Hostname: page-component-cd9895bd7-gvvz8 Total loading time: 0 Render date: 2024-12-27T12:12:47.138Z Has data issue: false hasContentIssue false
  • English
  • Français

The older brain, inflammation, vaccination and the prevention of dementia

Part of: Bespoke shallow archive Weizmann

Published online by Cambridge University Press:  13 July 2010

JW Neal
JW Neal*
Affiliation:
Department of Histopathology, University Hospital of Wales and Cardiff University Medical School, Cardiff, UK
*
Address for correspondence: Dr JW Neal, Department of Histopathology, University Hospital of Wales and Cardiff University Medical School, Heath Park, Cardiff CF14 4XN. Email: jwneal@doctors.org.uk
Get access Rights & Permissions [Opens in a new window]

Summary

An important protective function of the brain's innate immune system is to detect the presence of proteins such as amyloid and to remove them before they become neurotoxic, as is thought to occur in Alzheimer's disease (AD). Ageing affects the immune system response to infection and can influence the systemic response to vaccination and other potential immunotherapeutic agents. The generation of systemic antibodies is a vital component of the immune response, facilitating the identification and clearance of pathogens from the central nervous system (CNS). Experimental evidence using transgenic animal models of AD has shown successful clearance of amyloid from the CNS following vaccination with an amyloid peptide, and consequently a trial of amyloid beta peptide (Aβ) vaccination was undertaken in older people with AD. This produced some unexpected results, as not only was there evidence for amyloid plaque removal, but also a small number of cases developed encephalitis. A detailed review of the response to vaccination and the neuropathology findings are discussed, showing that the findings are understandable given the effects of ageing upon the innate immune system in the brain. Finally, the therapeutic potential of manipulating the regulatory components of the ageing innate immune system in order to inhibit brain inflammation and reduce cognitive decline is outlined.

Keywords

ageing brainAlzheimer's diseasedementiainnate immunitygliaamyloidvaccination
Type
Neuropsychiatry of old age
Information
Reviews in Clinical Gerontology , Volume 20 , Issue 4 , November 2010 , pp. 288 - 308
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Lowenstein, PR. Immunology of viral-vector-mediated gene transfer into the brain: an evolutionary and developmental perspective. Trends Immunol 2002; 23: 23–30.CrossRefGoogle Scholar
2Hauwel, M, Furon, E, Canova, C, Griffiths, M, Neal, J, Gasque, P. Innate (inherent) control of brain infection, brain inflammation and brain repair; the role of microglia, astrocytes, ‘protective’ glial stem cells and stromal ependymal cell. Brain Res Rev 2005; 48: 220–33.Google Scholar
3Nguyen, MD, Julien, JP, Rivest, S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 2002; 3: 216–27.CrossRefGoogle ScholarPubMed
4Elward, K, Gasque, P. ‘Eat me’ and ‘don't eat me’ signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system. Mol Immunol 2003; 40: 85–94.Google Scholar
5Husemann, J, Loike, JD, Anankov, R, Febbraio, M, Silverstein, SC. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 2002; 40: 195–205.CrossRefGoogle ScholarPubMed
6Gregory, CD. CD14-dependent clearance of apoptotic cells; relevance to the immune system. Curr Opin Immunol 2000; 12: 27–34.Google Scholar
7Coraci, IS, Husemann, J, Berman, JW, Hulette, C, Dufour, JH, Campanella, GK, Luster, AD, Silverstein, SC, El-Khoury, JB. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 2002; 160: 101–112.CrossRefGoogle Scholar
8El Khoury, JB, Moore, KJ, Means, TK, Leung, J, Terada, K, Toft, M, Freeman, MW, Luster, AD. CD36 mediates the innate host response to beta-amyloid. J Exp Med 2003; 197: 1657–66.CrossRefGoogle ScholarPubMed
9Fassbender, K, Walter, S, Kühl, S, Landmann, R, Ishii, K, Bertsch, T, Stalder, AK, Muehlhauser, F, Liu, Y, Ulmer, AJ, Rivest, S, Lentschat, A, Gulbins, E, Jucker, M, Staufenbiel, M, Brechtel, K, Walter, J, Multhaup, G, Penke, B, Adachi, Y, Hartmann, T, Beyreuther, K. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J 2004; 18: 203–5.CrossRefGoogle ScholarPubMed
10Alarcon, R, Fuenzalida, C, Santibanez, M, von Bernhard, R. Expression of scavenger receptors in glial cells. Comparing the adhesion of astrocytes and microglia from neonatal rats to surface-bound beta-amyloid. J Biol Chem 2005; 280: 30406–15.Google ScholarPubMed
11Griffiths, 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 2009; 68: 217–26.Google Scholar
12Mims, C, Nash, A, Stephen, J. Mims’ Pathogenesis of Infectious Disease, 5th edn.San Diego: Academic Press, 2001.Google Scholar
13Gasque, P, Fontaine, M, Morgan, BP. Complement expression in human brain. Biosynthesis of terminal pathway components and regulators in human glial cells and cell lines. J Immunol 1995; 154: 4726–33.CrossRefGoogle ScholarPubMed
14Gasque, P, Neal, JW, Singhrao, SK, McGreal, EP, Dean, YD, Van, BJ, Morgan, BP. Roles of the complement system in human neurodegenerative disorders: pre-inflammatory and tissue remodelling activities. Mol Neurobiol 2002; 25: 1–17.CrossRefGoogle Scholar
15Griffiths, M, Neal, JW, Gasque, P. Innate immunity and protective neuroinflammation: new emphasis on the role of neuroimmune regulatory proteins. Int Rev Neurobiol 2007; 82: 29–55.Google Scholar
16Morgan, BP, Meri, S. Membrane proteins that protect against complement lysis. Springer Semin Immunopathol 1994; 15: 369–96.CrossRefGoogle ScholarPubMed
17Wyss-Coray, T, Loike, JD, Brionne, TC, Lu, E, Anankov, R, Yan, F, Silverstein, SC, Husemann, J. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 2003; 9: 453–57.CrossRefGoogle ScholarPubMed
18Ishizuka, K, Kimura, T, Igata-yi, R, Katsuragi, S, Takamatsu, J, Miyakawa, T. Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer's disease. Psychiatry Clin Neurosci 1997; 51: 135–38.CrossRefGoogle ScholarPubMed
19Bruni, JE. Ependymal development, proliferation, and functions: a review. Microsc Res Tech 1998; 41: 2–13.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
20Canova, C, Neal, JW, Gasque, P. Expression of innate immune complement regulators on brain epithelial cells during human bacterial meningitis. J Neuroinflammation 2006; 3: 22.Google Scholar
21Webster, 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: 127–38.CrossRefGoogle ScholarPubMed
22Ross, GD. Role of the lectin domain of Mac-1/CR3(CD11b/CD18) in regulating intercellular adhesion. Immunol Res 2002; 25: 219–27.Google Scholar
23Reichert, F, Rotshenker, S. Complement-receptor-3 and scavenger-receptor-AI/II mediated myelin phagocytosis in microglia and macrophages. Neurobiol Dis 2003; 12: 65–72.CrossRefGoogle ScholarPubMed
24Bamberger, ME, Harris, ME, McDonald, DR, Husemann, J, Landreth, GE. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 2003; 23: 2665–74.CrossRefGoogle ScholarPubMed
25Liu, Y, Walter, S, Stagi, M, Cherny, D, Letiembre, M, Schulz-Schaeffer, W, Heine, H, Penke, B, Neumann, H, Fassbender, K. LPS receptor (CD14): a receptor for phagocytises of Alzheimer's amyloid peptide. Brain 2005; 128: 1778–89.Google Scholar
26Song, X, Tanaka, S, Cox, D, Lee, SC. FC gamma receptor signalling in primary human microglia; differential roles of PI-3K and Ras/ERK MAPK pathway in phagocytosis and chemokine induction. J Leukoc Biol 2004; 75: 1147–55.Google Scholar
27Komine-Kobayashi, M, Chou, N, Mochizuki, H, Nakao, A, Mizuno, Y, Urabe, T. Dual role of Fc gamma receptor in transient focal cerebral ischaemia in mice. Stroke 2004; 35: 958–63.Google Scholar
28Santambrogio, L, Belyanskaya, SL, Fischer, FR, Cipriani, B, Brosnan, CF, Ricciardi-Castagnoli, P, Stern, LJ, Strominger, JL, Riese, R. Developmental plasticity of CNS microglia. Proc Natl Acad Sci USA 2001; 98: 6295–300.Google Scholar
29Monsonego, A, Weiner, HL. Immunotherapeutic approaches to Alzheimer's disease. Science 2003; 302: 834–38.CrossRefGoogle ScholarPubMed
30Weiner, HLFrenkel, D. Immunology and immunotherapy of Alzheimer's disease. Nat Rev Immunol 2006; 6: 404–16.CrossRefGoogle ScholarPubMed
31Korb, LC, Ahearn, JM. C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol 1997; 158: 4525–28.Google Scholar
32Nicholson-Weller, A, Klickstein, LB. C1q binding proteins and C1q receptors. Curr Opin Immunol 1999; 11: 42–46.CrossRefGoogle ScholarPubMed
33Singhrao, SK, Neal, JW, Rushmere, NK, Morgan, BP, Gasque, P. Differential expression of individual complement regulators in the brain and choroid plexus. Lab Invest 1999; 79: 1247–59.Google ScholarPubMed
34Abbas, AK, Lichtman, AH, Pillai, S. Cellular and Molecular Immunology, 6th edition.London, WB Saunders, 2007.Google Scholar
35Giunta, B, Fernandez, F, Nikolic, WV, Obregon, D, Rrapo, E, Town, T, Tan, J. Inflammaging as a prodrome to Alzheimer's disease. J Neuroinflammation 2008; 5: 51.CrossRefGoogle ScholarPubMed
36Almanzar, G, Schwaiger, S, Jenewein, B, Keller, M, Herndler-Brandstetter, D, Würzner, R, Schönitzer, D, Grubeck-Loebenstein, B. Long term cytomegalovirus infection leads to significant changes in the composition of the CD8+T-cell repertoire which may be the basis for an imbalance in the cytokine production profile in elderly person. J Virol 2005; 79: 3675–83.Google Scholar
37Yang, X, Stedra, J, Cerny, J. Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centres of aged mice. J Exp Med 1996; 183: 959–70.CrossRefGoogle Scholar
38Franceschi, C, Bonafe, M, Valensin, S. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann NY Acad Sci 2000; 908: 244–54.CrossRefGoogle ScholarPubMed
39Perlmutter, LS, Scott, SA, Barron, E, Chui, HC. MHC class II-positive microglia in human brain associated with Alzheimer lesions. J Neurosci Res 1992; 33: 549–58.CrossRefGoogle ScholarPubMed
40Saurwein-Teissl, M, Lung, TL, Marx, F, Gschösser, C, Asch, E, Blasko, I, Parson, W, Böck, G, Schönitzer, D, Trannoy, E, Grubeck-Loebenstein, B. Lack of antibody production following immunization in old age: association CD8(+)CD28(−)T cell clonal expansions and an imbalance in production of Th1 and Th2 cytokines. J Immunol 2002; 168: 5893–99.CrossRefGoogle Scholar
41Ouyang, Q, Wanger, WM, Voehringer, D et al. Age-associated accumulation of CMV specific CD8+T cells expressing the inhibitory killer cell lectin-like receptor GI (KLRGI). Exp Gerontol 2003; 38: 911–20.Google Scholar
42Swain, S, Cllise-Dwyer, K, Haynes, L. Homeostasis and age associated defect of CD4T cells. Semin Immunol 2005; 17: 370–77.CrossRefGoogle Scholar
43Frasca, D, Riley, RL, Bloomberg, BB. Humoral immune response and B-cell functions including immunoglobulin class switch are downregulated in aged mice and humans. Semin Immunol 2005; 17: 378–84.Google Scholar
44Uyemura, K, Castle, SC, Makinodan, T. The frail elderly: role of dendritic cells in susceptibility of infection. Mech Ageing Dev 2002; 123: 955–62.CrossRefGoogle ScholarPubMed
45Herrero, C, Marques, L, Lloberas, J, Celada, A. IFN-gamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice. J Clin Invest 2001; 107: 485–93.Google Scholar
46Fagiolo, U, Cossarizza, A, Scala, E, Fanales-Belasio, E, Ortolani, C, Cozzi, E, Monti, D, Franceschi, C, Paganelli, R. Increased cytokine production in mononuclear cells in healthy elderly people. Eur J Immunol 1993; 23: 2375–78.Google Scholar
47Aspinal, R. Longevity and the immune response. Biogerontology 2000; 1: 273–78.Google Scholar
48Allman, D, Miller, JP. B cell development and receptor diversity during aging. Curr Opin Immunol 2005; 17: 463–67.Google Scholar
49Combrinck, MI, Perry, VH, Cunningham, C. Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience 2002; 112: 7–11.Google Scholar
50Dilger, RN, Johnson, RW. Aging, microglial cell priming and the discordant central inflammatory response to signals from the peripheral immune system. J Leukoc Biol 2008; 84: 932–39.Google Scholar
51Perry, VH, Cunningham, C, Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nature Rev Immunol 2007; 7: 161–67.Google Scholar
52Godbout, JP, Chen, J, Abraham, J, Richwine, AF, Berg, BM, Kelley, KW, Johnson, RW. Exaggerated neuroinflammation and sickness behaviour in aged mice following activation of the peripheral innate immune system. FASEB J 2005; 19: 1329–31.Google Scholar
53Dantzer, R, O'Connor, JC, Freund, GG, Johnson, RW, Kelley, KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neuro Sci 2008; 9: 46–56.Google Scholar
54Holmes, C, El-Okl, M, Williams, AL, Cunningham, C, Wilcockson, D, Perry, VH. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer's disease. J Neurol Neurosurg Psych 2003; 74: 788–89.CrossRefGoogle ScholarPubMed
55Simard, AR, Soulet, D, Gowing, G, Julien, JP, Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 2006; 49: 489–502.CrossRefGoogle ScholarPubMed
56Simard, AR, Rivest, S. Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglial. FASEB J 2004; 18: 998–1000.CrossRefGoogle Scholar
57Frackowiak, J, Wisniewski, HM, Wegiel, J, Merz, GS, Iqbal, K, Wang, KC. Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol 1992; 84: 225–33.Google Scholar
58Hickman, SE, Allison, EK, El Khoury, J. Microglial dysfunction and defective beta-amyloid clearance pathways in ageing Alzheimer's disease mice. J Neurosci 2008; 28: 8354–60.CrossRefGoogle ScholarPubMed
59Fiala, M, Cribbs, DH, Rosenthal, M, Bernard, G. Phagocytosis of amyloid-beta and inflammation: two faces of innate immunity in Alzheimer's disease. J Alzheimer Dis 2007; 11: 457–63.Google Scholar
60Blasko, I, Marx, F, Steiner, E, Hartmann, T, Grubeck-Loebenstein, B. TNF alpha plus IFN gamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J 1999; 13: 63–68.CrossRefGoogle Scholar
61Duyckaerts, C, Dickson, D. Neuropathology of Alzheimer's disease. In Dickson, D (ed). Neurodegeneration: the Molecular Pathology of Dementia and Movement Disorders. Basel: ISN Neuropath Press, pp. 47–65.Google Scholar
62Weller, RO, Subash, M, Preston, SD, Mazanti, I, Carare, RO. Perivascular drainage of amyloid-beta peptide from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol 2008; 18: 253–66.CrossRefGoogle ScholarPubMed
63McGeer, PL, McGeer, G. Complement proteins and complement inhibitors in Alzheimer's disease. Res Immunol 1992; 143: 621–24.Google Scholar
64Eikelenboom, P, Bate, C, Van Gool, WA, Hoozemans, JJ. Neuroinflammation in Alzheimer's disease and prion disease. Glia 2002; 40: 232–39.Google Scholar
65Veerhuis, R, Janseen, I, Hoozemans, JJ, DeGroot, CJ, Hack, CE, Eikelenboom, P. Complement c1-inhibitor expression in Alzheimer's disease. Acta Neuropathol 1998; 96: 287–96.Google Scholar
66Chen, K, Iribarren, P, Hu, J, Chen, J, Gong, W, Cho, EH, Lockett, S, Dunlop, NM, Wang, JM. Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer's disease associated amyloid beta peptide. J Biol Chem 2006; 281: 3651–59.CrossRefGoogle Scholar
67Paresce, DM, Ghosh, RN, Maxfield, FR. Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta protein via a scavenger receptor. Neuron 1996; 17: 553–65.Google Scholar
68Schenk, D, Barbour, R, Dunn, W, Gordon, G, Grajeda, H, Guido, T, Hu, K, Huang, J, Johnson-Wood, K, Khan, K, Kholodenko, D, Lee, M, Liao, Z, Lieberburg, I, Motter, R, Mutter, L, Soriano, F, Shopp, G, Vasquez, N, Vandevert, C, Walker, S, Wogulis, M, Yednock, T, Games, D, Seubert, P. Immunization with amyloid beta attenuates Alzheimer-disease-like pathology in PDAPP mouse. Nature 1999; 400: 173–77.Google Scholar
69Schenk, D, Hagen, M, Seubert, P. Current progress in beta-amyloid immunotherapy. Curr Opin Immunol 2004; 16: 599–606.Google Scholar
70Janus, C, Pearson, J, McLaurin, J, Mathews, PM, Jiang, Y, Schmidt, SD, Chishti, MA, Horne, P, Heslin, D, French, J, Mount, HT, Nixon, RA, Mercken, M, Bergeron, C, Fraser, PE, St George-Hyslop, P, Westaway, D. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 2000; 408: 979–82.Google Scholar
71Morgan, D, Diamond, DM, Gottschall, PE, Ugen, KE, Dickey, C, Hardy, J, Duff, K, Jantzen, P, DiCarlo, G, Wilcock, D, Connor, K, Hatcher, J, Hope, C, Gordon, M, Arendash, GW. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's Disease. Nature 2000; 408: 982–85.Google Scholar
72Bard, F, Cannon, C, Barbour, R, Burke, RL, Games, D, Grajeda, H, Guido, T, Hu, K, Huang, J, Johnson-Wood, K, Khan, K, Kholodenko, D, Lee, M, Lieberburg, I, Motter, R, Nguyen, M, Soriano, F, Vasquez, N, Weiss, K, Welch, B, Seubert, P, Schenk, D, Yednock, T. Peripherally administered antibodies against amyloid-beta peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer's disease. Nat Med 2000; 6: 916–19.CrossRefGoogle Scholar
73Bacskai, BJ, Kajdasz, ST, McLellan, ME, Games, D, Seubert, P, Schenk, D, Hyman, BT. Non-Fc-mediated mechanisms are involved in the clearance of amyloid-beta in vivo by immunotherapy. J Neurosci 2002; 22: 7873–78.Google Scholar
74Bacskai, BJ, Kajdasz, ST, Christie, RH, Carter, C, Games, D, Seubert, P, Schenk, D, Hyman, BT. Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nature Med 2001; 7: 369–72.Google Scholar
75Bard, F, Barbour, R, Cannon, C, Carretto, R, Fox, M, Games, D, Guido, T, Hoenow, K, Hu, K, Johnson-Wood, K, Khan, K, Kholodenko, D, Lee, C, Lee, M, Motter, R, Nguyen, M, Reed, A, Schenk, D, Tang, P, Vasquez, N, Seubert, P, Yednock, T. Epitope and isotype specificities of antibodies to beta-amyloid peptide protection against Alzheimer's disease like neuropathy. Proc Natl Acad Sci USA 2003; 100: 2023–28.CrossRefGoogle Scholar
76Koenigsknecht-Talboo, J, Meyer-Luehmann, M, Parsadanian, M, Garcia-Alloza, M, Finn, MB, Hyman, BT, Bacskai, BJ, Holtzman, DM. Rapid microglial response around amyloid pathology after systemic anti Abeta antibody administration in PDAPP mice. J Neurosci 2008; 28: 14156–64.CrossRefGoogle ScholarPubMed
77Zlokovic, BV, Deane, R, Sallstrom, J, Chow, N, Miano, MJ. Neurovascular pathways and Alzheimer amyloid, beta-peptide. Brain Pathol 2005; 15: 78–83.Google Scholar
78Poduslo, JF, Curran, GL, Wengenack, TM, Malester, B, Duff, K. Permeability of proteins at the blood brain barrier in the normal adult mouse and double transgenic mouse model of Alzheimer's disease. Neurobiol Dis 2001; 8: 555–67.Google Scholar
79Asuni, AA, Boutajangout, A, Quatermain, D, Sigurdsson, EM. Immunotherapy targeting pathological tau conformers in a tangles mouse model reduces brain pathology with associated functional improvements. J Neurosci 2007; 27: 9115–29.CrossRefGoogle Scholar
80Masliah, E, Rockenstein, E, Adame, A et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron 2005; 46: 857–68.Google Scholar
81Fabian, RH. Uptake of anti-neuronal IgM by CNS neurons; comparison with anti neuronal IgG. Neurology 1990; 40: 419–22.Google Scholar
82Mohamed, HA, Mosier, DR, Zou, LL, Siklós, L, Alexianu, ME, Engelhardt, JI, Beers, DR, Le, WD, Appel, SH. Immunoglobulin Fc gamma receptor promotes immunoglobulin uptake, immunoglobulin-mediated calcium increase, and neurotransmitter release in motor neurons. J Neurosci Res 2002; 69: 110–16.Google Scholar
83Reichwald, J, Danner, S, Wiederhold, KH, Staufenbiel, M. Expression of complement system components during aging and amyloid deposition in APP transgenic mice. J Neuroinflam 2009; 17: 35.Google Scholar
84Wyss-Coray, T, Yan, F, Lin, AH, Lambris, JD. Prominent neurodegeneration and increased plaque formation in complement-inhibited mice. Proc Natl Acad Sci USA 2002; 16: 10837–44.CrossRefGoogle Scholar
85Wyss-Coray, T, Mucke, L. Inflammation in neurodegenerative disease – a double edged sword. Neuron 2002; 35: 419–32.Google Scholar
86Maier, M, Peng, Y, Jiang, L, Seabrook, TJ, Carroll, MC, Lemere, CA. Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegneration and modulation of the microglial/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 2008; 28: 6333–41.Google Scholar
87Zhou, J, Fonseca, MI, Pisalyaput, K, Tenner, AJ. Complement C3 and C4 expressions in C1q sufficient and deficient mouse models of Alzheimer's disease. J Neurochem 2008; 106: 2080–92.Google Scholar
88DeMattos, RB, Bales, KB, Cummins, DJ, Dodart, JC, Paul, SM, Holtzman, DM. Peripheral anti-A beta antibody CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 2001; 98: 8850–55.Google Scholar
89Solomon, B, Koppel, R, Frankel, D, Hanan-Aharon, E. Disaggregation of Alzheimer beta-amyloid by site directed mAB. Proc Natl Acad Sci USA 1997; 94: 4109112.Google Scholar
90Weller, RO. Pathology of cerebrospinal fluid and interstial fluid of the CNS: significance for Alzheimer disease prion disorders and multiple sclerosis. J Neuropath Exp Neurol 1998; 57: 885–94.Google Scholar
91Preston, SD, Steart, PV, Wilkinson, A, Nicoll, JA, Weller, RO. Capillary and arterial cerebral amyloid angiopathy in Alzheimer's disease: defining a perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 2003; 29: 106–17.Google Scholar
92Levites, Y, Smithson, LA, Price, RW, Dakin, RS, Yuan, B, Sierks, MR, Kim, J, McGowan, E, Reed, DK, Rosenberry, TL, Das, P, Golde, TE. Insights into the mechanism of action of anti-Abeta antibodies in Alzheimer's disease mouse models. FASEB J 2006; 20: 2575–78.Google Scholar
93Grubeck-Loebenstein, B, Della Bella, S, Iorio, AM, Michel, JP, Pawelec, G, Solana, R. Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res 2009; 21: 201–9.Google Scholar
94Treib, K, Ransmayr, G, Sgonc, R, Lassman, H, Grubeck-Loebenstein, B. APP peptide stimulates lymphocyte proliferation in normals but not in patients with Alzheimer's disease. Neurobiol Ageing 1996; 17: 541–47.Google Scholar
95Monsonego, A, Maron, R, Zota, V, Selkoe, DJ, Weiner, HL. Immune hyporesponsiveness to amyloid beta peptide in amyloid precursor protein transgenic mice: implications for pathogenesis and treatment of Alzheimer's disease. Proc Natl Acad Sci USA 2001; 98: 10273–78.Google Scholar
96Monsonego, A, Zota, V, Karni, A, Krieger, JI, Bar-Or, A, Bitan, G, Budson, AE, Sperling, R, Selkoe, DJ, Weiner, HL. Increased T cell reactivity to amyloid beta in older humans and patients with Alzheimer's disease. J Clin Invest 2003; 12: 415–22.CrossRefGoogle Scholar
97Cserr, HF, Harling Berg, CJ, Knopf, PM. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol 1992; 2: 269–76.Google Scholar
98Bayer, AJ, Bullock, R, Jones, RW, Wilkinson, D, Paterson, KR, Jenkins, L, Millais, SB, Donoghue, S. Evaluation of the safety and immunogenicity of synthetic Abeta 42 (AN1792) in patients with AD. Neurology 2005; 64: 94–101.Google Scholar
99Orgogozo, JM, Gilman, S, Dartigues, JF, Laurent, B, Puel, M, Kirby, LC, Jouanny, P, Dubois, B, Eisner, L, Flitman, S, Michel, BF, Boada, M, Frank, A, Hock, C. Sub-acute meningoencephalitis in a subset of patients with AD after Abeta 42 immunization. Neurology 2003; 61: 46–54.Google Scholar
100Nicoll, JA, Wilkinson, D, Holmes, C, Steart, P, Markham, H, Weller, RO. Neuropathology of human Alzheimer's disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003; 9: 448–452.Google Scholar
101Ferrer, I, Boada Rovira, M, Sánchez Guerra, ML, Rey, MJ, Costa-Jussá, F. Neuropathology and pathogenesis of encephalitis following amyloid- beta immunization in Alzheimer's disease. Brain Pathol 2004; 14: 11–20.CrossRefGoogle ScholarPubMed
102Masliah, E, Hansen, L, Adame, A, Crews, L, Bard, F, Lee, C, Seubert, P, Games, D, Kirby, L, Schenk, D. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 2005; 64: 129–31.Google Scholar
103Monsonego, A, Imitola, J, Petrovic, S, Zota, V, Nemirovsky, A, Baron, R, Fisher, Y, Owens, T, Weiner, HL. Abeta induced meningoencephalitis is IFN-gamma dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 2006; 103: 5048–53.CrossRefGoogle Scholar
104McLaurin, J, Cecal, R, Kierstead, ME, Tian, X, Phinney, AL, Manea, M, French, JE, Lambermon, MH, Darabie, AA, Brown, ME, Janus, C, Chishti, MA, Horne, P, Westaway, D, Fraser, PE, Mount, HT, Przybylski, M, St George-Hyslop, P. Therapeutically effective against amyloid-beta peptide target amyloid-beta residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nat Med 2002; 8: 1263–69.CrossRefGoogle ScholarPubMed
105Hock, C, Konietzko, U, Papassotiropoulos, A, Wollmer, A, Streffer, J, von Rotz, RC, Davey, G, Moritz, E, Nitsch, RM. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer's disease. Nat Med 2002; 8: 1270–75.Google Scholar
106Hock, C, Konietzko, U, Streffer, JR, Tracy, J et al. Antibodies against beta amyloid slow cognitive decline in Alzheimer's disease. Neuron 2004; 38: 547–54.Google Scholar
107Nicoll, JA, Barton, E, Bouche, D et al. Abeta species removal after Abeta42 immunization. J Neuropathol Exp Neurol 2006; 65: 1040–48.Google Scholar
108Lee, M, Bard, F, Johnson-Wood, K, Lee, C, Hu, K, Griffith, SG, Black, RS, Schenk, D, Seubert, P. Abeta42 immunization in Alzheimer's disease generates Abeta terminal antibodies. Ann Neurol 2005; 58: 430–35.Google Scholar
109Wilcock, DM, Rojiani, A, Rosenthal, A, Levkowitz, G, Subbarao, S, Alamed, J, Wilson, D, Wilson, N, Freeman, MJ, Gordon, MN, Morgan, D. Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci 2004; 246: 6144–51.Google Scholar
110Holmes, C, Boche, D, Wilkinson, D, Yadegarfar, G, Hopkins, V, Bayer, A, Jones, RW, Bullock, R, Love, S, Neal, JW, Zotova, E, Nicoll, JA. Long term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase 1 trial. Lancet 2008; 372: 216–23.Google Scholar
111Davis, DG, Schmitt, FA, Wekstein, DR, Markesbery, WR. Alzheimer neuropathologic alterations in aged cognitively normal subject. J Neuropathol Exp Neurol 1999; 58: 376–88.Google Scholar
112Klunk, WE, Mathis, CA, Price, JC, Lopresti, BJ, DeKosky, ST. Two year follow up of amyloid deposition in patients with Alzheimer's disease. Brain 2006; 129: 2805–7.CrossRefGoogle ScholarPubMed
113Patton, RL, Kalback, WM, Esh, CL, Kokjohn, TA, Van Vickle, GD, Luehrs, DC, Kuo, YM, Lopez, J, Brune, D, Ferrer, I, Masliah, E, Newel, AJ, Beach, TG, Castaño, EM, Roher, AE. Amyloid-beta peptide remnants in AN-1792 immunized Alzheimer's disease patients: a biochemical analysis. Am J Pathol 2006; 169: 1048–63.Google Scholar
114Pride, MW, Black, RS, Hagen, M et al. P4–348Evaluation of potential immunologic mechanisms in the pathogenesis of treatment-induced meningoencephalitis in Alzheimer's disease patients treated with AN1792(QS-21). Neurobiol Aging 2004; 25 suppl 2: S574.Google Scholar
115Boche, D, Zotova, E, Weller, RO, Love, S, Neal, JW, Pickering, RM, Wilkinson, D, Holmes, C, Nicoll, JA. Consequences of Abeta immunization on the vasculature of human Alzheimer's disease. Brain 2008; 131: 3299–31.Google Scholar
116McDermott, JR, Gibson, AM. Degradation of Alzheimer's beta-amyloid protein by human and rat brain peptidases: involvement of insulin-degrading enzyme. Neurochem Res 1997; 22: 49–56.Google Scholar
117Shibata, M, Yamada, S, Kumar, SR, Calero, M, Bading, J, Frangione, B, Holtzman, DM, Miller, CA, Strickland, DK, Ghiso, J, Zlokovic, BV. Clearance of Alzheimer's amyloid–ss (1–40) peptide from brain by LDL receptor-related protein-1 at the blood brain barrier. J Clin Invest 2000; 106: 1489–99.Google Scholar
118Jones, RW, Kivipelto, M, Feldman, H, Sparks, L, Doody, R, Waters, DD, Hey-Hadavi, J, Breazna, A, Schindler, RJ, Ramos, H; LEADe investigators. The Atorvastatin/Donepezil in Alzheimer's disease study (LEADe): design and baseline characteristics. Alzheimer's Dement 2008; 4: 145–53.Google Scholar
119Neugroschl, J, Sano, M. An update on treatment and prevention strategies for Alzheimer's disease. Curr Neurol Neurosci Rep 2009; 9: 368–76.Google Scholar
120Chauhan, NB, Siegel, GJ, Lichtor, T. Effect of age on the duration and extent of amyloid plaque reduction and microglial activation after injection of anti-Abeta antibody into the third ventricle of TgCRN8 mice. J Neurosci Res 2004; 78: 732–41.Google Scholar
121Dodel, RC, Du, Y, Depboylu, C, Hampel, H, Frölich, L, Haag, A, Hemmeter, U, Paulsen, S, Teipel, SJ, Brettschneider, S, Spottke, A, Nölker, C, Möller, HJ, Wei, X, Farlow, M, Sommer, N, Oertel, WH. Intravenous immunoglobulins containing antibodies against beta-amyloid for treatment of Alzheimer's disease. J Neurol Neurosurg Psych 2004; 75: 1472–74.Google Scholar
122Oddo, S, Billing, L, Kesslak, JP et al. Abeta immunotherapy leads to clearance of early but not late, hyperphoshorylated tau aggregates via proteasome. Neuron 2004; 43: 321–32.Google Scholar
123Hutton, M, McGowan, E. Clearing tau pathology with Abeta immunotherapy-reversible and irreversible stages revealed. Neuron 2004; 43: 293–94.Google Scholar
124Sigurdsson, EM, Brown, DR, Daniels, M, Kascsak, RJ, Kascsak, R, Carp, R, Meeker, HC, Frangione, B, Wisniewski, T. Immunization delays the onset of prion disease in mice. Am J Pathol 2002; 161: 13–17.Google Scholar
125Heppner, FL, Aguzzi, A. Recent developments in prison immunotherapy. Curr Opin Immunol 2004; 16: 594–98.Google Scholar
126Yasuhara, O, Aimi, Y, McGeer, EG, McGeer, PL. Expression of the complement membrane attack complex and its inhibitor in Pick disease brain. Brain Res 1994; 652: 346–49.Google Scholar
127Rogers, J, Cooper, NR, Webster, S et al. Complement activation by beta amyloid in Alzheimer's disease. Proc Natl Acad Sci USA 1992; 89: 10016–20.Google Scholar
128Singhrao, SK, Neal, JW, Gasque, P, Morgan, BP, Newman, GR. Role of complement in the aetiology of Pick's disease? J Neuropathol Exp Neurol 1996; 55: 578–93.Google Scholar
129Griffiths, MR, Neal, JW, Fontaine, M, Das, T, Gasque, P. Complement Factor H, a marker of self protects against experimental autoimmune encephalomyelitis. J Immunol 2009; 182: 4368–77.Google Scholar
130de Cordoba, SR, de Jorge, EG. Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clin Exp Immunol 2008; 151: 1–13.Google Scholar
131Haines, JL, Hauser, MA, Schmidt, S, Scott, WK, Olson, LM, Gallins, P, Spencer, KL, Kwan, SY, Noureddine, M, Gilbert, JR, Schnetz-Boutaud, N, Agarwal, A, Postel, EA, Pericak-Vance, MA. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308: 419–21.Google Scholar
132Zetterberg, M, Landgren, S, Andersson, ME, Palmér, MS, Gustafson, DR, Skoog, I, Minthon, L, Thelle, DS, Wallin, A, Bogdanovic, N, Andreasen, N, Blennow, K, Zetterberg, H. Association of complement factors H Y402H gene polymorphism with Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet 2008; 5: 720–26.Google Scholar
133Hye, A, Lynham, S, Thambisetty, M, Causevic, M, Campbell, J, Byers, HL, Hooper, C, Rijsdijk, F, Tabrizi, SJ, Banner, S, Shaw, CE, Foy, C, Poppe, M, Archer, N, Hamilton, G, Powell, J, Brown, RG, Sham, P, Ward, M, Lovestone, S. Proteome-based plasma biomarkers for Alzheimer's disease. Brain 2006; 129: 3042–50.Google Scholar
134Honda, S, Itoh, F, Yoshimoto, M, Ohno, S, Hinoda, Y, Imai, K. Association between complement regulatory protein H and AM34 antigen detected in senile plaques. J Gerontol A 2000; 55: 265–69.Google Scholar
135Strohmeyer, 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 disease brain. J Neuroimmunol 2002; 131: 135–46.Google Scholar
136Rinne, JO, Brooks, DJ, Rossor, MN, Fox, NC, Bullock, R, Klunk, WE, Mathis, CA, Blennow, K, Barakos, J, Okello, AA, Rodriguez Martinez de Liano, S, Liu, E, Koller, M, Gregg, KM, Schenk, D, Black, R, Grundman, M. 11C-PiB PET assessment of change in fibrillar amyloid beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double blind, placebo controlled, ascending-dose study. Lancet Neurol 2010; 9: 363–72.Google Scholar