Histological and direct evidence for the role of complement in the neuroinflammation of AD

Current Alzheimer Research

Volumn 8, Issue 1, 2011, Pages 34-58

  Veerhuis, Robert ^a  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Alzheimer's disease; Amyloid; Complement; Complement receptors; Microglia; Neuroinflammation

Indexed keywords

AMYLOID BETA PROTEIN; BENZOXAZINONE DERIVATIVE; BETA2 INTEGRIN; CLUSTERIN; COMPLEMENT COMPONENT C1Q; COMPLEMENT COMPONENT C2; COMPLEMENT COMPONENT C3A; COMPLEMENT COMPONENT C3B RECEPTOR; COMPLEMENT COMPONENT C5A RECEPTOR; ENOXAPARIN; ISOCOUMARIN DERIVATIVE; NAFAMSTAT MESILATE; PD 156050; PEPTIDE DERIVATIVE; PMX 205; POT 4; PROTEINASE INHIBITOR; RECEPTOR BLOCKING AGENT; ROSIGLITAZONE; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ARTICLE; BLOOD CLOTTING; CELL ACTIVATION; CENTRAL NERVOUS SYSTEM; COMPLEMENT ACTIVATION; COMPLEMENT SYSTEM; DRUG INHIBITION; GENOME; HUMAN; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; MICROGLIA; NERVE CELL; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN SYNTHESIS; PROTEOMICS; RETINA MACULA AGE RELATED DEGENERATION; VASCULAR AMYLOIDOSIS;

ALZHEIMER DISEASE; ANIMALS; ANTIGENS, CD; CENTRAL NERVOUS SYSTEM; COMPLEMENT SYSTEM PROTEINS; GENE EXPRESSION REGULATION; GENOME-WIDE ASSOCIATION STUDY; HUMANS; INFLAMMATION; MODELS, BIOLOGICAL; PLAQUE, AMYLOID; PROTEOMICS; RECEPTORS, COMPLEMENT; SIGNAL TRANSDUCTION;

EID: 79951708091     PISSN: 15672050     EISSN: None     Source Type: Journal    
DOI: 10.2174/156720511794604589     Document Type: Article

References (248)

1. Finch CE, Longo VD. The gero-inflammatory manifold. In: Rogers J (ed.), Neuroinflammatory mechanisms in Alzheimer's disease. Basel; Boston; Berlin: Birkhäuser; 2001: 237-256.
2. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev128: 92-105 (2007).
3. Braak H, Braak E. Neuropathological stageing of Alzheimerrelated changes. Acta Neuropathol (Berl) 82: 239-259 (1991).
4. Braak H, Braak E. Evolution of neuronal changes in the course of Alzheimer's disease. J Neural Transm Suppl 53: 127-140 (1998).
5. Hoozemans JJ, Veerhuis R, Rozemuller JM, Eikelenboom P. Neuroinflammation and regeneration in the early stages of Alzheimer's disease pathology. Int J Dev Neurosci 24: 157-165 (2006).
6. Veerhuis R, Boshuizen RS, Familian A. Amyloid associated proteins in Alzheimer's and prion disease. Curr Drug Targets CNS Neurol Disord 4: 235-248 (2005).
7. Cannella B, Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 37: 424-435 (1995).
8. Nottet HS, Persidsky Y, Sasseville VG, Nukuna AN, Bock P, Zhai QH, et al. Mechanisms for the transendothelial migration of HIV- 1-infected monocytes into brain. J Immunol 156: 1284-1295 (1996).
9. Eikelenboom P, Veerhuis R. The role of complement and activated microglia in the pathogenesis of Alzheimer's disease. Neurobiol Aging 17: 673-680 (1996).
10. Eikelenboom P, Veerhuis R, Scheper W, Rozemuller AJ, van Gool WA, Hoozemans JJ. The significance of neuroinflammation in understanding Alzheimer's disease. J Neural Transm 113: 1685-1695 (2006).
11. Griffiths MR, Gasque P, Neal JW. The multiple roles of the innate immune system in the regulation of apoptosis and inflammation in the brain. J Neuropathol Exp Neurol 68: 217-226 (2009).
12. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000; 21: 383-421.
13. Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Inflammation in Alzheimer's disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol 87: 181-194 (2009).
14. Emmerling MR, Spiegel K, Watson MD. Inhibiting the formation of classical C3-convertase on the Alzheimer's beta-amyloid peptide. Immunopharmacology 38: 101-109 (1997).
15. Veerhuis R, Hoozemans JJ, Cagnin A, Eikelenboom P, Banati RB. The activation of microglia as an early sign of disease progression in Alzheimer's disease. In: H.Kettenmann and B.R.Ransom (ed.), Neuroglia, 2nd ed. Oxford University Press; 2004: 563-572.
16. Yasojima K, Schwab C, McGeer EG, McGeer PL. Up-regulated production and activation of the complement system in Alzheimer's disease brain. Am J Pathol 154: 927-936 (1999).
17. Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, et al. Interleukin-6 and alpha-2-macroglobulin indicate an acutephase state in Alzheimer's disease cortices. FEBS Lett 285: 111-114 (1999).
18. Morgan BP, Gasque P. Expression of complement in the brain: role in health and disease. Immunol Today 17: 461-466 (1996).
19. Yasojima K, Schwab C, McGeer EG, McGeer PL. Human neurons generate C-reactive protein and amyloid P: upregulation in Alzheimer's disease. Brain Res 887: 80-89 (2000).
20. Streit WJ. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40: 133-9 (2002).
21. Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease-- a double-edged sword. Neuron 2002; 35: 419-32.
22. Fischer O. Miliare nekrosen mit drusigen Wuchurungen der Neurofibrillen, eine regelmassige Veranderung der Hirnrinde bei seniler Demenz. Monatsch fur Psychiatrie und Neurologie 22: 361-372 (1907).
23. Bouman L. Senile plaques. Brain 57: 128-142 (1934).
24. Zhan SS, Kamphorst W, Van Nostrand WE, Eikelenboom P. Distribution of neuronal growth-promoting factors and cytoskeletal proteins in altered neurites in Alzheimer's disease and nondemented elderly. Acta Neuropathol 89: 356-362 (1995).
25. Hoozemans JJ, Bruckner MK, Rozemuller AJ, Veerhuis R, Eikelenboom P, Arendt T. Cyclin D1 and cyclin E are co-localized with cyclo-oxygenase 2 (COX-2) in pyramidal neurons in Alzheimer disease temporal cortex. J Neuropathol Exp Neurol 61: 678-688 (2002).
26. Hoozemans JJ, Veerhuis R, Rozemuller AJ, Arendt T, Eikelenboom P. Neuronal COX-2 expression and phosphorylation of pRb precede p38 MAPK activation and neurofibrillary changes in AD temporal cortex. Neurobiol Dis 15: 492-499 (2004).
27. Arendt T. Synaptic degeneration in Alzheimer's disease. Acta Neuropathol 118: 167-179 (2009).
28. Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW. Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci USA 101: 2173-2178 (2004).
29. Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 70: 462-473 (2002).
30. 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 41: 1094-1099 (2009).
31. 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 41: 1088-1093 (2009).
32. Mandrekar S, Jiang Q, Lee CY, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE. Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J Neurosci 29: 4252-4262 (2009).
33. Yamaguchi H, Sugihara S, Ogawa A, Saido TC, Ihara Y. Diffuse plaques associated with astroglial amyloid beta protein, possibly showing a disappearing stage of senile plaques. Acta Neuropathol 95: 217-222 (1998).
34. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9: 453-457 (2003).
35. Nielsen HM, Veerhuis R, Holmqvist B, Janciauskiene S. Binding and uptake of A beta1-42 by primary human astrocytes in vitro. Glia 57: 978-988 (2009).
36. Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, et al. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J 18: 203-205 (2004).
37. Bate C, Veerhuis R, Eikelenboom P, Williams A. Microglia kill amyloid-beta1-42 damaged neurons by a CD14-dependent process. Neuroreport 15: 1427-1430 (2004).
38. Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem 20: 947-956 (2007).
39. Fiala M, Veerhuis R. Biomarkers of inflammation and amyloidbeta phagocytosis in patients at risk of Alzheimer disease. Exp Gerontol 45: 57-63 (2010).
40. Ulvestad E, Williams K, Bjerkvig R, Tiekotter K, Antel J, Matre R. Human microglial cells have phenotypic and functional characteristics in common with both macrophages and dendritic antigenpresenting cells. J Leukoc Biol 56: 732-740 (1994).
41. Webster SD, Park M, Fonseca MI, Tenner AJ. Structural and functional evidence for microglial expression of C1qR(P), the C1q receptor that enhances phagocytosis. J Leukoc Biol 67: 109-116 (2000).
42. Gasque P, Dean YD, McGreal EP, VanBeek J, Morgan BP. Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 49: 171-186 (2000).
43. Gasque P, Singhrao SK, Neal JW, Gotze O, Morgan BP. Expression of the receptor for complement C5a (CD88) is up-regulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human central nervous system. Am J Pathol 150: 31-41 (1997).
44. Rozemuller JM, Eikelenboom P, Pals ST, Stam FC. Microglial cells around amyloid plaques in Alzheimer's disease express leucocyte adhesion molecules of the LFA-1 family. Neurosci Lett 101: 288-292 (1989).
45. Muller-Eberhard HJ. Molecular organization and function of the complement system. Annu Rev Biochem 57: 321-347 (1988).
46. Woodruff TM, Costantini KJ, Taylor SM, Noakes PG. Role of complement in motor neuron disease: animal models and therapeutic potential of complement inhibitors. Adv Exp Med Biol 632: 143-158 (2008).
47. Bonifati DM, Kishore U. Role of complement in neurodegeneration and neuroinflammation. Mol Immunol 44: 999-1010 (2007).
48. Morgan BP, Gasque P. Extrahepatic complement biosynthesis: where, when and why? Clin Exp Immunol 107: 1-7 (1997).
49. Yao J, Harvath L, Gilbert DL, Colton CA. Chemotaxis by a CNS macrophage, the microglia. J Neurosci Res 27: 36-42 (1990).
50. Law SK, Lichtenberg NA, Levine RP. Evidence for an ester linkage between the labile binding site of C3b and receptive surfaces. J Immunol 123: 1388-1394 (1979).
51. Cole DS, Morgan BP. Beyond lysis: how complement influences cell fate. Clin Sci (Lond) 104: 455-466 (2003).
52. Beinrohr L, Dobo J, Zavodszky P, Gal P. C1, MBL-MASPs and C1-inhibitor: novel approaches for targeting complement-mediated inflammation. Trends Mol Med 14: 511-521 (2008).
53. Garred P, Honore C, Ma YJ, Munthe-Fog L, Hummelshoj T. MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement. Mol Immunol 46: 2737-2744 (2009).
54. Austen KF, Fearon DT. A molecular basis of activation of the alternative pathway of human complement. Adv Exp Med Biol 120B: 3-17 (1979).
55. Shen Y, Meri S. Yin and Yang: complement activation and regulation in Alzheimer's disease. Prog Neurobiol 70: 463-472 (2003).
56. Bergamaschini L, Rossi L, Vergani C, De Simoni MG. Alzheimer's disease: another target for heparin therapy. ScientificWorldJournal 9: 891-908 (2009).
57. Elward K, Griffiths M, Mizuno M, Harris CL, Neal JW, Morgan BP, et al. CD46 plays a key role in tailoring innate immune recognition of apoptotic and necrotic cells. J Biol Chem 80: 36342-36354 (2005).
58. van Kooten C, Fiore N, Trouw LA, Csomor E, Xu W, Castellano G, et al. Complement production and regulation by dendritic cells: molecular switches between tolerance and immunity. Mol Immunol 45: 4064-4072 (2008).
59. Roos A, Xu W, Castellano G, Nauta AJ, Garred P, Daha MR, et al. Mini-review: A pivotal role for innate immunity in the clearance of apoptotic cells. Eur J Immunol 34: 921-929 (2004).
60. 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 45: 3649-3660 (2008).
61. Kemper C, Hourcade DE. Properdin: New roles in pattern recognition and target clearance. Mol Immunol 45: 4048-4056 (2008).
62. Botto M, Kirschfink M, Macor P, Pickering MC, Wurzner R, Tedesco F. Complement in human diseases: Lessons from complement deficiencies. Mol Immunol 46: 2774-2783 (2009).
63. Carroll MC. The complement system in regulation of adaptive immunity. Nat Immunol 5: 981-986 (2004).
64. Erdei A, Isaak A, Torok K, Sandor N, Kremlitzka M, Prechl J, et al. Expression and role of CR1 and CR2 on B and T lymphocytes under physiological and autoimmune conditions. Mol Immunol 46: 2767-2773 (2009).
65. Cornacoff JB, Hebert LA, Smead WL, VanAman ME, Birmingham DJ, Waxman FJ. Primate erythrocyte-immune complex-clearing mechanism. J Clin Invest 71: 236-247 (1983).
66. Diamond MS, Garcia-Aguilar J, Bickford JK, Corbi AL, Springer TA. The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands. J Cell Biol 120: 1031-1043 (1993).
67. Kohl J. Self, non-self, and danger: a complementary view. Adv Exp Med Biol 586: 71-94 (2006).
68. He JQ, Wiesmann C, van Lookeren CM. A role of macrophage complement receptor CRIg in immune clearance and inflammation. Mol Immunol 45: 4041-4047 (2008).
69. Fonseca MI, Carpenter PM, Park M, Palmarini G, Nelson EL, Tenner AJ. C1qR(P), a myeloid cell receptor in blood, is predominantly expressed on endothelial cells in human tissue. J Leukoc Biol 70: 793-800 (2001).
70. McGreal EP, Ikewaki N, Akatsu H, Morgan BP, Gasque P. Human C1qRp is identical with CD93 and the mNI-11 antigen but does not bind C1q. J Immunol 168: 5222-5232 (2002).
71. Ogden CA, deCathelineau A, Hoffmann PR, Bratton D, Ghebrehiwet B, Fadok VA, et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med 194: 781-795 (2001).
72. Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, et al. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56: 66-78 (2007).
73. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J. The role of the anaphylatoxins in health and disease. Mol Immunol 46: 2753-2766 (2009).
74. 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 25: 1364-1374 (2006).
75. Gendrel M, Rapti G, Richmond JE, Bessereau JL. A secreted complement- control-related protein ensures acetylcholine receptor clustering. Nature 461: 992-996 (2009).
76. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell 131: 1164-1178 (2007).
77. Yuzaki M. Cbln and C1q family proteins: new transneuronal cytokines. Cell Mol Life Sci 65: 1698-1705 (2008).
78. Afagh A, Cummings BJ, Cribbs DH, Cotman CW, Tenner AJ. Localization and cell association of C1q in Alzheimer's disease brain. Exp Neurol 138: 22-32 (1996).
79. Rozovsky I, Morgan TE, Willoughby DA, Dugichi-Djordjevich MM, Pasinetti GM, Johnson SA, et al. Selective expression of clusterin (SGP-2) and complement C1qB and C4 during responses to neurotoxins in vivo and in vitro. Neuroscience 62: 741-758 (1994).
80. Fan R, Tenner AJ. Differential regulation of Abeta42-induced neuronal C1q synthesis and microglial activation. J Neuroinflammation 2: 1 (2005).
81. Eikelenboom P, Stam FC. Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol 57: 239-242 (1982).
82. Eikelenboom P, Stam FC. An immunohistochemical study on cerebral vascular and senile plaque amyloid in Alzheimer's dementia. Virchows Arch B Cell Pathol Incl Mol Pathol 47: 17-25 (1984).
83. Ishii T, Haga S. Immuno-electron-microscopic localization of complements in amyloid fibrils of senile plaques. Acta Neuropathol 63: 296-300 (1984).
84. Pouplard A, Emile J. New immunological findings in senile dementia. Interdiscipl Topics Geront 19: 62-71 (1985).
85. McGeer PL, Akiyama H, Itagaki S, McGeer EG. Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett 107: 341-346 (1989).
86. Eikelenboom P, Hack CE, Rozemuller JM, Stam FC. Complement activation in amyloid plaques in Alzheimer's dementia. Virchows Arch B Cell Pathol Incl Mol Pathol 56: 259-262 (1989).
87. Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease. Neurobiol Aging 9: 339-349 (1988).
88. McGeer PL, Itagaki S, Tago H, McGeer EG. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79: 195-200 (1987).
89. Zhan SS, Veerhuis R, Kamphorst W, Eikelenboom P. Distribution of beta amyloid associated proteins in plaques in Alzheimer's disease and in the non-demented elderly. Neurodegeneration 4: 291- 297 (1995).
90. Loeffler DA, Camp DM, Bennett DA. Plaque complement activation and cognitive loss in Alzheimer's disease. J Neuroinflammation 5: 9 (2008).
91. Terai K, Walker DG, McGeer EG, McGeer PL. Neurons express proteins of the classical complement pathway in Alzheimer disease. Brain Res 769: 385-390 (1997).
92. Veerhuis R, van der Valk, Janssen I, Zhan SS, Van Nostrand WE, Eikelenboom P. Complement activation in amyloid plaques in Alzheimer's disease brains does not proceed further than C3. Virchows Arch 426: 603-610 (1995).
93. Veerhuis R, Van Breemen MJ, Hoozemans JM, Morbin M, Ouladhadj J, Tagliavini F, et al. Amyloid beta plaque-associated proteins C1q and SAP enhance the Abeta1-42 peptide-induced cytokine secretion by adult human microglia in vitro. Acta Neuropathol 105: 135-144 (2003).
94. Zanjani H, Finch CE, Kemper C, Atkinson J, McKeel D, Morris JC, et al. Complement activation in very early Alzheimer disease. Alzheimer Dis Assoc Disord 19: 55-66 (2005).
95. Veerhuis R, Janssen I, Hack CE, Eikelenboom P. Early complement components in Alzheimer's disease brains. Acta Neuropathol 91: 53-60 (1996).
96. Lue LF, Rydel R, Brigham EF, Yang LB, Hampel H, Murphy GM, Jr., et al. Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro. Glia 35: 72-79 (2001).
97. Tacnet-Delorme P, Chevallier S, Arlaud GJ. Beta-amyloid fibrils activate the C1 complex of complement under physiological conditions: evidence for a binding site for A beta on the C1q globular regions. J Immunol 167: 6374-6381 (2001).
98. 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 152: 5050-5059 (1994).
99. Snyder SW, Wang GT, Barrett L, Ladror US, Casuto D, Lee CM, et al. Complement C1q does not bind monomeric beta-amyloid. Exp Neurol 128: 136-142 (1994).
100. Fonseca MI, Kawas CH, Troncoso JC, Tenner AJ. Neuronal localization of C1q in preclinical Alzheimer's disease. Neurobiol Dis 15: 40-46 (2004).
101. Hicks PS, Saunero-Nava L, Du Clos TW, Mold C. Serum amyloid P component binds to histones and activates the classical complement pathway. J Immunol 149: 3689-3694 (1992).
102. Ying SC, Gewurz AT, Jiang H, Gewurz H. Human serum amyloid P component oligomers bind and activate the classical complement pathway via residues 14-26 and 76-92 of the A chain collagen-like region of C1q. J Immunol 150: 169-176 (1993).
103. Sasaki A, Yamaguchi H, Ogawa A, Sugihara S, Nakazato Y. Microglial activation in early stages of amyloid beta protein deposition. Acta Neuropathol 94: 316-322 (1997).
104. Vehmas AK, Kawas CH, Stewart WF, Troncoso JC. Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol Aging 24: 321-31 (2003).
105. Arends YM, Duyckaerts C, Rozemuller JM, Eikelenboom P, Hauw JJ. Microglia, amyloid and dementia in alzheimer disease. A correlative study. Neurobiol Aging 21: 39-47 (2000).
106. Webster SD, Yang AJ, Margol L, Garzon-Rodriguez W, Glabe CG, Tenner AJ. Complement component C1q modulates the phagocytosis of Abeta by microglia. Exp Neurol 161: 127-138 (2000).
107. Lacy M, Jones J, Whittemore SR, Haviland DL, Wetsel RA, Barnum SR. Expression of the receptors for the C5a anaphylatoxin, interleukin-8 and FMLP by human astrocytes and microglia. J Neuroimmunol 61: 71-78 (1995).
108. Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3: 27 (2006).
109. Stoltzner SE, Grenfell TJ, Mori C, Wisniewski KE, Wisniewski TM, Selkoe DJ, et al. Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease. Am J Pathol 156: 489-499 (2000).
110. Reichwald J, Danner S, Wiederhold KH, Staufenbiel M. Expression of complement system components during aging and amyloid deposition in APP transgenic mice. J Neuroinflammation 6: 35 (2009).
111. Cadman ED, Puttfarcken PS. Beta-amyloid peptides initiate the complement cascade without producing a comparable effect on the terminal pathway in vitro. Exp Neurol 146: 388-394 (1997).
112. Schwab C, Steele JC, McGeer PL. Neurofibrillary tangles of Guam parkinson-dementia are associated with reactive microglia and complement proteins. Brain Res 707: 196-205 (1996).
113. Singhrao SK, Morgan BP, Neal JW, Newman GR. A functional role for corpora amylacea based on evidence from complement studies. Neurodegeneration 4: 335-345 (1995).
114. Rostagno A, Revesz T, Lashley T, Tomidokoro Y, Magnotti L, Braendgaard H, et al. Complement activation in chromosome 13 dementias. Similarities with Alzheimer's disease. J Biol Chem 277: 49782-49790 (2002).
115. Strohmeyer R, Ramirez M, Cole GJ, Mueller K, Rogers J. Association of factor H of the alternative pathway of complement with agrin and complement receptor 3 in the Alzheimer's disease brain. J Neuroimmunol 131: 135-146 (2002).
116. Strohmeyer R, Shen Y, Rogers J. Detection of complement alternative pathway mRNA and proteins in the Alzheimer's disease brain. Brain Res Mol Brain Res 81: 7-18 (2000).
117. Sjoberg AP, Trouw LA, Blom AM. Complement activation and inhibition: a delicate balance. Trends Immunol 30: 83-90 (2009).
118. Zetterberg H, Ruetschi U, Portelius E, Brinkmalm G, Andreasson U, Blennow K, et al. Clinical proteomics in neurodegenerative disorders. Acta Neurol Scand 118: 1-11 (2008).
119. Hye A, Lynham S, Thambisetty M, Causevic M, Campbell J, Byers HL, et al. Proteome-based plasma biomarkers for Alzheimer's disease. Brain 129: 3042-3050 (2006).
120. Zhang R, Barker L, Pinchev D, Marshall J, Rasamoelisolo M, Smith C, et al. Mining biomarkers in human sera using proteomic tools. Proteomics 4: 244-256 (2004).
121. Cutler P, Akuffo EL, Bodnar WM, Briggs DM, Davis JB, Debouck CM, et al. Proteomic identification and early validation of complement 1 inhibitor and pigment epithelium-derived factor: two novel biomarkers of Alzheimer's disease in human plasma. Proteomics Clin Appl 467-477 (2008).
122. Simonsen AH, McGuire J, Hansson O, Zetterberg H, Podust VN, Davies HA, et al. Novel panel of cerebrospinal fluid biomarkers for the prediction of progression to Alzheimer dementia in patients with mild cognitive impairment. Arch Neurol 64: 366-370 (2007).
123. Finehout EJ, Franck Z, Lee KH. Complement protein isoforms in CSF as possible biomarkers for neurodegenerative disease. Dis Markers 21: 93-101 (2005).
124. Finehout EJ, Franck Z, Choe LH, Relkin N, Lee KH. Cerebrospinal fluid proteomic biomarkers for Alzheimer's disease. Ann Neurol 61: 120-129 (2007).
125. Zetterberg M, Landgren S, Andersson ME, Palmer MS, Gustafson DR, Skoog I, et al. Association of complement factor H Y402H gene polymorphism with Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet 147B: 720-726 (2008).
126. Le Fur I, Laumet G, Richard F, Fievet N, Berr C, Rouaud O, et al. Association study of the CFH Y402H polymorphism with Alzheimer's disease. Neurobiol Aging 31: 165-166 (2010).
127. 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 41: 1088-1093 (2009).
128. 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 41: 1094- 1099 (2009).
129. van Beek J, van MM, 't Hart BA, Brok HP, Neal JW, Chatagner A, et al. Decay-accelerating factor (CD55) is expressed by neurons in response to chronic but not acute autoimmune central nervous system inflammation associated with complement activation. J Immunol 174: 2353-2365 (2005).
130. Singhrao SK, Neal JW, Rushmere NK, Morgan BP, Gasque P. Differential expression of individual complement regulators in the brain and choroid plexus. Lab Invest 79: 1247-1259 (1999).
131. 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 27: 1733- 1739 (2006).
132. Zhan SS, Veerhuis R, Janssen I, Kamphorst W, Eikelenboom P. Immunohistochemical distribution of the inhibitors of the terminal complement complex in Azlheimer's disease. Neurodegeneration 3: 111-117 (1994).
133. Lidstrom AM, Bogdanovic N, Hesse C, Volkman I, Davidsson P, Blennow K. Clusterin (apolipoprotein J) protein levels are increased in hippocampus and in frontal cortex in Alzheimer's disease. Exp Neurol 154: 511-521 (1998).
134. May PC, Lampert-Etchells M, Johnson SA, Poirier J, Masters JN, Finch CE. Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat. Neuron 5: 831-839 (1990).
135. Pasinetti GM, Johnson SA, Oda T, Rozovsky I, Finch CE. Clusterin (SGP-2): a multifunctional glycoprotein with regional expression in astrocytes and neurons of the adult rat brain. J Comp Neurol 339: 387-400 (1994).
136. Freixes M, Puig B, Rodriguez A, Torrejon-Escribano B, Blanco R, Ferrer I. Clusterin solubility and aggregation in Creutzfeldt-Jakob disease. Acta Neuropathol 108: 295-301 (2004).
137. Yasojima K, McGeer EG, McGeer PL. Complement regulators C1 inhibitor and CD59 do not significantly inhibit complement activation in Alzheimer disease. Brain Res 833: 297-301 (1999).
138. Oda T, Wals P, Osterburg HH, Johnson SA, Pasinetti GM, Morgan TE, et al. Clusterin (apoJ) alters the aggregation of amyloid betapeptide (A beta 1-42) and forms slowly sedimenting A beta complexes that cause oxidative stress. Exp Neurol 136: 22-31 (1995).
139. DeMattos RB, O'Dell MA, Parsadanian M, Taylor JW, Harmony JA, Bales KR, et al. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 99: 10843-10848 (2002).
140. Nielsen HM, Mulder SD, Belien JA, Musters RJ, Eikelenboom P, Veerhuis R. Astrocytic A beta 1-42 uptake is determined by A beta-aggregation state and the presence of amyloid-associated proteins. Glia 58: 1235-1246 (2010).
141. Ghiso J, Matsubara E, Koudinov A, Choi-Miura NH, Tomita M, Wisniewski T, et al. The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. Biochem J 293 (Pt 1): 27-30 (1993).
142. Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, et al. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 27: 909- 918 (2007).
143. Bradt BM, Kolb WP, Cooper NR. Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide. J Exp Med 188: 431-438 (1998).
144. Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci USA 99: 10837-10842 (2002).
145. Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, et al. Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci USA 89: 10016-10020 (1992).
146. Rostagno A, Lashley T, Ng D, Meyerson J, Braendgaard H, Plant G, et al. Preferential association of serum amyloid P component with fibrillar deposits in familial British and Danish dementias: similarities with Alzheimer's disease. J Neurol Sci 257: 88-96 (2007).
147. Jiang H, Cooper B, Robey FA, Gewurz H. DNA binds and activates complement via residues 14-26 of the human C1q A chain. J Biol Chem 267: 25597-25601 (1992).
148. McGrath FD, Brouwer MC, Arlaud GJ, Daha MR, Hack CE, Roos A. Evidence that complement protein C1q interacts with C-reactive protein through its globular head region. J Immunol 176: 2950- 2957 (2006).
149. Blanquet-Grossard F, Thielens NM, Vendrely C, Jamin M, Arlaud GJ. Complement protein C1q recognizes a conformationally modified form of the prion protein. Biochemistry 44: 4349-4356 (2005).
150. 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 3: 77-79 (1997).
151. Watson MD, Roher AE, Kim KS, Spiegel K, Emmerling MR. Complement interactions with amyloid-β1-42: A nidus for inflammation in AD brains. Amyloid: Int Exp Clin Invest 4: 147-156 (1997).
152. Brachova L, Lue LF, Schultz J, el RT, Rogers J. Association cortex, cerebellum, and serum concentrations of C1q and factor B in Alzheimer's disease. Brain Res Mol Brain Res 18: 329-334 (1993).
153. Sarvari M, Vago I, Weber CS, Nagy J, Gal P, Mak M, et al. Inhibition of C1q-beta-amyloid binding protects hippocampal cells against complement mediated toxicity. J Neuroimmunol 137: 12-18 (2003).
154. Familian A, Eikelenboom P, Veerhuis R. Minocycline does not affect amyloid beta phagocytosis by human microglial cells. Neurosci Lett 416: 87-91 (2007).
155. Wright SD, Craigmyle LS, Silverstein SC. Fibronectin and serum amyloid P component stimulate C3b- and C3bi-mediated phagocytosis in cultured human monocytes. J Exp Med 158: 1338-1343 (1983).
156. Nauta AJ, Castellano G, Xu W, Woltman AM, Borrias MC, Daha MR, et al. Opsonization with C1q and mannose-binding lectin targets apoptotic cells to dendritic cells. J Immunol 173: 3044-3050 (2004).
157. Fraser DA, Bohlson SS, Jasinskiene N, Rawal N, Palmarini G, Ruiz S, et al. C1q and MBL, components of the innate immune system, influence monocyte cytokine expression. J Leukoc Biol 80: 107-116 (2006).
158. Fraser DA, Arora M, Bohlson SS, Lozano E, Tenner AJ. Generation of inhibitory NFkappaB complexes and phosphorylated cAMP response element-binding protein correlates with the antiinflammatory activity of complement protein C1q in human monocytes. J Biol Chem 282: 7360-7367 (2007).
159. Mold C, Gresham HD, Du Clos TW. Serum amyloid P component and C-reactive protein mediate phagocytosis through murine Fc gamma Rs. J Immunol 166: 1200-1205 (2001).
160. Colton CA, Gilbert DL. Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett 223: 284-288 (1987).
161. Van Muiswinkel FL, Veerhuis R, Eikelenboom P. Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetate-induced respiratory burst activity. J Neurochem 66: 2468-2476 (1996).
162. Veerhuis R, Van Muiswinkel FL, Hack CE, Eikelenboom P. Role and regulation of early complement activation products in Alzheimer's disease. In: Rogers J (ed.), Neuroinflammatory mechanisms in Alzheimer's disease; Basic and Clinical Research. Basel- Boston-Berlin: Birkhäuser 67-87 (2001).
163. Korotzer AR, Watt J, Cribbs D, Tenner AJ, Burdick D, Glabe C, et al. Cultured rat microglia express C1q and receptor for C1q: implications for amyloid effects on microglia. Exp Neurol 134: 214-221 (1995).
164. Taguchi J, Fujii A, Fujino Y, Tsujioka Y, Takahashi M, Tsuboi Y, et al. Different expression of calreticulin and immunoglobulin binding protein in Alzheimer's disease brain. Acta Neuropathol 100: 153-160 (2000).
165. Steino A, Jorgensen CS, Laursen I, Houen G. Interaction of C1q with the receptor calreticulin requires a conformational change in C1q. Scand J Immunol 59: 485-495 (2004).
166. Luo X, Weber GA, Zheng J, Gendelman HE, Ikezu T. C1qcalreticulin induced oxidative neurotoxicity: relevance for the neuropathogenesis of Alzheimer's disease. J Neuroimmunol 135: 62-71 (2003).
167. Bordin S, Whitfield D. Cutting edge: proliferating fibroblasts respond to collagenous C1q with phosphorylation of p38 mitogenactivated protein kinase and apoptotic features. J Immunol 170: 667-671 (2003).
168. Hoozemans JJ, Veerhuis R, Janssen I, Rozemuller AJ, Eikelenboom P. Interleukin-1beta induced cyclooxygenase 2 expression and prostaglandin E2 secretion by human neuroblastoma cells: implications for Alzheimer's disease. Exp Gerontol 36: 559-570 (2001).
169. Trinder PK, Faust D, Petry F, Loos M. Modulation of mRNA expression and secretion of C1q in mouse macrophages by antiinflammatory drugs and cAMP: evidence for the partial involvement of a pathway that includes cyclooxygenase, prostaglandin E2 and adenylate cyclase. Immunology 84: 638-644 (1995).
170. Spielman L, Winger D, Ho L, Aisen PS, Shohami E, Pasinetti GM. Induction of the complement component C1qB in brain of transgenic mice with neuronal overexpression of human cyclooxygenase- 2. Acta Neuropathol (Berl) 103: 157-162 (2002).
171. Fan R, Tenner AJ. Complement C1q expression induced by Abeta in rat hippocampal organotypic slice cultures. Exp Neurol 185: 241-253 (2004).
172. Pisalyaput K, Tenner AJ. Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem 104: 696-707 (2008).
173. Jauneau AC, Ischenko A, Chatagner A, Benard M, Chan P, Schouft MT, et al. Interleukin-1beta and anaphylatoxins exert a synergistic effect on NGF expression by astrocytes. J Neuroinflammation 3: 8 (2006).
174. 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 170: 5764-5771 (2003).
175. Schupf N, Williams CA, Berkman A, Cattell WS, Kerper L. Binding specificity and presynaptic action of anaphylatoxin C5a in rat brain. Brain Behav Immun 3: 28-38 (1989).
176. Mukherjee P, Pasinetti GM. Complement anaphylatoxin C5a neuroprotects through mitogen-activated protein kinase-dependent inhibition of caspase 3. J Neurochem 77: 43-49 (2001).
177. Pasinetti GM, Tocco G, Sakhi S, Musleh WD, DeSimoni MG, Mascarucci P, et al. Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions. Neurobiol Dis 3: 197-204 (1996).
178. Gavrilyuk V, Kalinin S, Hilbush BS, Middlecamp A, McGuire S, Pelligrino D, et al. Identification of complement 5a-like receptor (C5L2) from astrocytes: characterization of anti-inflammatory properties. J Neurochem 92: 1140-1149 (2005).
179. Walker DG, McGeer PL. Complement gene expression in human brain: comparison between normal and Alzheimer disease cases. Brain Res Mol Brain Res 14: 109-116 (1992).
180. Johnson SA, Lampert-Etchells M, Pasinetti GM, Rozovsky I, Finch CE. Complement mRNA in the mammalian brain: responses to Alzheimer's disease and experimental brain lesioning. Neurobiol Aging 13: 641-648 (1992).
181. Walker DG, McGeer PL. Complement gene expression in neuroblastoma and astrocytoma cell lines of human origin. Neurosci Lett 157: 99-102 (1993).
182. Gasque P, Ischenko A, Legoedec J, Mauger C, Schouft MT, Fontaine M. Expression of the complement classical pathway by human glioma in culture. A model for complement expression by nerve cells. J Biol Chem 268: 25068-25074 (1993).
183. Barnum SR. Complement biosynthesis in the central nervous system. Crit Rev Oral Biol Med 6: 132-146 (1995).
184. Veerhuis R, Janssen I, de Groot CJ, Van Muiswinkel FL, Hack CE, Eikelenboom P. Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor. Exp Neurol 160: 289-299 (1999).
185. Shen Y, Li R, McGeer EG, McGeer PL. Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res 769: 391-395 (1997).
186. Tooyama I, Sato H, Yasuhara O, Kimura H, Konishi Y, Shen Y, et al. Correlation of the expression level of C1q mRNA and the number of C1q-positive plaques in the Alzheimer Disease temporal cortex. analysis of C1q mrna and its protein using adjacent or nearby sections. Dement Geriatr Cogn Disord 12: 237-242 (2001).
187. Goldsmith SK, Wals P, Rozovsky I, Morgan TE, Finch CE. Kainic acid and decorticating lesions stimulate the synthesis of C1q protein in adult rat brain. J Neurochem 68: 2046-2052 (1997).
188. Lue LF, Walker DG, Rogers J. Modeling microglial activation in Alzheimer's disease with human postmortem microglial cultures. Neurobiol Aging 22: 945-956 (2001).
189. Walker DG, Yasuhara O, Patston PA, McGeer EG, McGeer PL. Complement C1 inhibitor is produced by brain tissue and is cleaved in Alzheimer disease. Brain Res 675: 75-82 (1995).
190. Gasque P, Morgan BP. Complement regulatory protein expression by a human oligodendrocyte cell line: cytokine regulation and comparison with astrocytes. Immunology 89: 338-347 (1996).
191. Singhrao SK, Neal JW, Rushmere NK, Morgan BP, Gasque P. Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis. Am J Pathol 157: 905-918 (2000).
192. Canova C, Neal JW, Gasque P. Expression of innate immune complement regulators on brain epithelial cells during human bacterial meningitis. J Neuroinflammation 3: 22 (2006).
193. Veerhuis R, Janssen I, Hoozemans JJ, de Groot CJ, Hack CE, Eikelenboom P. Complement C1-inhibitor expression in Alzheimer's disease. Acta Neuropathol 96: 287-296 (1998).
194. 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 158: 1345-1354 (2001).
195. 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 24: 6457-6465 (2004).
196. 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 106: 2080-2092 (2008).
197. Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, et al. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 7: 612-618 (2001).
198. Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA. 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: 6333-6341 (2008).
199. Fan R, DeFilippis K, Van Nostrand WE. Induction of complement proteins in a mouse model for cerebral microvascular A beta deposition. J Neuroinflammation 4: 22 (2007).
200. Mirnics K, Norstrom EM, Garbett K, Choi SH, Zhang X, Ebert P, et al. Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice. Mol Neurodegener 3: 14 (2008).
201. Verbeek MM, Otte-Holler I, Veerhuis R, Ruiter DJ, de Waal RM. Distribution of A beta-associated proteins in cerebrovascular amyloid of Alzheimer's disease. Acta Neuropathol 96: 628-636 (1998).
202. Eikelenboom P, Veerhuis R, Familian A, Hoozemans JJ, van Gool WA, Rozemuller AJ. Neuroinflammation in plaque and vascular beta-amyloid disorders: clinical and therapeutic implications. Neurodegener Dis 5: 190-193 (2008).
203. Yamada M, Itoh Y, Suematsu N, Otomo E, Matsushita M. Vascular variant of Alzheimer's disease characterized by severe plaque-like beta protein angiopathy. Dement Geriatr Cogn Disord 8: 163-168 (1997).
204. Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 29: 95-112 (2010).
205. Wang J, Ohno-Matsui K, Yoshida T, Kojima A, Shimada N, Nakahama K, et al. Altered function of factor I caused by amyloid beta: implication for pathogenesis of age-related macular degeneration from Drusen. J Immunol 181: 712-720 (2008).
206. Wu Z, Lauer TW, Sick A, Hackett SF, Campochiaro PA. Oxidative stress modulates complement factor H expression in retinal pigmented epithelial cells by acetylation of FOXO3. J Biol Chem 282: 22414-22425 (2007).
207. Zhou J, Jang YP, Kim SR, Sparrow JR. Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci USA 103: 16182- 16187 (2006).
208. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to agerelated macular degeneration. Proc Natl Acad Sci USA 102: 7227- 7232 (2005).
209. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38: 458-462 (2006).
210. Scholl HP, Charbel IP, Walier M, Janzer S, Pollok-Kopp B, Borncke F, et al. Systemic complement activation in age-related macular degeneration. PLoS ONE 3: e2593 (2008).
211. Hakobyan S, Harris CL, Tortajada A, Goicochea de JE, Garcia-Layana A, Fernandez-Robredo P, et al. Measurement of factor H variants in plasma using variant-specific monoclonal antibodies: application to assessing risk of age-related macular degeneration. Invest Ophthalmol Vis Sci 49: 1983-1990 (2008).
212. Hamilton G, Proitsi P, Williams J, O'Donovan M, Owen M, Powell J, et al. Complement factor H Y402H polymorphism is not associated with late-onset Alzheimer's disease. Neuromolecular Med 9: 331-334 (2007).
213. Zetterberg M, Landgren S, Andersson ME, Palmer MS, Gustafson DR, Skoog I, et al. Association of complement factor H Y402H gene polymorphism with Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet 147B: 720-726 (2008).
214. Hakobyan S, Harris CL, Williams J, Abraham R, Morgan BP. Measurement of factor H and the Y402H polymorphism in Alzheimer's disease. Mol Immunol 45: 416-(abstract) (2008).
215. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 357: 553-561 (2007).
216. Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, et al. Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet 372: 1828- 1834 (2008).
217. Choi BH, Kim RC, Vaughan PJ, Lau A, Van Nostrand WE, Cotman CW, et al. Decreases in protease nexins in Alzheimer's disease brain. Neurobiol Aging 16: 557-562 (1995).
218. Soeda S, Koyanagi S, Kuramoto Y, Kimura M, Oda M, Kozako T, et al. Anti-apoptotic roles of plasminogen activator inhibitor-1 as a neurotrophic factor in the central nervous system. Thromb Haemost 100: 1014-1020 (2008).
219. Osterwalder T, Cinelli P, Baici A, Pennella A, Krueger SR, Schrimpf SP, et al. The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin. J Biol Chem 273: 2312-2321 (1998).
220. Davis AE, III, Mejia P, Lu F. Biological activities of C1 inhibitor. Mol Immunol 45: 4057-4063 (2008).
221. Bergamaschini L, Parnetti L, Pareyson D, Canziani S, Cugno M, Agostoni A. Activation of the contact system in cerebrospinal fluid of patients with Alzheimer disease. Alzheimer Dis Assoc Disord 12: 102-108 (1998).
222. Bergamaschini L, Canziani S, Bottasso B, Cugno M, Braidotti P, Agostoni A. Alzheimer's beta-amyloid peptides can activate the early components of complement classical pathway in a C1qindependent manner. Clin Exp Immunol 115: 526-533 (1999).
223. Jansen PM, Pixley RA, Brouwer M, de J, I, Chang AC, Hack CE, et al. Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase. Blood 87: 2337-2344 (1996).
224. Vasthare US, Barone FC, Sarau HM, Rosenwasser RH, DiMartino M, Young WF, et al. Complement depletion improves neurological function in cerebral ischemia. Brain Res Bull 45: 413-419 (1998).
225. De Simoni MG, Storini C, Barba M, Catapano L, Arabia AM, Rossi E, Bergamaschini L. Neuroprotection by complement (C1) inhibitor in mouse transient brain ischemia. J Cereb Blood Flow Metab 23: 232-239 (2003).
226. 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 164: 1857-1863 (2004).
227. Huang J, Kim LJ, Mealey R, Marsh HC, Jr., Zhang Y, Tenner AJ, et al. Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein. Science 285: 595-599 (1999).
228. Storini C, Rossi E, Marrella V, Distaso M, Veerhuis R, Vergani C, et al. C1-inhibitor protects against brain ischemia-reperfusion injury via inhibition of cell recruitment and inflammation. Neurobiol Dis 19: 10-17 (2005).
229. Cai S, Dole VS, Bergmeier W, Scafidi J, Feng H, Wagner DD, et al. A direct role for C1 inhibitor in regulation of leukocyte adhesion. J Immunol 174: 6462-6466 (2005).
230. Spiegel K, Emmerling MR, Barnum SR. Strategies for inhibition of complement activation in the treatment of neurodegenerative diseases. In: Wood PL (ed.), Neuroinflammation: Mechanisms and Management. Totowa, N.J.: Humana Press Inc.; 1997: 129-176.
231. Bureeva S, Andia-Pravdivy J, Kaplun A. Drug design using the example of the complement system inhibitors' development. Drug Discov Today 10: 1535-1542 (2005).
232. Ricklin D, Lambris JD. Complement-targeted therapeutics. Nat Biotechnol 25: 1265-1275 (2007).
233. Wagner E, Frank MM. Therapeutic potential of complement modulation. Nat Rev Drug Discov 9: 43-56 (2010).
234. Bergamaschini L, Rossi E, Storini C, Pizzimenti S, Distaso M, Perego C, et al. Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and beta-amyloid accumulation in a mouse model of Alzheimer's disease. J Neurosci 24: 4181-4186 (2004).
235. Akuffo EL, Davis JB, Fox SM, Gloger IS, Hosford D, Kinsey EE, et al. The discovery and early validation of novel plasma biomarkers in mild-to-moderate Alzheimer's disease patients responding to treatment with rosiglitazone. Biomarkers 13: 618-636 (2008).
236. Bureeva S, Andia-Pravdivy J, Petrov G, Igumnov M, Romanov S, Kolesnikova E, et al. Inhibition of classical pathway of complement activation with negative charged derivatives of bisphenol A and bisphenol disulphates. Bioorg Med Chem 13: 1045-1052 (2005).
237. Roumenina L, Bureeva S, Kantardjiev A, Karlinsky D, Ndia- Pravdivy JE, Sim R, et al. Complement C1q-target proteins recognition is inhibited by electric moment effectors. J Mol Recognit 20: 405-415 (2007).
238. Daly J, Kotwal GJ. Pro-inflammatory complement activation by the A beta peptide of Alzheimer's disease is biologically significant and can be blocked by vaccinia virus complement control protein. Neurobiol Aging 19: 619-627 (1998).
239. Nilsson B, Larsson R, Hong J, Elgue G, Ekdahl KN, Sahu A, et al. Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation. Blood 92: 1661- 1667 (1998).
240. Janssen BJ, Halff EF, Lambris JD, Gros P. Structure of compstatin in complex with complement component C3c reveals a new mechanism of complement inhibition. J Biol Chem 282: 29241- 29247 (2007).
241. Kulkarni AP, Pillay NS, Kellaway LA, Kotwal GJ. Intracranial administration of vaccinia virus complement control protein in Mo/Hu APPswe PS1dE9 transgenic mice at an early age shows enhanced performance at a later age using a cheese board maze test. Biogerontology 9: 405-420 (2008).
242. 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 183: 1375-1383 (2009).
243. Ager RR, Fonseca MI, Chu SH, Sanderson SD, Taylor SM, Woodruff TM, et al. Microglial C5aR (CD88) expression correlates with amyloid-beta deposition in murine models of Alzheimer's disease. J Neurochem 113: 389-401 (2010).
244. Ong GL, Mattes MJ. Mouse strains with typical mammalian levels of complement activity. J Immunol Methods 125: 147-158 (1989).
245. Osmers I, Szalai AJ, Tenner AJ, Barnum SR. Complement in BuB/BnJ mice revisited: serum C3 levels and complement opsonic activity are not elevated. Mol Immunol 43: 1722-1725 (2006).
246. Li M, Ager RR, Fraser DA, Tjokro NO, Tenner AJ. Development of a humanized C1q A chain knock-in mouse: assessment of antibody independent beta-amyloid induced complement activation. Mol Immunol 45: 3244-3252 (2008).
247. Sethi P, Lukiw WJ. Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer's disease temporal lobe neocortex. Neurosci Lett 459: 100-104 (2009).
248. Lukiw WJ, Zhao Y, Cui JG. An NF-kappaB-sensitive micro RNA- 146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem 283: 31315-31322 (2008).