Complement activation, and the subsequent induction of inflammation, does occur in the CNS. In addition however, as summarized here, recent data support protec-tive functions for complement which are distinct from the detrimental consequences of dysregulated complement activation. What remains to be determined is the rela-tive contribution of complement to inflammation and subsequent loss of neuronal function, and additionally the specific biochemical pathways through which the different complement activation products play counterbalancing roles in injury and repair in each disease. Therapeutic interventions in murine models of Alzheimer’s Disease targeting inflammation and oxidative stress have proven successful in reducing amyloid plaque burden/pathology as well as the proinflammatory cytokine IL-1β and other indicators of oxidative stress (Yao et al., 2004). If complement does contribute to the exacerbation of inflammation and neuronal loss as suggested in murine models of the disease, specific complement inhibitors that would block pathogenic activation but not the systemic protective functions of the complement system could be valuable therapeutics. While there are multiple potential targets for therapeutic intervention in neurodegenerative studies, different approaches will likely be beneficial at different stages of each disease, and thus a cocktail
Central Nervous System Diseases and Inflammation 167
of therapeutic reagents, including targeted complement inhibitors rather than a single drug, may be more successful in preventing or slowing CNS degeneration.
Acknowledgements Authors thank Cheryl Cotman for illustrations in Figs. 8.1 and 8.3 and Dr. Maria Fonseca for Fig. 8.2. The work in the authors’ lab was supported by NIH NS 35144 and AG 00538 and NIH training grant AG00096-21.
References
Afagh, A., Cummings, B.J., Cribbs, D.H., Cotman, C.W., and Tenner, A.J. (1996). Localization and cell association of C1q in Alzheimer’s disease brain. Exp. Neurol. 138, 22–32.
Aimone, J.B., Leasure, J.L., Perreau, V.M., and Thallmair, M. (2004). Spatial and temporal gene expression profiling of the contused rat spinal cord. Exp. Neurol. 189, 204–221.
Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G.M., Cooper, N.R., Eikelenboom, P., Emmerling, M., Fiebich, B.L., Finch, C.E., Frautschy, S., Griffin, W.S., Hampel, H., Hull, M., Landreth, G., Lue, L., Mrak, R., Mackenzie, I.R., McGeer, P.L., O’Banion, M.K., Pachter, J., Pasinetti, G., Plata-Salaman, C., Rogers, J., Rydel, R., Shen, Y., Streit, W., Strohmeyer, R., Tooyoma, I., Van Muiswinkel, F.L., Veerhuis, R., Walker, D., Webster, S., Wegrzyniak, B., Wenk, G., and Wyss-Coray, T. (2000). Inflammation and Alzheimer’s disease. Neurobiol.
Aging 21, 383–421.
Anderson, A.J., Robert, S., Huang, W., Young, W., and Cotman, C.W. (2004). Activation of comple-ment pathways after contusion-induced spinal cord injury. J. Neurotrauma 21, 1831–1846.
Anderson, A.J., Najbauer, J., Huang, W., Young, W., and Robert, S. (2005). Upregulation of com-plement inhibitors in association with vulnerable cells following contusion-induced spinal cord injury. J. Neurotrauma 22, 382–397.
Arnett, H.A., Wang, Y., Matsushima, G.K., Suzuki, K., and Ting, J.P. (2003). Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration.
J. Neurosci. 23, 9824–9832.
Barnum, S.R. (1995). Complement biosynthesis in the central nervous system. Crit. Rev. Oral Biol. Med. 6, 132–146.
Barnum, S.R. and Szalai, A.J. (2006). Complement and demyelinating disease: no MAC needed?
Brain Res. Brain Res. Rev. 52, 58–68.
Baudouin, C., Peyman, G.A., Fredj-Reygrobellet, D., Gordon, W.C., Lapalus, P., Gastaud, P., and Bazan, N.G. (1992). Immunohistological study of subretinal membranes in age-related macu-lar degeneration. Jpn. J. Ophthalmol. 36, 443–451.
Benard, M., Gonzalez, B.J., Schouft, M.T., Falluel-Morel, A., Vaudry, D., Chan, P., Vaudry, H., and Fontaine, M. (2004). Characterization of C3a and C5a receptors in rat cerebellar granule neurons during maturation. Neuroprotective effect of C5a against apoptotic cell death. J. Biol.
Chem. 279, 43487–43496.
Bensa, J.C., Reboul, A., and Colomb, M.G. (1983). Biosynthesis in vitro of complement subcom-ponents C1q, C1s and C1 inhibitor by resting and stimulated human monocytes. Biochem.
J. 216, 385–392.
Bergamaschini, L., Rossi, E., Storini, C., Pizzimenti, S., Distaso, M., Perego, C., De Luigi, A., Vergani, C., and Grazia, D.S. (2004). 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.
Blom, A.M., Kask, L., and Dahlback, B. (2001). Structural requirements for the complement regu-latory activities of C4BP. J. Biol. Chem. 276, 27136–27144.
Bobak, D.A., Gaither, T.G., Frank, M.M., and Tenner, A.J. (1987). Modulation of FcR function by complement: subcomponent C1q enhances the phagocytosis of IgG-opsonized targets by human monocytes and culture-derived macrophages. J. Immunol. 138, 1150–1156.
168 A.J. Tenner and K. Pisalyaput
Bohlson, S.S., Fraser, D.A., and Tenner, A.J. (2007). Complement proteins C1q and MBL are pattern recognition molecules that signal immediate and long-term protective immune func-tions. Mol. Immunol. 44, 33–43.
Boos, L., Campbell, I.L., Ames, R., Wetsel, R.A., and Barnum, S.R. (2004). Deletion of the com-plement anaphylatoxin c3a receptor attenuates, whereas ectopic expression of c3a in the brain exacerbates, experimental autoimmune encephalomyelitis. J. Immunol. 173, 4708–4714.
Boos, L.A., Szalai, A.J., and Barnum, S.R. (2005). Murine complement C4 is not required for experimental autoimmune encephalomyelitis. Glia 49, 158–160.
Botto, M., Dell’agnola, C., Bygrave, A.E., Thompson, E.M., Cook, H.T., Petry, F., Loos, M., Pandolfi, P.P., and Walport, M.J. (1998). Homozygous C1q deficiency causes glomerulone-phritis associated with multiple apoptotic bodies. Nat. Genet. 19, 56–59.
Bracken, M.B. (2000). The use of methylprednisolone. J. Neurosurg. 93, 340–341.
Bradt, B.M., Kolb, W.P., and Cooper, N.R. (1998). Complement-dependent proinflammatory properties of the Alzheimer’s disease β-peptide. J. Exp. Med. 188, 431–438.
Carlson, S.L., Parrish, M.E., Springer, J.E., Doty, K., and Dossett, L. (1998). Acute inflammatory response in spinal cord following impact injury. Exp. Neurol. 151, 77–88.
Chen, S., Frederickson, R.C., and Brunden, K.R. (1996). Neuroglial-mediated immunoinflamma-tory responses in Alzheimer’s disease: complement activation and therapeutic approaches.
Neurobiol. Aging 17, 781–787.
Dandoy-Dron, F., Guillo, F., Benboudjema, L., Deslys, J.P., Lasmezas, C., Dormont, D., Tovey, M.G., and Dron, M. (1998). Gene expression in scrapie. Cloning of a new scrapie-responsive gene and the identification of increased levels of seven other mRNA transcripts. J. Biol. Chem.
273, 7691–7697.
Dhib-Jalbut, S., Arnold, D.L., Cleveland, D.W., Fisher, M., Friedlander, R.M., Mouradian, M.M., Przedborski, S., Trapp, B.D., Wyss-Coray, T., and Yong, V.W. (2006). Neurodegeneration and neuroprotection in multiple sclerosis and other neurodegenerative diseases. J. Neuroimmunol.
176, 198–215.
Dietzschold, B., Schwaeble, W., Schäfer, M.K.H., Hooper, D.C., Zehng, Y.M., Petry, F., Sheng, H., Fink, T., Loos, M., Koprowski, H., and Weihe, E. (1995). Expression of C1q, a subcompo-nent of the rat complement system, is dramatically enhanced in brains of rats with either Borna disease or experimental allergic encephalomyelitis. J. Neurol. Sci. 130, 11–16.
Dyer, J.K., Bourque, J.A., and Steeves, J.D. (1998). Regeneration of brainstem-spinal axons after lesion and immunological disruption of myelin in adult rat. Exp. Neurol. 154, 12–22.
Dyer, J.K., Bourque, J.A., and Steeves, J.D. (2005). The role of complement in immunological demyelination of the mammalian spinal cord. Spinal Cord 43, 417–425.
Eikelenboom, P., Hack, C.E., Rozemuller, J.M., and Stam, F.C. (1989). Complement activation in amyloid plaques in Alzheimer’s dementia. Virchows Arch. B Cell Pathol. 56, 259–262.
El-Agnaf, O.M., Nagala, S., Patel, B.P., and Austen, B.M. (2001). Non-fibrillar oligomeric species of the amyloid ABri peptide, implicated in familial British dementia, are more potent at induc-ing apoptotic cell death than protofibrils or mature fibrils. J. Mol. Biol. 310, 157–168.
Ember, J.A., Jagels, M.A., and Hugli, T. (1998). Characterization of complement anaphylatoxins and biological responses. In The Human Complement System in Health and Disease, J.E. Volanakis and M.M. Frank, eds. (New York, NY: Marcel Dekker), pp. 241–284.
Fonseca, M.I., Zhou, J., Botto, M., and Tenner, A.J. (2004). Absence of C1q leads to less neuropa-thology in transgenic mouse models of Alzheimer’s disease. J. Neurosci. 24, 6457–6465.
Fraser, D.A., Bohlson, S.S., Jasinskiene, N., Rawal, N., Palmarini, G., Ruiz, S., Rochford, R., and Tenner, A.J. (2006). C1q and MBL, components of the innate immune system, influence monocyte cytokine expression. J. Leukoc. Biol. 80, 107–116.
Fraser, D.A., Arora, M., Bohlson, S.S., Lozano, E., and Tenner, A.J. (2007). Generation of inhibi-tory NFkappa B complexes and pCREB correlates with the anti-inflammainhibi-tory activity of complement protein C1q in human monocytes. J. Biol. Chem. 282, 7360–7367.
Gao, H., Neff, T.A., Guo, R.F., Speyer, C.L., Sarma, J.V., Tomlins, S., Man, Y., Riedemann, N.C., Hoesel, L.M., Younkin, E., Zetoune, F.S., and Ward, P.A. (2005). Evidence for a functional role of the second C5a receptor C5L2. FASEB J. 19, 1003–1005.
Central Nervous System Diseases and Inflammation 169
Gasque, P. (2004). Complement: a unique innate immune sensor for danger signals. Mol. Immunol.
41, 1089–1098.
Gasque, P., Dean, Y.D., McGreal, E.P., VanBeek, J., and Morgan, B.P. (2000). Complement com-ponents of the innate immune system in health and disease in the CNS. Immunopharmacology 49, 171–186.
Gavrilyuk, V., Kalinin, S., Hilbush, B.S., Middlecamp, A., McGuire, S., Pelligrino, D., Weinberg, G., and Feinstein, D.L. (2005). Identification of complement 5a-like receptor (C5L2) from astrocytes: characterization of anti-inflammatory properties. J. Neurochem. 92, 1140–1149.
Gerard, N.P., Lu, B., Liu, P., Craig, S., Fujiwara, Y., Okinaga, S., and Gerard, C. (2005). An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. J. Biol.
Chem. 280, 39677–39680.
Gibson, G., Gunasekera, N., Lee, M., Lelyveld, V., El-Agnaf, O.M., Wright, A., and Austen, B.
(2004). Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia. J. Neurochem. 88, 281–290.
Golde, T.E. (2005). The Abeta hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease. Brain Pathol. 15, 84–87.
Goldsmith, S.K., Wals, P., Rozovsky, I., Morgan, T.E., and Finch, C.E. (1997). Kainic acid and decorticating lesions stimulate the synthesis of C1q protein in adult rat brain. J. Neurochem.
68, 2046–2052.
Griffin, W.S. and Mrak, R.E. (2002). Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease. J. Leukoc. Biol. 72, 233–238.
Grimsley, C. and Ravichandran, K.S. (2003). Cues for apoptotic cell engulfment: eat-me, don’t eat-me and come-get-me signals. Trends Cell Biol. 13, 648–656.
Guo, R.F. and Ward, P.A. (2005). Role of C5a in inflammatory responses. Annu. Rev. Immunol.
23, 821–852.
Hageman, G.S., Luthert, P.J., Victor Chong, N.H., Johnson, L.V., Anderson, D.H., and Mullins, R.F. (2001). An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration.
Prog. Retin. Eye Res. 20, 705–732.
Hageman, G.S., Anderson, D.H., Johnson, L.V., Hancox, L.S., Taiber, A.J., Hardisty, L.I., Hageman, J.L., Stockman, H.A., Borchardt, J.D., Gehrs, K.M., Smith, R.J., Silvestri, G., Russell, S.R., Klaver, C.C., Barbazetto, I., Chang, S., Yannuzzi, L.A., Barile, G.R., Merriam, J.C., Smith, R.T., Olsh, A.K., Bergeron, J., Zernant, J., Merriam, J.E., Gold, B., Dean, M., and Allikmets, R. (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, 7227–7232.
Haines, J.L., Hauser, M.A., Schmidt, S., Scott, W.K., Olson, L.M., Gallins, P., Spencer, K.L., Kwan, S.Y., Noureddine, M., Gilbert, J.R., Schnetz-Boutaud, N., Agarwal, A., Postel, E.A., and Pericak-Vance, M.A. (2005). Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–420.
Hanayama, R., Tanaka, M., Miyasaka, K., Aozasa, K., Koike, M., Uchiyama, Y., and Nagata, S.
(2004). Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150.
Hawlisch, H., Belkaid, Y., Baelder, R., Hildeman, D., Gerard, C., and Kohl, J. (2005). C5a nega-tively regulates toll-like receptor 4-induced immune responses. Immunity 22, 415–426.
Heese, K., Hock, C., and Otten, U. (1998). Inflammatory signals induce neurotrophin expression in human microglial cells. J. Neurochem. 70, 699–707.
Heller, T., Hennecke, M., Baumann, U., Gessner, J.E., zu Vilsendorf, A.M., Baensch, M., Boulay, F., Kola, A., Klos, A., Bautsch, W., and Kohl, J. (1999). Selection of a C5a receptor antagonist from phage libraries attenuating the inflammatory response in immune complex disease and ischemia/reperfusion injury. J. Immunol. 163, 985–994.
Huang, J., Kim, L.J., Mealey, R., Marsh, Jr.H.C., Zhang, Y., Tenner, A.J., Connolly, E.S., Jr., and Pinsky, D.J. (1999). Neuronal protection in stroke by an sLex-glycosylated complement inhibi-tory protein. Science 285, 595–599.
170 A.J. Tenner and K. Pisalyaput
Jauneau, A.C., Ischenko, A., Chatagner, A., Benard, M., Chan, P., Schouft, M.T., Patte, C., Vaudry, H., and Fontaine, M. (2006). Interleukin 1b and anaphylatoxins exert a synergistic effect on NGF expression by astrocytes. J. Neuroinflammation. 3, 8.
Jiang, H., Burdick, D., Glabe, C.G., Cotman, C.W., and Tenner, A.J. (1994). β-amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain.
J. Immunol. 152, 5050–5059.
Johnson, S.A., Lampert-Etchells, M., Pasinetti, G.M., Rozovsky, I., and Finch, C. (1992).
Complement mRNA in the mammalian brain: Responses to Alzheimer’s disease and experi-mental brain lesioning. Neurobiol. Aging 13, 641–648.
Johnson, L.V., Leitner, W.P., Rivest, A.J., Staples, M.K., Radeke, M.J., and Anderson, D.H.
(2002). The Alzheimer’s A{beta}-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc. Natl.
Acad. Sci. U.S.A. 99, 14682–14687.
Klein, R.J., Zeiss, C., Chew, E.Y., Tsai, J.Y., Sackler, R.S., Haynes, C., Henning, A.K., Sangiovanni, J.P., Mane, S.M., Mayne, S.T., Bracken, M.B., Ferris, F.L., Ott, J., Barnstable, C., and Hoh, J. (2005). Complement factor H polymorphism in age-related macular degenera-tion. Science 308, 385–389.
Koistinaho, M., Ort, M., Cimadevilla, J.M., Vondrous, R., Cordell, B., Koistinaho, J., Bures, J., and Higgins, L.S. (2001). Specific spatial learning deficits become severe with age in beta – amyloid precursor protein transgenic mice that harbor diffuse beta – amyloid deposits but do not form plaques. Proc. Natl. Acad. Sci. U.S.A. 98, 14675–14680.
Konteatis, Z.D., Siciliano, S.J., Van, R.G., Molineaux, C.J., Pandya, S., Fischer, P., Rosen, H., Mumford, R.A., and Springer, M.S. (1994). Development of C5a receptor antagonists.
Differential loss of functional responses. J. Immunol. 153, 4200–4205.
Korb, L.C. and Ahearn, J.M. (1997). C1q binding directly and specifically to surface blebs of apoptotic human keratinocytes. J. Immunol. 158, 4525–4528.
Kulkarni, A.P., Kellaway, L.A., Lahiri, D.K., and Kotwal, G.J. (2004). Neuroprotection from complement-mediated inflammatory damage. Ann. N.Y. Acad. Sci. 1035, 147–164.
Lampert-Etchells, M., Pasinetti, G.M., Finch, C.E., and Johnson, S.A. (1993). Regional localiza-tion of cells containing complement C1q and C4 mRNAs in the frontal cortex during Alzheimer’s disease. Neurodegeneration 2, 111–121.
Lee, C.K., Weindruch, R., and Prolla, T.A. (2000). Gene-expression profile of the ageing brain in mice. Nat. Genet. 25, 294–297.
Maller, J., George, S., Purcell, S., Fagerness, J., Altshuler, D., Daly, M.J., and Seddon, J.M.
(2006). Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat. Genet. 38, 1055–1059.
Markiewski, M.M., Mastellos, D., Tudoran, R., DeAngelis, R.A., Strey, C.W., Franchini, S., Wetsel, R.A., Erdei, A., and Lambris, J.D. (2004). C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury.
J. Immunol. 173, 747–754.
Mastellos, D., Papadimitriou, J.C., Franchini, S., Tsonis, P.A., and Lambris, J.D. (2001). A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration. J. Immunol. 166, 2479–2486.
Matsuoka, Y., Picciano, M., Malester, B., LaFrancois, J., Zehr, C., Daeschner, J.M., Olschowka, J.A., Fonseca, M.I., O’Banion, M.K., Tenner, A.J., Lemere, C.A., and Duff, K. (2001).
Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease.
Am. J. Pathol. 158, 1345–1354.
Mocco, J., Sughrue, M.E., Ducruet, A.F., Komotar, R.J., Sosunov, S.A., and Connolly, E.S., Jr.
(2006). The complement system: a potential target for stroke therapy. Adv. Exp. Med. Biol.
586, 189–201.
Möller, T., Nolte, C., Burger, R., Verkhratsky, A., and Kettenmann, H. (1997). Mechanisms of C5a and C3a complement fragment-induced [Ca2+]i signaling in mouse microglia. J. Neurosci.
17, 615–624.
Central Nervous System Diseases and Inflammation 171
Morgan, B.P. and Gasque, P. (1997). Extrahepatic complement biosynthesis: where, when and why? Clin. Exp. Immunol. 107, 1–7.
Morgan, B.P., Griffiths, M., Khanom, H., Taylor, S.M., and Neal, J.W. (2004). Blockade of the C5a receptor fails to protect against experimental autoimmune encephalomyelitis in rats. Clin.
Exp. Immunol. 138, 430–438.
Mukherjee, P. and Pasinetti, G.M. (2001). Complement anaphylatoxin C5a neuroprotects through mitogen-activated protein kinase-dependent inhibition of caspase 3. J. Neurochem. 77, 43–49.
Nataf, S., Stahel, P.F., Davoust, N., and Barnum, S.R. (1999). Complement anaphylatoxin recep-tors on neurons: new tricks for old receprecep-tors? Trends Neurosci 22, 397–402.
Nataf, S., Carroll, S.L., Wetsel, R.A., Szalai, A.J., and Barnum, S.R. (2000). Attenuation of experimental autoimmune demyelination in complement- deficient mice. J. Immunol. 165, 5867–5873.
Navratil, J.S., Watkins, S.C., Wisnieski, J.J., and Ahearn, J.M. (2001). The globular heads of C1q specifically recognize surface blebs of apoptotic vascular endothelial cells. J. Immunol. 166, 3231–3239.
Niculescu, T., Weerth, S., Niculescu, F., Cudrici, C., Rus, V., Raine, C.S., Shin, M.L., and Rus, H.
(2004). Effects of complement C5 on apoptosis in experimental autoimmune encephalomyeli-tis. J. Immunol. 172, 5702–5706.
Norsworthy, P.J., Fossati-Jimack, L., Cortes-Hernandez, J., Taylor, P.R., Bygrave, A.E., Thompson, R.D., Nourshargh, S., Walport, M.J., and Botto, M. (2004). Murine CD93 (C1qRp) contributes to the removal of apoptotic cells in vivo but is not required for C1q-mediated enhancement of phagocytosis. J. Immunol. 172, 3406–3414.
O’Barr, S.A., Caguioa, J., Gruol, D., Perkins, G., Ember, J.A., Hugli, T., and Cooper, N.R. (2001).
Neuronal expression of a functional receptor for the C5a complement activation fragment.
J. Immunol. 166, 4154–4162.
Oddo, S., Caccamo, A., Shepherd, J.D., Murphy, M.P., Golde, T.E., Kayed, R., Metherate, R., Mattson, M.P., Akbari, Y., and LaFerla, F.M. (2003). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409–421.
Ogden, C.A., deCathelineau, A., Hoffmann, P.R., Bratton, D., Ghebrehiwet, B., Fadok, V.A., and Henson, P.M. (2001). C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194, 781–796.
Ohmi, K., Greenberg, D.S., Rajavel, K.S., Ryazantsev, S., Li, H.H., and Neufeld, E.F. (2003).
Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc.
Natl. Acad. Sci. U.S.A. 100, 1902–1907.
Ohno, M., Hirata, T., Enomoto, M., Araki, T., Ishimaru, H., and Takahashi, T.A. (2000). A puta-tive chemoattractant receptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells. Mol. Immunol. 37, 407–412.
Okinaga, S., Slattery, D., Humbles, A., Zsengeller, Z., Morteau, O., Kinrade, M.B., Brodbeck, R.M., Krause, J.E., Choe, H.R., Gerard, N.P., and Gerard, C. (2003). C5L2, a nonsignaling C5A binding protein. Biochemistry 42, 9406–9415.
Osaka, H., Mukherjee, P., Aisen, P.S., and Pasinetti, G.M. (1999). Complement-derived anaphyla-toxin C5a protects against glutamate- mediated neurotoxicity. J. Cell. Biochem. 73, 303–311.
Pangburn, M.K. (2000). Host recognition and target differentiation by factor H, a regulator of the alternative pathway of complement. Immunopharmacology 49, 149–157.
Pasinetti, G.M., Tocco, G., Sakhi, S., Musleh, W.D., DeSimoni, M.G., Mascarucci, P., Schreiber, S., Baudry, M., and Finch, C.E. (1996). Hereditary deficiencies in complement C5 are associ-ated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions. Neurobiol. Dis. 3, 197–204.
Popovich, P.G., Wei, P., and Stokes, B.T. (1997). Cellular inflammatory response after spinal cord injury in Sprague–Dawley and Lewis rats. J. Comp Neurol. 377, 443–464.
172 A.J. Tenner and K. Pisalyaput
Proctor, L.M., Arumugam, T.V., Shiels, I., Reid, R.C., Fairlie, D.P., and Taylor, S.M. (2004).
Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury. Br. J. Pharmacol. 142, 756–764.
Proctor, L.M., Woodruff, T.M., Sharma, P., Shiels, I.A., and Taylor, S.M. (2006). Transdermal pharmacology of small molecule cyclic C5a antagonists. Adv. Exp. Med. Biol. 586, 329–345.
Qiao, F., Atkinson, C., Song, H., Pannu, R., Singh, I., and Tomlinson, S. (2006). Complement plays an important role in spinal cord injury and represents a therapeutic target for improving recovery following trauma. Am. J. Pathol. 169, 1039–1047.
Rahpeymai, Y., Hietala, M.A., Wilhelmsson, U., Fotheringham, A., Davies, I., Nilsson, A.K., Zwirner, J., Wetsel, R.A., Gerard, C., Pekny, M., and Pekna, M. (2006). Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 25, 1364–1374.
Reboul, A., Prandini, M.H., Bensa, J.C., and Colomb, M.G. (1985). Characterization of C1q, C1s and C1 Inh synthesized by stimulated human monocytes in vitro. FEBS Lett. 190, 65–68.
Reca, R., Mastellos, D., Majka, M., Marquez, L., Ratajczak, J., Franchini, S., Glodek, A., Honczarenko, M., Spruce, L.A., Janowska-Wieczorek, A., Lambris, J.D., and Ratajczak, M.Z.
(2003). Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells, and C3a enhances their homing-related responses to SDF-1. Blood 101, 3784–3793.
Reiman, R., Gerard, C., Campbell, I.L., and Barnum, S.R. (2002). Disruption of the C5a receptor gene fails to protect against experimental allergic encephalomyelitis. Eur. J. Immunol. 32, 1157–1163.
Reiman, R., Torres, A.C., Martin, B.K., Ting, J.P., Campbell, I.L., and Barnum, S.R. (2005).
Expression of C5a in the brain does not exacerbate experimental autoimmune encephalomy-elitis. Neurosci. Lett. 390, 134–138.
Rogers, J., Cooper, N.R., Webster, S., Schultz, J., McGeer, P.L., Styren, S.D., Civin, W.H., Brachova, L., Bradt, B., Ward, P., and Lieberburg, I. (1992). Complement activation by beta-amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 89, 10016–10020.
Rostagno, A., Revesz, T., Lashley, T., Tomidokoro, Y., Magnotti, L., Braendgaard, H., Plant, G., Bojsen-Moller, M., Holton, J., Frangione, B., and Ghiso, J. (2002). Complement activation in chromosome 13 dementias. Similarities with Alzheimer’s disease. J. Biol. Chem. 277, 49782–49790.
Rostagno, A., Tomidokoro, Y., Lashley, T., Ng, D., Plant, G., Holton, J., Frangione, B., Revesz, T., and Ghiso, J. (2005). Chromosome 13 dementias. Cell Mol. Life Sci. 62, 1814–1825.
Rus, H., Cudrici, C., and Niculescu, F. (2005a). C5b-9 complement complex in autoimmune demyelination and multiple sclerosis: dual role in neuroinflammation and neuroprotection.
Ann. Med. 37, 97–104.
Rus, H., Cudrici, C., and Niculescu, F. (2005b). The role of the complement system in innate immunity. Immunol. Res. 33, 103–112.
Rus, H., Cudrici, C., David, S., and Niculescu, F. (2006). The complement system in central nerv-ous system diseases. Autoimmunity 39, 395–402.
Sahu, A. and Lambris, J.D. (2001). Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol. Rev. 180, 35–48.
Savill, J. and Fadok, V. (2000). Corpse clearance defines the meaning of cell death. Nature 407, 784–788.
Scott, R.S., McMahon, E.J., Pops, S.M., Reap, E.A., Caricchio, R., Cohen, P.L., Earp, H.S., and Matsushima, G.K. (2001). Phagocytosis and clearance of apoptotic cells is mediated by mer.
Nature 411, 207–211.
Sewell, D.L., Nacewicz, B., Liu, F., Macvilay, S., Erdei, A., Lambris, J.D., Sandor, M., and Fabry, Z. (2004). Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist. J. Neuroimmunol. 155, 55–63.
Shen, Y., Li, R., McGeer, E.G., and McGeer, P.L. (1997). Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res. 769, 391–395.
Central Nervous System Diseases and Inflammation 173
Singhrao, S.K., Neal, J.W., Morgan, B.P., and Gasque, P. (1999). Increased complement biosyn-thesis by microglia and complement activation on neurons in Huntington’s disease. Exp.
Neurol. 159, 362–376.
Song, W.C. (2004). Membrane complement regulatory proteins in autoimmune and inflammatory tissue injury. Curr. Dir. Autoimmun. 7, 181–199.
Spitzer, D., Unsinger, J., Bessler, M., and Atkinson, J.P. (2004). ScFv-mediated in vivo targeting of DAF to erythrocytes inhibits lysis by complement. Mol. Immunol. 40, 911–919.
Spitzer, D., Wu, X., Ma, X., Xu, L., Ponder, K.P., and Atkinson, J.P. (2006). Cutting edge: treat-ment of completreat-ment regulatory protein deficiency by retroviral in vivo gene therapy. J. Immunol.
177, 4953–4956.
Streit, W.J. (2004). Microglia and Alzheimer’s disease pathogenesis. J. Neurosci. Res. 77, 1–8.
Streit, W.J., Semple-Rowland, S.L., Hurley, S.D., Miller, R.C., Popovich, P.G., and Stokes, B.T.
(1998). Cytokine mRNA profiles in contused spinal cord and axotomized facial nucleus sug-gest a beneficial role for inflammation and gliosis. Exp. Neurol. 152, 74–87.
Strohmeyer, R., Shen, Y., and Rogers, J. (2000). Detection of complement alternative pathway mRNA and proteins in Alzheimer’s disease brain. Mol. Brain Res. 81, 7–18.
Stuart, L.M., Takahashi, K., Shi, L., Savill, J., and Ezekowitz, R.A. (2005). Mannose-binding lec-tin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotype.
J. Immunol. 174, 3220–3226.
Takahashi, R.H., Milner, T.A., Li, F., Nam, E.E., Edgar, M.A., Yamaguchi, H., Beal, M.F., Xu, H., Greengard, P., and Gouras, G.K. (2002). Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am. J. Pathol. 161, 1869–1879.
Tan, J., Town, T., Paris, D., Mori, T., Suo, Z., Crawford, F., Mattson, M.P., Flavell, R.A., and Mullan, M. (1999). Microglial activation resulting from CD40-CD40L interaction after β-amyloid stimulation. Science 286, 2352–2355.
Tanzi, R.E. and Bertram, L. (2005). Twenty years of the Alzheimer’s disease amyloid hypothesis:
a genetic perspective. Cell 120, 545–555.
Taylor, P.R., Carugati, A., Fadok, V.A., Cook, H.T., Andrews, M., Carroll, M.C., Savill, J.S., Henson, P.M., Botto, M., and Walport, M.J. (2000). A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366.
Tenner, A.J. and Fonseca, M.I. (2006). The double-edged flower: roles of complement protein C1q in neurodegenerative diseases. Adv. Exp. Med. Biol. 586, 153–176.
Tocco, G., Musleh, W., Sakhi, S., Schreiber, S.S., Baudry, M., and Pasinetti, G.M. (1997).
Complement and glutamate neurotoxicity. Genotypic influences of C5 in a mouse model of hippocampal neurodegeneration. Mol. Chem. Neuropathol. 31, 289–300.
Todd, R.J., Volmar, C.H., Dwivedi, S., Town, T., Crescentini, R., Crawford, F., Tan, J., and Mullan, M. (2004). Behavioral effects of CD40-CD40L pathway disruption in aged PSAPP mice.
Brain Res. 1015, 161–168.
Van Beek, J., Nicole, O., Ali, C., Ischenko, A., MacKenzie, E.T., Buisson, A., and Fontaine, M.
(2001). Complement anaphylatoxin C3a is selectively protective against NMDA-induced neu-ronal cell death. Neuroreport 12, 289–293.
Van Beek, J., Elward, K., and Gasque, P. (2003). Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann. N.Y. Acad. Sci. 992, 56–71.
Vandivier, R.W., Ogden, C.A., Fadok, V.A., Hoffmann, P.R., Brown, K.K., Botto, M., Walport, M.J., Fisher, J.H., Henson, P.M., and Greene, K.E. (2002). Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J. Immunol. 169, 3978–3986.
Vanguri, P., Koski, C.L., Silverman, B., and Shin, M.L. (1982). Complement activation by isolated myelin: activation of the classical pathway in the absence of myelin-specific antibodies. Proc.
Natl. Acad. Sci. U.S.A. 79, 3290–3294.
Walker, D.G. and McGeer, P.L. (1992). Complement gene expression in human brain: comparison between normal and Alzheimer disease cases. Brain Res. Mol. Brain Res. 14, 109–116.
Walport, M.J. (2001). Complement. Second of two parts. N. Engl. J. Med. 344, 1140–1144.