Modified immunotherapies against Alzheimer's disease: Toward safer and effective amyloid-β clearance

Journal of Alzheimer's Disease

Volumn 21, Issue 4, 2010, Pages 1065-1075

  Wang, Yan Jiang ^a   Zhou, Hua Dong ^a   Zhou, Xin Fu ^b  

^a THIRD MILITARY MEDICAL UNIVERSITY   (China)

^b FLINDERS UNIVERSITY   (Australia)

Author keywords

Alzheimer's disease; amyloid ; autoantibody; immunotherapy; oligomer; single chain antibody; vaccine

Indexed keywords

ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN ANTIBODY; AMYLOID BETA PROTEIN[1-42]; BAPINEUZUMAB; CHOLERA TOXIN B SUBUNIT; CYTOKINE; DNA VACCINE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; IMMUNOGLOBULIN G; IMMUNOLOGICAL ADJUVANT; INTERLEUKIN 4; MACROPHAGE DERIVED CHEMOKINE; OLIGOMER; SINGLE CHAIN FRAGMENT VARIABLE ANTIBODY;

ACTIVE IMMUNIZATION; ALZHEIMER DISEASE; AUTOIMMUNE DISEASE; AUTOIMMUNE MENINGOENCEPHALITIS; BLOOD BRAIN BARRIER; BRAIN HEMORRHAGE; CYTOKINE RELEASE; DRUG HALF LIFE; DRUG PROTEIN BINDING; GENE THERAPY; HUMAN; HUMORAL IMMUNITY; IMMUNOTHERAPY; MENINGOENCEPHALITIS; MICROGLIA; NONHUMAN; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE;

EID: 78650507352     PISSN: 13872877     EISSN: None     Source Type: Journal    
DOI: 10.3233/JAD-2010-100195     Document Type: Review

References (104)

1. World Health Organization. World Health Report 2003-Shapingthe future. Geneva: WHO, 2003.
2. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366, 2112-2117.
3. Vellas B, Coley N, Andrieu S (2008) Disease modifying trials in Alzheimer's disease: perspectives for the future. J Alzheimers Dis 15, 289-301.
4. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356.
5. Hanger DP, Anderton BH, Noble W (2009) Tau phosphory-lation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med 15, 112-119.
6. Wang YJ, Zhou HD, Zhou XF (2006) Clearance of amyloid-beta in Alzheimer's disease: progress, problems and perspectives. DrugDiscov Today 11, 931-938.
7. Delacourte A (2008) Tau pathology and neurodegeneration: an obvious but misunderstood link. J Alzheimers Dis 14, 437-440.
8. Schenk 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 (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173-177.
9. Bard 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 (2003) Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's diseaselike neuropathology. Proc Natl Acad Sci U S A 100, 20232028.
10. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM (2002) Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci 5, 452-457.
11. Wilcock DM, Munireddy SK, Rosenthal A, Ugen KE, Gordon MN, Morgan D (2004) Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis 15, 11-20.
12. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 45, 675-688.
13. Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C, Lemere CA (2006) Short amyloid-beta (Abeta) immuno-gens reduce cerebral Abeta load and learning deficits in an Alzheimer's disease mouse model in the absence of an Abeta-specific cellular immune response. JNeurosci 26, 4717-4728.
14. Janus 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 (2000) Abeta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408, 979-982.
15. Morgan 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 (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408, 982-985.
16. Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F (2004) Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol 14, 11-20.
17. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9, 448-452.
18. Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, Seubert P, Games D, Kirby L, Schenk D (2005) Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64, 129-131.
19. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553-1562.
20. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216-223.
21. Holtzman JL (2008) Amyloid-beta vaccination for Alzheimer's dementia. Lancet 372, 1381; author reply 13811382.
22. St George-Hyslop PH, Morris JC (2008) Will anti-amyloid therapies work for Alzheimer's disease? Lancet 372, 180182.
23. Petrushina I, Ghochikyan A, Mktrichyan M, Mamikonyan Movsesyan N, Davtyan H, Patel A, Head E, Cribbs DH, Agadjanyan MG (2007) Alzheimer's disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Abe-ta species in amyloid precursor protein transgenic mice. J Neurosci 27, 12721-12731.
24. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM (2001) Peripheral anti-A beta antibody alters 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 98, 8850-8855.
25. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda 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 (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6, 916-919.
26. Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Abel T, Lee VM (2006) Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. J Biol Chem 281, 4292-4299.
27. Wilcock DM, Rojiani A, Rosenthal A, Levkowitz G, Sub-barao S, Alamed J, Wilson D, Wilson N, Freeman MJ, Gordon MN, Morgan D (2004) Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a trans-genic mouse model of amyloid deposition. J Neurosci 24, 6144-6151.
28. Chauhan NB, Siegel GJ (2004) Intracerebroventricular passive immunization in transgenic mouse models of Alzheimer's disease. Expert Rev Vaccines 3, 717-725.
29. Sheridan C (2009) J&J's billion dollar punt on anti-amyloid antibody. NatBiotechnol 27, 679-681.
30. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73, 2061-2070.
31. Wilcock DM, Gordon MN, Ugen KE, Gottschall PE, DiCarlo G, Dickey C, Boyett KW, Jantzen PT, Connor KE, Melachri-no J, Hardy J, Morgan D (2001) Number of Abeta inoculations in APP+PS1 transgenic mice influences antibody titers, microglial activation, and congophilic plaque levels. DNA Cell Biol 20, 731-736.
32. Brazil MI, Chung H, Maxfield FR (2000) Effects of incorporation of immunoglobulin G and complement component C1q on uptake and degradation of Alzheimer's disease amyloid fibrils by microglia. J Biol Chem 275, 16941-16947.
33. Solomon B, Koppel R, Hanan E, Katzav T (1996) Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci U S A 93, 452-455.
34. Solomon B, Koppel R, Frankel D, Hanan-Aharon E (1997) Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci USA 94, 4109-4112.
35. Bacskai BJ, Kajdasz ST, McLellan ME, Games D, Seubert P, Schenk D, Hyman BT (2002) Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci 22, 7873-7878.
36. Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE (2003) Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/-knock-out mice. J Neurosci 23, 8532-8538.
37. Moir RD, Tseitlin KA, Soscia S, Hyman BT, Irizarry MC, Tanzi RE (2005) Autoantibodies to redox-modified oligomer-ic Abeta are attenuated in the plasma of Alzheimer's disease patients. J Biol Chem 280, 17458-17463.
38. Orgogozo 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 (2003) Subacute menin-goencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61, 46-54.
39. Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Str-effer J, von Rotz RC, Davey G, Moritz E, Nitsch RM (2002) Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med 8, 12701275.
40. Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M (2002) Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 298, 1379.
41. Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D (2004) Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation 1, 24.
42. Burbach GJ, Vlachos A, Ghebremedhin E, Del Turco D, Coomaraswamy J, Staufenbiel M, Jucker M, Deller T (2007) Vessel ultrastructure in APP23 transgenic mice after passive anti-Abeta immunotherapy and subsequent intracerebral hemorrhage. Neurobiol Aging 28, 202-212.
43. Patton RL, Kalback WM, Esh CL, Kokjohn TA, Van Vick-le GD, Luehrs DC, Kuo YM, Lopez J, Brune D, Ferrer I, Masliah E, Newel AJ, Beach TG, Castano EM, Roher AE (2006) Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients: a biochemical analysis. Am J Pathol 169, 1048-1063.
44. Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, Piroozi KS, Jordan WH, Brown DD, Hoffman WP, Holtzman DM, Bales KR, Gitter BD, May PC, Paul SM, DeMattos RB (2005) Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci 25, 629-636.
45. Thakker DR, Weatherspoon MR, Harrison J, Keene TE, Lane DS, Kaemmerer WF, Stewart GR, Shafer LL (2009) In-tracerebroventricular amyloid-beta antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice. Proc Natl Acad Sci USA 106, 45014506.
46. Christie R, Yamada M, Moskowitz M, Hyman B (2001) Structural and functional disruption ofvascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. Am J Pathol 158, 1065-1071.
47. Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Sturchler-Pierrat C, Burki K, van Duinen SG, Maat-Schieman ML, Staufenbiel M, Mathews PM, Jucker M (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7, 954-960.
48. Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M, Jucker M (2001) Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci 21, 1619-1627.
49. Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T, Gill D, Basi G, Schenk D, Seubert P, Games D (2008) Immunotherapy reduces vascular amyloid-beta in PDAPP mice. JNeurosci 28, 6787-6793.
50. Kaufer D, Gandy S (2009) APOE {epsilon}4 and bap-ineuzumab: Infusing pharmacogenomics into Alzheimer disease therapeutics. Neurology 73, 2052-2053.
51. Gelinas DS, DaSilva K, Fenili D, St George-Hyslop P, McLaurin J (2004) Immunotherapy for Alzheimer's disease. Proc Natl Acad Sci USA 101, 14657-14662.
52. Qu B, Rosenberg RN, Li L, Boyer PJ, Johnston SA (2004) Gene vaccination to bias the immune response to amyloid-beta peptide as therapy for Alzheimer disease. Arch Neurol 61, 1859-1864.
53. Horikoshi Y, Mori T, Maeda M, Kinoshita N, Sato K, Ya-maguchi H (2004) Abeta N-terminal-end specific antibody reduced beta-amyloid in Alzheimer-model mice. Biochem Biophys Res Commun 325, 384-387.
54. McLaurin 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 (2002) Ther-apeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis. Nat Med 8, 1263-1269.
55. Bussiere T, Bard F, Barbour R, Grajeda H, Guido T, Khan K, Schenk D, Games D, Seubert P, Buttini M (2004) Morphological characterization of Thioflavin-S-positive amyloid plaques in transgenic Alzheimer mice and effect of passive Abeta immunotherapy on their clearance. Am J Pathol 165, 987-995.
56. Lee M, Bard F, Johnson-Wood K, Lee C, Hu K, Griffith SG, Black RS, Schenk D, Seubert P (2005) Abeta42 immunization in Alzheimer's disease generates Abeta N-terminal antibodies. Ann Neurol 58, 430-435.
57. Hara H, Monsonego A, Yuasa K, Adachi K, Xiao X, Takeda S, Takahashi K, Weiner HL, Tabira T (2004) Development of a safe oral Abeta vaccine using recombinant adeno-associated virus vector for Alzheimer's disease. J Alzheimers Dis 6, 483-488.
58. DaSilva KA, Brown ME, McLaurin J (2009) Reduced oligomeric and vascular amyloid-beta following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine. Vaccine 27, 1365-1376.
59. Okura Y, Miyakoshi A, Kohyama K, Park IK, Staufenbiel M, Matsumoto Y (2006) Nonviral Abeta DNA vaccine therapy against Alzheimer's disease: long-term effects and safety. Proc Natl Acad Sci USA 103, 9619-9624.
60. Kim HD, Maxwell JA, Kong FK, Tang DC, Fukuchi K (2005) Induction of anti-inflammatory immune response by an adenovirus vector encoding 11 tandem repeats of Abeta1-6: toward safer and effective vaccines against Alzheimer's disease. Biochem Biophys Res Commun 336, 84-92.
61. Ghochikyan A, Vasilevko V, Petrushina I, Movsesyan N, Babikyan D, Tian W, Sadzikava N, Ross TM, Head E, Cribbs DH, Agadjanyan MG (2003) Generation and characterization ofthe humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene. Eur J Immunol 33, 3232-3241.
62. Zhang J, Wu X, Qin C, Qi J, Ma S, Zhang H, Kong Q, Chen D, Ba D, He W (2003) A novel recombinant adeno-associated virus vaccine reduces behavioral impairment and beta-amyloid plaques in a mouse model of Alzheimer's disease. Neurobiol Dis 14, 365-379.
63. He Y, Sun SH, Chen RW, Guo YJ, He XW, Huang L, Chen ZH, Shi K, Zhu WJ (2005) Effects of epitopes combination and adjuvants on immune responses to anti-Alzheimer disease DNA vaccines in mice. Alzheimer Dis Assoc Disord 19, 171-177.
64. Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG (2008) Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine -a novel immunotherapeutic strategy. PLoS ONE 3, e2124.
65. Lemere CA, Maier M, Jiang L, Peng Y, Seabrook TJ (2006) Amyloid-beta immunotherapy for the prevention and treatment of Alzheimer disease: lessons from mice, monkeys, and humans. Rejuvenation Res 9, 77-84.
66. Tamura Y, Hamajima K, Matsui K, Yanoma S, Narita M, Tajima N, Xin KQ, Klinman D, Okuda K (2005) The F(ab)'2 fragment of an Abeta-specific monoclonal antibody reduces Abeta deposits in the brain. Neurobiol Dis 20, 541-549.
67. Takata K, Hirata-Fukae C, Becker AG, Chishiro S, Gray AJ, Nishitomi K, Franz AH, Sakaguchi G, Kato A, Mattson MP, Laferla FM, Aisen PS, Kitamura Y, Matsuoka Y (2007) Deg-lycosylated anti-amyloid beta antibodies reduce microglial phagocytosis and cytokine production while retaining the capacity to induce amyloid beta sequestration. Eur J Neurosci 26, 2458-2468.
68. Wilcock DM, Alamed J, Gottschall PE, Grimm J, Rosenthal A, Pons J, Ronan V, Symmonds K, Gordon MN, Morgan D (2006) Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. J Neurosci 26, 5340-5346.
69. Holliger P, Hudson PJ (2005) Engineered antibody fragments and the rise of single domains. NatBiotechnol 23, 1126-1136.
70. Fukuchi K, Tahara K, Kim HD, Maxwell JA, Lewis TL, Accavitti-Loper MA, Kim H, Ponnazhagan S, Lalonde R (2006) Anti-Abeta single-chain antibody delivery via adeno-associated virus for treatment of Alzheimer's disease. Neu-robiolDis 23, 502-511.
71. Levites Y, Jansen K, Smithson LA, Dakin R, Holloway VM, Das P, Golde TE (2006) Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid beta, amyloid beta40, and amyloid beta42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice. J Neurosci 26, 11923-11928.
72. Wang YJ, Pollard A, Zhong JH, Dong XY, Wu XB, Zhou HD, Zhou XF (2009) Intramuscular delivery of a single chain antibody gene reduces brain Abeta burden in a mouse model of Alzheimer's disease. Neurobiol Aging 30, 364-376.
73. Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D, Seubert P, Schenk D, Holmes C (2006) Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol 65, 10401048.
74. Liu R, Yuan B, Emadi S, Zameer A, Schulz P, McAllister C, Lyubchenko Y, Goud G, Sierks MR (2004) Single chain variable fragments against beta-amyloid (Abeta) can inhibit Abeta aggregation and prevent abeta-induced neurotoxicity. Biochemistry 43, 6959-6967.
75. Zameer A, Schulz P, Wang MS, Sierks MR (2006) Single Chain Fv Antibodies against the 25-35 Abeta Fragment Inhibit Aggregation and Toxicity of Abeta42. Biochemistry 45, 11532-11539
76. Frenkel D, Solomon B, Benhar I (2000) Modulation of Alzheimer's beta-amyloid neurotoxicity by site-directed single-chain antibody. JNeuroimmunol 106, 23-31.
77. Lafaye P, Achour I, England P, Duyckaerts C, Rougeon F (2009) Single-domain antibodies recognize selectively small oligomeric forms of amyloid beta, prevent Abeta-induced neurotoxicity and inhibit fibril formation. Mol Immunol 46, 695-704.
78. Habicht G, Haupt C, Friedrich RP, Hortschansky P, Sachse C, Meinhardt J, Wieligmann K, Gellermann GP, Brodhun M, Gotz J, Halbhuber KJ, Rocken C, HornU, Fandrich M (2007) Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Abeta protofibrils. Proc Natl Acad Sci USA 104, 19232-19237.
79. Robert R, Dolezal O, Waddington L, Hattarki MK, Cappai R, Masters CL, Hudson PJ, Wark KL (2009) Engineered antibody intervention strategies for Alzheimer's disease and related dementias by targeting amyloid and toxic oligomers. Protein Eng Des Sel 22, 199-208.
80. Meli G, Visintin M, Cannistraci I, Cattaneo A (2009) Direct in vivo intracellular selection of conformation sensitive antibody domains targeting Alzheimer's Amyloid-beta Oligomers. J Mol Biol 387, 584-606.
81. Paganetti P, Calanca V, Galli C, Stefani M, Molinari M (2005) beta-site specific intrabodies to decrease and prevent generation of Alzheimer's Abeta peptide. J Cell Biol 168, 863-868.
82. Rangan SK, Liu R, Brune D, Planque S, Paul S, Sierks MR (2003) Degradation of beta-amyloid by proteolytic antibody light chains. Biochemistry 42, 14328-14334.
83. Taguchi H, Planque S, Sapparapu G, Boivin S, Hara M, Nishiyama Y, Paul S (2008) Exceptional amyloid beta peptide hydrolyzing activity of non-physiological immunoglobulin variable domain scaffolds. J Biol Chem 238, 4714-4712.
84. Chirino AJ, Ary ML, Marshall SA (2004) Minimizing the immunogenicity of protein therapeutics. DrugDiscov Today 9, 82-90.
85. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shep-ardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14, 837-842.
86. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers ofamyloid beta protein potently inhibit hippocam-pal long-term potentiation in vivo. Nature 416, 535-539.
87. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci 27, 796-807.
88. Dahlgren KN, Manelli AM, Stine WB, Jr., Baker LK, Krafft GA, LaDu MJ (2002) Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 277, 32046-32053.
89. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440, 352-357.
90. Wang XP, Zhang JH, Wang YJ, Feng Y, Zhang X, Sun XX, Li JL, Du XT, Lambert MP, Yang SG, Zhao M, Klein WL, Liu RT (2009) Conformation-dependent single-chain variable fragment antibodies specifically recognize beta-amyloid oligomers. FEBSLett 583, 579-584.
91. Zameer A, Kasturirangan S, Emadi S, Nimmagadda SV, Sierks MR (2008) Anti-oligomeric Abeta single-chain variable domain antibody blocks abeta-induced toxicity against human neuroblastoma cells. J Mol Biol 384, 917-928.
92. Zurbriggen R, Amacker M, Kammer AR, Westerfeld N, Borghgraef P, Van Leuven F, Van der Auwera I, Wera S (2005) Virosome-based active immunization targets soluble amyloid species rather than plaques in a transgenic mouse model of Alzheimer's disease. J Mol Neurosci 27, 157-166.
93. Brettschneider S, Morgenthaler NG, Teipel SJ, Fischer-Schulz C, Burger K, Dodel R, Du Y, Moller HJ, Bergmann A, Hampel H (2005) Decreased serum amyloid beta(1-42) autoantibody levels in Alzheimer's disease, determined by a newly developed immuno-precipitation assay with radiola-beled amyloid beta(1-42) peptide. Biol Psychiatry 57, 813816.
94. Geylis V, Kourilov V, Meiner Z, Nennesmo I, Bogdanovic N, Steinitz M (2005) Human monoclonal antibodies against amyloid-beta from healthy adults. Neurobiol Aging 26, 597606.
95. Mruthinti S, Buccafusco JJ, Hill WD, Waller JL, Jackson TW, Zamrini EY, Schade RF (2004) Autoimmunity in Alzheimer's disease: increased levels of circulating IgGs binding Abeta and RAGE peptides. Neurobiol Aging 25, 1023-1032.
96. Szabo P, Relkin N, Weksler ME (2008) Natural human anti-bodies to amyloid beta peptide. Autoimmun Rev 7, 415-420.
97. Relkin NR, Mujalli DM, Shenoy SA, Adamiak B, Weksler ME, Kayed R, Glabe C, Szabo P (2007) IVIg contains antibodies against oligomers and fibrils of beta amyloid. Alzheimers Dement 3, S196.
98. Du Y, Wei X, Dodel R, Sommer N, Hampel H, Gao F, Ma Z, Zhao L, Oertel WH, Farlow M (2003) Human anti-beta-amyloid antibodies block beta-amyloid fibril formation and prevent beta-amyloid-induced neurotoxicity. Brain 126, 1935-1939.
99. Liu R, McAllister C, Lyubchenko Y, Sierks MR (2004) Pro-teolytic antibody light chains alter beta-amyloid aggregation and prevent cytotoxicity. Biochemistry 43, 9999-10007.
100. Paul S, Nishiyama Y, Planque S, Karle S, Taguchi H, Hanson C, Weksler ME (2005) Antibodies as defensive enzymes. Springer Semin Immunopathol 26, 485-503.
101. Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME (2009) 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging 30, 1728-1736.
102. Dodel RC, Du Y, Depboylu C, Hampel H, Frolich L, Haag A, HemmeterU, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nolker C, Moller HJ, Wei X, Farlow M, Sommer N, Oertel WH (2004) Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry 75, 1472-1474.
103. Anthony RM, Wermeling F, Karlsson MC, Ravetch JV (2008) Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci USA 105, 19571-19578.
104. Prada CM, Garcia-Alloza M, Betensky RA, Zhang-Nunes SX, Greenberg SM, Bacskai BJ, Frosch MP (2007) Antibody-mediated clearance of amyloid-beta peptide from cerebral amyloid angiopathy revealed by quantitative in vivo imaging. J Neurosci 27, 1973-1980.