Using animal models to determine the significance of complement activation in Alzheimer's disease

Journal of Neuroinflammation

David A Loeffler¹ 

[1] Department of Neurology, William Beaumont Hospital Research Institute, Royal Oak, MI 48073, USA

关键词: transgenic mice;    complement activation;    animal models;    Alzheimer's disease;   

Others  :  1213689
DOI  :  10.1186/1742-2094-1-18

 received in 2004-08-05, accepted in 2004-10-12,  发布年份 2004

【 摘 要 】

Complement inflammation is a major inflammatory mechanism whose function is to promote the removal of microorganisms and the processing of immune complexes. Numerous studies have provided evidence for an increase in this process in areas of pathology in the Alzheimer's disease (AD) brain. Because complement activation proteins have been demonstrated in vitro to exert both neuroprotective and neurotoxic effects, the significance of this process in the development and progression of AD is unclear. Studies in animal models of AD, in which brain complement activation can be experimentally altered, should be of value for clarifying this issue. However, surprisingly little is known about complement activation in the transgenic animal models that are popular for studying this disorder. An optimal animal model for studying the significance of complement activation on Alzheimer's – related neuropathology should have complete complement activation associated with senile plaques, neurofibrillary tangles (if present), and dystrophic neurites. Other desirable features include both classical and alternative pathway activation, increased neuronal synthesis of native complement proteins, and evidence for an increase in complement activation prior to the development of extensive pathology. In order to determine the suitability of different animal models for studying the role of complement activation in AD, the extent of complement activation and its association with neuropathology in these models must be understood.

【 授权许可】

   
2004 Loeffler; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Bamberger ME, Landreth GE: Inflammation, apoptosis, and Alzheimer's disease. Neuroscientist 2002, 8:276-283.
• [2]Gupta A, Pansari K: Inflammation and Alzheimer's disease. Int J Clin Pract 2003, 57:36-39.
• [3]Hoozemans JJ, Veerhuis R, Rozemuller AJ, Eikelenboom P: The pathological cascade of Alzheimer's disease: the role of inflammation and its therapeutic implications. Drugs Today (Barc) 2002, 38:429-443.
• [4]McGeer EG, McGeer PL: Inflammatory processes in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 2003, 27:741-749.
• [5]Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T: Inflammation and Alzheimer's disease. Neurobiol Aging 2000, 21:383-421.
• [6]Combs CK, Karlo JC, Kao SC, Landreth GE: beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 2001, 21:1179-1188.
• [7]Griffin WS, Mrak RE: Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease. J Leukoc Biol 2002, 72:233-238.
• [8]Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE: Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol 1998, 8:65-72.
• [9]McGeer PL, Schulzer M, McGeer EG: Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 1996, 47:425-432.
• [10]Benveniste EN, Nguyen VT, O'Keefe GM: Immunological aspects of microglia: relevance to Alzheimer's disease. Neurochem Int 2001, 39:381-391.
• [11]Meda L, Baron P, Scarlato G: Glial activation in Alzheimer's disease: the role of Abeta and its associated proteins. Neurobiol Aging 2001, 22:885-893.
• [12]Mrak RE, Griffin WS: The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer's disease. Neurobiol Aging 2001, 22:915-922.
• [13]Emmerling MR, Watson MD, Raby CA, Spiegel K: The role of complement in Alzheimer's disease pathology. Biochim Biophys Acta 2000, 1502:158-171.
• [14]McGeer PL, McGeer EG: The possible role of complement activation in Alzheimer disease. Trends Mol Med 2002, 8:519-523.
• [15]Tenner AJ: Complement in Alzheimer's disease: opportunities for modulating protective and pathogenic events. Neurobiol Aging 2001, 22:849-861.
• [16]Abraham CR: Reactive astrocytes and alpha1-antichymotrypsin in Alzheimer's disease. Neurobiol Aging 2001, 22:931-936.
• [17]Kovacs DM: alpha2-macroglobulin in late-onset Alzheimer's disease. Exp Gerontol 2000, 35:473-479.
• [18]Loeffler DA, Sima AA, LeWitt PA: Ceruloplasmin immunoreactivity in neurodegenerative disorders. Free Radic Res 2001, 35:111-118.
• [19]Wood JA, Wood PL, Ryan R, Graff-Radford NR, Pilapil C, Robitaille Y, Quirion R: Cytokine indices in Alzheimer's temporal cortex: no changes in mature IL-1 beta or IL-1RA but increases in the associated acute phase proteins IL-6, alpha 2-macroglobulin and C-reactive protein. Brain Res 1993, 629:245-252.
• [20]McGeer PL, Rogers J: Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology 1992, 42:447-449.
• [21]Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, Zalinski J, Cofield M, Mansukhani L, Willson P, Kogan F: Clinical trial of indomethacin in Alzheimer's disease. Neurology 1993, 43:1609-1611.
• [22]Aisen PS, Davis KL, Berg JD, Schafer K, Campbell K, Thomas RG, Weiner MF, Farlow MR, Sano M, Grundman M, Thal LJ: A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study. Neurology 2000, 54:588-593.
• [23]Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ: Alzheimer's Disease Cooperative Study. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003, 289:2819-2826.
• [24]Sainetti SM, Ingram DM, Talwalker S, Geis GS: Results of a double-blind, randomized, placebo-controlled study of celecoxib in the treatment of progression of Alzheimer's disease [abstract]. Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy 2000, 180.
• [25]Van Gool WA, Weinstein HC, Scheltens P, Walstra GJ, Scheltens PK: Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study. Lancet 2001, 358:455-460.
• [26]Shen Y, Meri S: Yin and Yang: complement activation and regulation in Alzheimer's disease. Prog Neurobiol 2003, 70:463-472.
• [27]Wyss-Coray T, Mucke L: Inflammation in neurodegenerative disease–a double-edged sword. Neuron 2002, 35:419-432.
• [28]Neumann H: The immunological microenvironment in the CNS: implications on neuronal cell death and survival. J Neural Transm Suppl 2000, 59:59-68.
• [29]Polazzi E, Contestabile A: Reciprocal interactions between microglia and neurons: from survival to neuropathology. Rev Neurosci 2002, 13:221-242.
• [30]van Beek J, Elward K, Gasque P: Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann N Y Acad Sci 2003, 992:56-71.
• [31]Barnum SR: Complement biosynthesis in the central nervous system. Crit Rev Oral Biol Med 1995, 6:132-146.
• [32]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 1989, 56:259-262.
• [33]Eikelenboom P, Stam FC: Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol (Berl) 1982, 57:239-42.
• [34]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 1984, 47:17-25.
• [35]Ishii T, Haga S: Immuno-electron-microscopic localization of complements in amyloid fibrils of senile plaques. Acta Neuropathol (Berl) 1984, 63:296-300.
• [36]Veerhuis R, Janssen I, Hack CE, Eikelenboom P: Early complement components in Alzheimer's disease brains. Acta Neuropathol (Berl) 1996, 91:53-60.
• [37]Veerhuis R, van der Valk P, 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 1995, 426:603-610.
• [38]Itagaki S, Akiyama H, Saito H, McGeer PL: Ultrastructural localization of complement membrane attack complex (MAC)-like immunoreactivity in brains of patients with Alzheimer's disease. Brain Res 1994, 645:78-84.
• [39]Lue LF, Brachova L, Civin WH, Rogers J: Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration. J Neuropathol Exp Neurol 1996, 55:1083-1088.
• [40]McGeer PL, Akiyama H, Itagaki S, McGeer EG: Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett 1989, 107:341-346.
• [41]McGeer PL, Walker DG, Akiyama H, Kawamata T, Guan AL, Parker CJ, Okada N, McGeer EG: Detection of the membrane inhibitor of reactive lysis (CD59) in diseased neurons of Alzheimer brain. Brain Res 1991, 544:315-319.
• [42]Webster S, Lue L-F, Brachova L, Tenner AJ, McGeer PL, Terai K, Walker DG, Bradt B, Cooper NR, Rogers J: Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer's disease. Neurobiol Aging 1997, 18:415-421.
• [43]Webster S, Glabe C, Rogers J: Multivalent binding of complement protein C1q to the amyloid beta-peptide (A beta) promotes the nucleation phase of A beta aggregation. Biochem Biophys Res Commun 1995, 217:869-875.
• [44]Webster S, O'Barr S, Rogers J: Enhanced aggregation and beta structure of amyloid beta peptide after coincubation with C1q. J Neurosci Res 1994, 39:448-456.
• [45]Schultz J, Schaller J, McKinley M, Bradt B, Cooper N, May P, Rogers J: Enhanced cytotoxicity of amyloid beta-peptide by a complement dependent mechanism. Neurosci Lett 1994, 175:99-102.
• [46]Nolte C, Moller T, Walter T, Kettenmann H: Complement 5a controls motility of murine microglial cells in vitro via activation of an inhibitory G-protein and the rearrangement of the actin cytoskeleton. Neuroscience 1996, 73:1091-1107.
• [47]Yao J, Harvath L, Gilert DL, Colton CA: Chemotaxis by a CNS macrophage, the microglia. J Neurosci Res 1990, 27:36-42.
• [48]O'Barr S, Cooper NR: The C5a complement activation peptide increases IL-1beta and IL-6 release from amyloid-beta primed human monocytes: implications for Alzheimer's disease. J Neuroimmunol 2000, 109:87-94.
• [49]Veerhuis R, Van Breemen MJ, Hoozemans JM, Morbin M, Ouladhadj J, Tagliavini F, Eikelenboom P: Amyloid beta plaque-associated proteins C1q and SAP enhance the Abeta1–42 peptide-induced cytokine secretion by adult human microglia in vitro. Acta Neuropathol (Berl) 2003, 105:135-144.
• [50]Shen Y, Halperin JA, Lee CM: Complement-mediated neurotoxicity is regulated by homologous restriction. Brain Res 1995, 671:282-292.
• [51]Osaka H, Mukherjee P, Aisen PS, Pasinetti GM: Complement-derived anaphylatoxin C5a protects against glutamate-mediated neurotoxicity. J Cell Biochem 1999, 73:303-311.
• [52]van Beek J, Nicole O, Ali C, Ischenko A, MacKenzie ET, Buisson A, Fontaine M: Complement anaphylatoxin C3a is selectively protective against NMDA-induced neuronal cell death. Neuroreport 2001, 12:289-293.
• [53]O'Barr SA, Caguioa J, Gruol D, Perkins G, Ember JA, Hugli T, Cooper NR: Neuronal expression of a functional receptor for the C5a complement activation fragment. J Immunol 2001, 166:4154-4162.
• [54]Mukherjee P, Pasinetti GM: Complement anaphylatoxin C5a neuroprotects through mitogen-activated protein kinase-dependent inhibition of caspase 3. J Neurochem 2001, 77:43-49.
• [55]Soane L, Cho HJ, Niculescu F, Rus H, Shin ML: C5b-9 terminal complement complex protects oligodendrocytes from death by regulating Bad through phosphatidylinositol 3-kinase/Akt pathway. J Immunol 2001, 167:2305-2311.
• [56]Frautschy SA, Hammer H, Hu S, Hu W, Oh M, Miller SA, Lim GP, Harris-White ME, Tenner AJ: C1q stimulates Abeta clearance but worsens memory in Alzheimer model: too much C1q may be worse than too little. In Program No. 667.12. Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience; 2003.
• [57]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 2000, 161:127-138.
• [58]Sahu A, Lambris JD: Complement inhibitors: a resurgent concept in anti-inflammatory therapeutics. Immunopharmacol 2000, 49:133-148.
• [59]Morgan BP, Harris CL: Complement therapeutics; history and current progress. Mol Immunol 2003, 40:159-170.
• [60]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 2003, 23:232-239.
• [61]Kirschfink M: C1-inhibitor and transplantation. Immunobiology 2002, 205:534-541.
• [62]Quigg RJ: Role of complement and complement regulatory proteins in glomerulonephritis. Springer Semin Immunopathol 2003, 24:395-410.
• [63]de Zwaan C, van Dieijen-Visser MP, Hermens WT: Prevention of cardiac cell injury during acute myocardial infarction: possible role for complement inhibition. Am J Cardiovasc Drugs 2003, 3:245-251.
• [64]Farkas H, Harmat G, Fust G, Varga L, Visy B: Clinical management of hereditary angio-oedema in children. Pediatr Allergy Immunol 2002, 13:153-161.
• [65]Rozemuller AJ, Eikelenboom P, Theeuwes JW, Jansen Steur EN, de Vos RA: Activated microglial cells and complement factors are unrelated to cortical Lewy bodies. Acta Neuropathol (Berl) 2000, 100:701-708.
• [66]Stoltzner SE, Grenfell TJ, Mori C, Wisniewski KE, Wisniewski TM, Selkoe DJ, Lemere CA: Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease. Am J Pathol 2000, 156:489-499.
• [67]Rostagno A, Revesz T, Lashley T, Tomidokoro Y, Magnotti L, Braendgaard H, Plant G, Bojsen-Moller M, Holton J, Frangione B, Ghiso J: Complement activation in chromosome 13 dementias. Similarities with Alzheimer's disease. J Biol Chem 2002, 277:49782-49790.
• [68]Bradt BM, Kolb WP, Cooper NR: Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide. J Exp Med 1998, 188:431-438.
• [69]Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, Civin WH, Brachova L, Bradt B, Ward P, Lieberburg I: Complement activation by β-amyloid in Alzheimer disease. Proc Natl Acad Sci USA 1992, 89:10016-10020.
• [70]Shen Y, Lue L, Yang L, Roher A, Kuo Y, Strohmeyer R, Goux WJ, Lee V, Johnson GV, Webster SD, Cooper NR, Bradt B, Rogers J: Complement activation by neurofibrillary tangles in Alzheimer's disease. Neurosci Lett 2001, 305:165-168.
• [71]Webster S, Bradt B, Rogers J, Cooper N: Aggregation state-dependent activation of the classical complement pathway by the amyloid beta peptide. J Neurochem 1997, 69:388-398.
• [72]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 C1q-independent manner. Clin Exp Immunol 1999, 115:526-533.
• [73]Akiyama H, Mori H, Saido T, Kondo H, Ikeda K, McGeer PL: Occurrence of the diffuse amyloid beta-protein (Abeta) deposits with numerous Abeta-containing glial cells in the cerebral cortex of patients with Alzheimer's disease. Glia 1999, 25:324-331.
• [74]Rozemuller JM, van der Valk P, Eikelenboom P: Activated microglia and cerebral amyloid deposits in Alzheimer's disease. Res Immunol 1992, 143:646-649.
• [75]Lue LH, Rogers J: Full complement activation fails in diffuse plaques of the Alzheimer's disease cerebellum. Dementia 1992, 3:308-313.
• [76]Fonseca MI, Kawas CH, Troncoso JC, Tenner AJ: Neuronal localization of C1q in preclinical Alzheimer's disease. Neurobiol Dis 2004, 15:40-46.
• [77]Loeffler DA, Camp DM, Schonberger M, Singer DJ, LeWitt PA: ELISA measurement of C4d and iC3b in Alzheimer's disease and normal brain specimens. Neurobiol Aging 2004, 25:1001-1007.
• [78]Shen Y, Li R, McGeer EG, McGeer PL: Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Res 1997, 769:391-395.
• [79]Walker DG, McGeer PL: Complement gene expression in human brain: comparison between normal and Alzheimer disease cases. Brain Res Mol Brain Res 1992, 14:109-116.
• [80]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 1999, 154:927-936.
• [81]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 1995, 675:75-82.
• [82]Yasojima K, McGeer EG, McGeer PL: Complement regulators C1 inhibitor and CD59 do not significantly inhibit complement activation in Alzheimer disease. Brain Res 1999, 833:297-301.
• [83]Yang L-B, Li R, Meri S, Rogers J, Shen Y: Deficiency of complement defense protein CD59 may contribute to neurodegeneration in Alzheimer's disease. J Neurosci 2000, 20:7505-7509.
• [84]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 2002, 131:135-146.
• [85]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 2000, 81:7-18.
• [86]Janus C, Phinney AL, Chishti MA, Westaway D: New developments in animal models of Alzheimer's disease. Curr Neurol Neurosci Rep 2001, 1:451-457.
• [87]Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L: TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 2001, 7:612-618.
• [88]Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, Masliah E: Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci USA 2002, 99:10837-10842.
• [89]Lindorfer MA, Hahn CS, Foley PL, Taylor RP: Heteropolymer-mediated clearance of immune complexes via erythrocyte CR1: mechanisms and applications. Immunol Rev 2001, 183:10-24.
• [90]Molina H, Wong W, Kinoshita T, Brenner C, Foley S, Holers VM: Distinct receptor and regulatory properties of recombinant mouse complement receptor 1 (CR1) and Crry, the two genetic homologues of human CR1. J Exp Med 1992, 175:121-129.
• [91]Yu JX, Bradt BM, Hsiao K, Carrol MC, Cooper NR: Amyloid plaques in a transgenic mouse model of Alzheimer's disease contain complement components and pro-inflammatory cytokines. In Program No. 491.1. 2000 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience; 2000. Online
• [92]McGeer PL, Schwab C, Staufenbiel M, Hosokawa M, McGeer EG: Amyloid transgenic mice: an incomplete model of Alzheimer disease. In Program No. 295.2. 2002 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience; 2002. Online
• [93]Ebanks RO, Isenman DE: Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity. Mol Immunol 1996, 33:297-309.
• [94]Ong GL, Mattes MJ: Mouse strains with typical mammalian levels of complement activity. J Immunol Methods 1989, 125:147-158.
• [95]Webster SD, Tenner AJ, Poulos TL, Cribbs DH: The mouse C1q A-chain sequence alters beta-amyloid-induced complement activation. Neurobiol Aging 1999, 20:297-304.
• [96]Cruts M, Van Broeckhoven C: Presenilin mutations in Alzheimer's disease. Hum Mutat 1998, 11:183-190.
• [97]Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O'Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, Duff K: Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998, 4:97-100.
• [98]Matsuoka Y, Picciano M, Malester B, LaFrancois J, Zehr C, Daeschner JM, Olschowka JA, Fonseca MI, O'Banion MK, Tenner AJ, Lemere CA, Duff K: Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease. Am J Pathol 2001, 158:1345-1354.
• [99]Fonseca MI, Zhou J, Botto M, Tenner AJ: Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci 2004, 24:6457-6465.
• [100]Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G: Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996, 274:99-102.
• [101]Botto M, Dell'Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, Loos M, Pandolfi PP, Walport MJ: Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 1998, 19:56-59.
• [102]Coimbra C, Drake M, Boris-Moller F, Wieloch T: Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia. Stroke 1996, 27:1578-1585.
• [103]Sinigaglia-Coimbra R, Cavalheiro EA, Coimbra CG: Postischemic hyperthermia induces Alzheimer-like pathology in the rat brain. Acta Neuropathol (Berl) 2002, 103:444-452.
• [104]Lee JH, Kim SR, Bae CS, Kim D, Hong H, Nah S: Protective effect of ginsenosides, active ingredients of Panax ginseng, on kainic acid-induced neurotoxicity in rat hippocampus. Neurosci Lett 2002, 325:129-133.
• [105]Hyman BT, Van Horsen GW, Damasio AR, Barnes CL: Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 1984, 225:1168-1170.
• [106]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 1992, 13:641-648.
• [107]Johnson S, Young-Chan CS, Laping NJ, Finch CE: Perforant path transection induces complement C9 deposition in hippocampus. Exp Neurol 1996, 138:198-205.
• [108]Pasinetti GM, Johnson SA, Rozovsky I, Lampert-Etchells M, Morgan DG, Gordon MN, Morgan TE, Willoughby D, Finch CE: Complement C1qB and C4 mRNAs responses to lesioning in rat brain. Exp Neurol 1992, 118:117-125.
• [109]Rozovsky I, Morgan TE, Willoughby DA, Dugichi-Djordjevich MM, Pasinetti GM, Johnson SA, Finch CE: Selective expression of clusterin (SGP-2) and complement C1qB and C4 during responses to neurotoxins in vivo and in vitro. Neuroscience 1994, 62:741-758.
• [110]Sahu A, Rawal N, Pangburn MK: Inhibition of complement by covalent attachment of rosmarinic acid to activated C3b. Biochem Pharmacol 1999, 57:1439-1446.
• [111]Osakabe N, Yasuda A, Natsume M, Yoshikawa T: Rosmarinic acid inhibits epidermal inflammatory responses: anticarcinogenic effect of Perilla frutescens extract in the murine two-stage skin model. Carcinogenesis 2004, 25:549-557.
• [112]Youn J, Lee KH, Won J, Huh SJ, Yun HS, Cho WG, Paik DJ: Beneficial effects of rosmarinic acid on suppression of collagen induced arthritis. J Rheumatol 2003, 30:1203-1207.
• [113]Parejo I, Viladomat F, Bastida J, Schmeda-Hirschmann G, Burillo J, Codina C: Bioguided isolation and identification of the nonvolatile antioxidant compounds from fennel (Foeniculum vulgare Mill.) waste. J Agric Food Chem 2004, 52:1890-1897.
• [114]Ono K, Hasegawa K, Naiki H, Yamada M: Curcumin has potent anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro. J Neurosci Res 2004, 75:742-750.
• [115]Spillantini MG, Goedert M: Tau protein pathology in neurodegenerative diseases. Trends Neurosci 1998, 21:428-433.
• [116]Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E: Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001, 293:1487-1491.
• [117]Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM: Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003, 39:409-421.
• [118]Ruberti F, Capsoni S, Comparini A, Di Daniel E, Franzot J, Gonfloni S, Rossi G, Berardi N, Cattaneo A: Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen, and skeletal muscle dystrophy. J Neurosci 2000, 20:2589-2601.
• [119]Lauterborn JC, Isackson PJ, Gall CM: Nerve growth factor mRNA-containing cells are distributed within regions of cholinergic neurons in the rat basal forebrain. J Comp Neurol 1991, 306:439-446.
• [120]Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A: Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci USA 2000, 97:6826-6831.
• [121]Gearing M, Levey AI, Mirra SS: Diffuse plaques in the striatum in Alzheimer disease (AD): relationship to the striatal mosaic and selected neuropeptide markers. J Neuropathol Exp Neurol 1997, 56:1363-1370.
• [122]Braun J, Laitko S, Treharne J, Eggens U, Wu P, Distler A, Sieper J: Chlamydia pneumoniae –a new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis 1994, 53:100-105.
• [123]Sriram S, Stratton CW, Yao S, Tharp A, Ding L, Bannan JD, Mitchell WM: Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann Neurol 1999, 46:6-14.
• [124]Campbell LA, Kuo CC: Chlamydia pneumoniae –an infectious risk factor for atherosclerosis? Nat Rev Microbiol 2004, 2:23-32.
• [125]Balin BJ, Gerard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, Whittum-Hudson JA, Hudson AP: Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Med Microbiol Immunol (Berl) 1998, 187:23-42.
• [126]Mahony JB, Woulfe J, Munoz D, Browning D, Chong S, Smieja M: Identification of Chlamydiae pneumoniae in the Alzheimer's brain. World Alzheimer Congress 2000, 7:1120.
• [127]Ossewaarde JM, Gielis-Proper SK, Meijer A, Roholl PJM: Chlamydia pneumoniae antigens are present in the brains of Alzheimer patients, but not in the brains of patients with other dementias. In In Proceedings of the 4th Meeting of European Society for Chlamydia Research: 20–23 August 2000; Helsinki, Finland Edited by Saikku P. 284.
• [128]Gieffers J, Reusche E, Solbach W, Maass M: Failure to detect Chlamydia pneumoniae in brain sections of Alzheimer's disease patients. J Clin Microbiol 2000, 38:881-882.
• [129]Nochlin D, Shaw CM, Campbell LA, Kuo CC: Failure to detect Chlamydia pneumoniae in brain tissues of Alzheimer's disease. Neurology 1999, 53:1888.
• [130]Ring RH, Lyons JM: Failure to detect Chlamydia pneumoniae in the late-onset Alzheimer's brain. J Clin Microbiol 2000, 38:2591-2594.
• [131]Wozniak MA, Cookson A, Wilcock GK, Itzhaki RF: Absence of Chlamydia pneumoniae in brain of vascular dementia patients. Neurobiol Aging 2003, 24:761-765.
• [132]Little CS, Hammond CJ, MacIntyre A, Balin BJ, Appelt DM: Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiol Aging 2004, 25:419-429.
• [133]Jawetz E, Melnick JL, Adelberg EA: Review of Medical Microbiology. Los Altos: Lange Medical Publications; 1972:272.
• [134]Hall RT, Strugnell T, Wu X, Devine DV, Stiver HG: Characterization of kinetics and target proteins for binding of human complement component C3 to the surface-exposed outer membrane of Chlamydia trachomatis serovar L2. Infect Immun 1993, 61:1829-1834.
• [135]Megran DW, Stiver HG, Bowie WR: Complement activation and stimulation of chemotaxis by Chlamydia trachomatis. Infect Immun 1985, 49:670-673.
• [136]Satou T, Cummings BJ, Head E, Nielson KA, Hahn FF, Milgram NW, Velazquez P, Cribbs DH, Tenner AJ, Cotman CW: The progression of beta-amyloid deposition in the frontal cortex of the aged canine. Brain Res 1997, 774:35-43.
• [137]Head E, McCleary R, Hahn FF, Milgram NW, Cotman CW: Region-specific age at onset of beta-amyloid in dogs. Neurobiol Aging 2000, 21:89-96.
• [138]Cummings BJ, Satou T, Head E, Milgram NW, Cole GM, Savage MJ, Podlisny MB, Selkoe DJ, Siman R, Greenberg BD, Cotman CW: Diffuse plaques contain C-terminal A beta 42 and not A beta 40: evidence from cats and dogs. Neurobiol Aging 1996, 17:653-659.
• [139]Cummings BJ, Su JH, Cotman CW, White R, Russell MJ: Beta-amyloid accumulation in aged canine brain: a model of early plaque formation in Alzheimer's disease. Neurobiol Aging 1993, 14:547-560.
• [140]Cummings BJ, Head E, Afagh AJ, Milgram NW, Cotman CW: Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine. Neurobiol Learn Mem 1996, 66:11-23.
• [141]Cummings BJ, Head E, Ruehl W, Milgram NW, Cotman CW: The canine as an animal model of human aging and dementia. Neurobiol Aging 1996, 17:259-28.
• [142]Kimura N, Tanemura K, Nakamura S, Takashima A, Ono F, Sakakibara I, Ishii Y, Kyuwa S, Yoshikawa Y: Age-related changes of Alzheimer's disease-associated proteins in cynomolgus monkey brains. Biochem Biophys Res Commun 2003, 310:303-311.
• [143]Sloane JA, Pietropaolo MF, Rosene DL, Moss MB, Peters A, Kemper T, Abraham CR: Lack of correlation between plaque burden and cognition in the aged monkey. Acta Neuropathol (Berl) 1997, 94:471-478.
• [144]Gearing M, Rebeck GW, Hyman BT, Tigges J, Mirra SS: Neuropathology and apolipoprotein E profile of aged chimpanzees: implications for Alzheimer disease. Proc Natl Acad Sci USA 1994, 91:9382-9386.
• [145]Geula C, Nagykery N, Wu CK: Amyloid-beta deposits in the cerebral cortex of the aged common marmoset (Callithrix jacchus): incidence and chemical composition. Acta Neuropathol (Berl) 2002, 103:48-58.
• [146]Gearing M, Tigges J, Mori H, Mirra SS: A beta40 is a major form of beta-amyloid in nonhuman primates. Neurobiol Aging 1996, 17:903-908.
• [147]Schultz C, Hubbard GB, Rub U, Braak E, Braak H: Age-related progression of tau pathology in brains of baboons. Neurobiol Aging 2000, 21:905-912.
• [148]Schultz C, Hubbard GB, Tredici KD, Braak E, Braak H: Tau pathology in neurons and glial cells of aged baboons. Adv Exp Med Biol 2001, 487:59-69.
• [149]Bons N, Jallageas V, Silhol S, Mestre-Frances N, Petter A, Delacourte A: Immunocytochemical characterization of Tau proteins during cerebral aging of the lemurian primate Microcebus murinus. C R Acad Sci III 1995, 318:77-83.
• [150]Bons N, Mestre N, Petter A: Senile plaques and neurofibrillary changes in the brain of an aged lemurian primate, Microcebus murinus. Neurobiol Aging 1992, 13:99-105.
• [151]Giannakopoulos P, Silhol S, Jallageas V, Mallet J, Bons N, Bouras C, Delaere P: Quantitative analysis of tau protein-immunoreactive accumulations and beta amyloid protein deposits in the cerebral cortex of the mouse lemur, Microcebus murinus. Acta Neuropathol (Berl) 1997, 94:131-139.
• [152]Sparks DL, Schreurs BG: Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci USA 2003, 100:11065-11069.
• [153]Roertgen KE, Parisi JE, Clark HB, Barnes DL, O'Brien TD, Johnson KH: Abeta-associated cerebral angiopathy and senile plaques with neurofibrillary tangles and cerebral hemorrhage in an aged wolverine (Gulo gulo). Neurobiol Aging 1996, 17:243-247.
• [154]Tekirian TL, Saido TC, Markesbery WR, Russell MJ, Wekstein DR, Patel E, Geddes JW: N-terminal heterogeneity of parenchymal and cerebrovascular Abeta deposits. J Neuropathol Exp Neurol 1998, 57:76-94.
• [155]Bokisch VA, Muller-Eberhard HJ, Cochrane CG: Isolation of a fragment (C3a) of the third component of human complement containing anaphylatoxin and chemotactic activity and description of an anaphylatoxin inactivator of human serum. J Exp Med 1969, 129:1109-1130.
• [156]Gorski JP, Hugli TE, Muller-Eberhard HJ: C4a: the third anaphylatoxin of the human complement system. Proc Natl Acad Sci U S A 1979, 76:5299-5302.
• [157]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 2000, 49:171-186.