefGoogle Scholar
  72. Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50(4):427–434PubMedCrossRefGoogle Scholar
  73. Phillips JC (2000) Four novel mutations in the PITX2 gene in patients with Axenfeld-Rieger syndrome. Ophthalmic Res 34(5):324–326CrossRefGoogle Scholar
  74. Pisalyaput K, Tenner AJ (2008) Complement component C1q inhibits β-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem 104(3):696–707PubMedGoogle Scholar
  75. Renu A, Suresh G et al (2009) Current concepts in the pathophysiology of glaucoma. Indian J Ophthalmol 57:257–266CrossRefGoogle Scholar
  76. Rezaie T, Child A et al (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295(5557):1077PubMedCrossRefGoogle Scholar
  77. Ricklin D, Lambris JD (2008) Compstatin: a complement inhibitor on its way to clinical application. Adv Exp Med Biol 632:273PubMedGoogle Scholar
  78. Rothstein JD, Dykes-Hoberg M et al (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16(3):675PubMedCrossRefGoogle Scholar
  79. Rotshenker S (2003) Microglia and macrophage activation and the regulation of complement-receptor-3 (CR3/MAC-1)-mediated myelin phagocytosis in injury and disease. J Mol Neurosci 21(1):65–72PubMedCrossRefGoogle Scholar
  80. Ruiz-Ederra J, Verkman AS (2006) Mouse model of sustained elevation in intraocular pressure produced by episcleral vein occlusion. Exp Eye Res 82(5):879–884PubMedCrossRefGoogle Scholar
  81. Sahu A, Lambris JD (2000) Complement inhibitors: a resurgent concept in anti-inflammatory. Immunopharmacology 49:133–148PubMedCrossRefGoogle Scholar
  82. Sasaki S, Maruyama S (1994) Synapse loss in anterior horn neurons in amyotrophic lateral ­sclerosis. Acta Neuropathol 88(3):222–227PubMedCrossRefGoogle Scholar
  83. Sasaoka M, Nakamura K et al (2008) Changes in visual fields and lateral geniculate nucleus in monkey laser-induced high intraocular pressure model. Exp Eye Res 86(5):770–782PubMedCrossRefGoogle Scholar
  84. Schwartz M (2004) Optic nerve crush: protection and regeneration. Brain Res Bull 62(6):467–471PubMedCrossRefGoogle Scholar
  85. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298(5594):789PubMedCrossRefGoogle Scholar
  86. Shimazawa M, Yamashima T et al (2005) Neuroprotective effects of minocycline against in vitro and in vivo retinal ganglion cell damage. Brain Res 1053(1–2):185–194PubMedCrossRefGoogle Scholar
  87. Singhrao SK, Neal JW et al (1999) Differential expression of individual complement regulators in the brain and choroid plexus. Lab Invest 79(10):1247–1259PubMedGoogle Scholar
  88. Smith RS, Zabaleta A et al (2000) Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum Mol Genet 9(7):1021PubMedCrossRefGoogle Scholar
  89. Stasi K, Nagel D et al (2006) Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes. Invest Ophthalmol Vis Sci 47(3):1024PubMedCrossRefGoogle Scholar
  90. Steele MR, Inman DM et al (2006) Microarray analysis of retinal gene expression in the DBA/2J model of glaucoma. Invest Ophthalmol Vis Sci 47(3):977PubMedCrossRefGoogle Scholar
  91. Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440(7087):1054–1059PubMedCrossRefGoogle Scholar
  92. Stevens B, Allen NJ et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131(6):1164–1178PubMedCrossRefGoogle Scholar
  93. Tezel G, Carlo Nucci LCNNO et al (2008) TNF-[alpha] signaling in glaucomatous neurodegeneration. Prog Brain Res 173:409–421PubMedCrossRefGoogle Scholar
  94. Torborg CL, Feller MB (2005) Spontaneous patterned retinal activity and the refinement of retinal projections. Prog Neurobiol 76(4):213–235PubMedCrossRefGoogle Scholar
  95. Turner MR, Cagnin A et al (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15(3):601–609PubMedCrossRefGoogle Scholar
  96. Ullian EM, Christopherson KS et al (2004) Role for glia in synaptogenesis. Glia 47(3):209–216PubMedCrossRefGoogle Scholar
  97. Ullian EM, Sapperstein SK et al (2001) Control of synapse number by glia. Science 291:657–661PubMedCrossRefGoogle Scholar
  98. Vorwerk CK, Lipton SA et al (1996) Chronic low-dose glutamate is toxic to retinal ganglion cells Toxicity blocked by memantine. Invest Ophthalmol Vis Sci 37(8):1618PubMedGoogle Scholar
  99. Webster S, Lue LF et al (1997) Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer’s disease. Neurobiol Aging 18(4):415–421PubMedCrossRefGoogle Scholar
  100. Woldemussie E, Wijono M et al (2004) Muller cell response to laser-induced increase in intraocular pressure in rats. Glia 47(2):109–119PubMedCrossRefGoogle Scholar
  101. Wyss-Coray T, Yan F et al (2002) Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci U S A 99(16):10837PubMedCrossRefGoogle Scholar
  102. Yang GY, Gong C et al (1999) Tumor necrosis factor alpha expression produces increased blood–brain barrier permeability following temporary focal cerebral ischemia in mice. Mol Brain Res 69(1):135–143PubMedCrossRefGoogle Scholar
  103. Yang L-B, Li R et al (2000) Deficiency of complement defense protein CD59 may contribute to neurodegeneration in Alzheimer’s disease. J Neurosci 20(20):7505–7509PubMedGoogle Scholar
  104. Yoneda S, Hara H et al (2005) Vitreous fluid levels of -Amyloid (1–42) and Tau in patients with retinal diseases. Jpn J Ophthalmol 49(2):106–108PubMedCrossRefGoogle Scholar
  105. Yuan L, Neufeld AH et al (2000) Tumor necrosis factor-: a potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head. Glia 32:42–50PubMedCrossRefGoogle Scholar
  106. Yücel YH, Zhang Q et al (2003) Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res 22(4):465–481PubMedCrossRefGoogle Scholar
  107. Zhong YS, Leung CK, Pang CP (2007) Glial cells and glaucomatous neuropathy. Chin Med J 120(4):326–335PubMedGoogle Scholar
  108. Zipfel PF, Skerka C (2009) Complement regulators and inhibitory proteins. Nat Rev Immunol 9(10):729–740PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.F.M. Kirby Neurobiology Center, Children’s Hospital Boston and Department of NeurologyHarvard Medical SchoolBostonUSA

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