Advertisement

Immunotherapeutic Approaches Against Amyloid-β in Drug Discovery for Alzheimer’s Disease

  • Seung-Hoon Yang
  • Jiyoon Kim
  • YoungSoo KimEmail author

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia. The major pathological hallmark and culprit of AD is aggregation of the amyloid-β (Aβ) peptide. Since the Aβ abnormality begins in the asymptomatic stage of AD, immunotherapeutic approaches clearing Aβ aggregates are investigated as the most promising treatment in clinical trials. Both active and passive immunization against Aβ showed significant reduction of Aβ levels in the brain and enhancement of learning and memory. Albeit pathologically effective, these immunotherapeutic vaccines need to overcome side effects such as vasogenic edema and microhemorrhages. In this chapter, we introduce the basic concept of immunotherapy for clearance of Aβ, compare putative immunotherapeutic vaccine candidates, and discuss their benefits, disadvantages, and challenges.

Keywords

Alzheimer’s disease Amyloid-β Active immunotherapy Passive immunotherapy Vaccination 

References

  1. Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, Lohmann S, Piorkowska K, Gafner V, Atwal JK, Maloney J, Chen M, Gogineni A, Weimer RM, Mortensen DL, Friesenhahn M, Ho C, Paul R, Pfeifer A, Muhs A, Watts RJ (2012) An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci 32(28):9677–9689PubMedCrossRefGoogle Scholar
  2. Aisen PS, Vellas B (2013) Passive immunotherapy for Alzheimer’s disease: what have we learned, and where are we headed? J Nutr Health Aging 17(1):49–50PubMedCrossRefGoogle Scholar
  3. Alves RP, Yang MJ, Batista MT, Ferreira LC (2014) Alzheimer’s disease: is a vaccine possible? Braz J Med Biol Res 47(6):438–444PubMedCentralPubMedCrossRefGoogle Scholar
  4. Alzheimer’s A (2012) Alzheimer’s disease facts and figures. Alzheimers Dement 8(2):131–168CrossRefGoogle Scholar
  5. Araki S (2010) Current status of Alzheimer’s disease immunotherapy and pharmacologic effect of BAN2401. Nihon Yakurigaku Zasshi 136(1):21–25PubMedCrossRefGoogle Scholar
  6. Backman L, Jones S, Berger AK, Laukka EJ, Small BJ (2004) Multiple cognitive deficits during the transition to Alzheimer’s disease. J Intern Med 256(3):195–204PubMedCrossRefGoogle Scholar
  7. Bacskai BJ, Kajdasz ST, Christie RH, Carter C, Games D, Seubert P, Schenk D, Hyman BT (2001) Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med 7(3):369–372PubMedCrossRefGoogle Scholar
  8. Banks WA, Terrell B, Farr SA, Robinson SM, Nonaka N, Morley JE (2002) Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer’s disease. Peptides 23(12):2223–2226PubMedCrossRefGoogle Scholar
  9. Bard 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 (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(8):916–919PubMedCrossRefGoogle Scholar
  10. 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 disease-like neuropathology. Proc Natl Acad Sci U S A 100(4):2023–2028PubMedCentralPubMedCrossRefGoogle Scholar
  11. Barten DM, Meredith JE Jr, Zaczek R, Houston JG, Albright CF (2006) Gamma-secretase inhibitors for Alzheimer’s disease: balancing efficacy and toxicity. Drugs R D 7(2):87–97PubMedCrossRefGoogle Scholar
  12. Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, Millais SB, Donoghue S (2005) Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 64(1):94–101PubMedCrossRefGoogle Scholar
  13. Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, Grundman M, Liu E, A. A. B. Investigators (2012) Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 69(8):1002–1010PubMedCrossRefGoogle Scholar
  14. Boado RJ, Lu JZ, Hui EK, Sumbria RK, Pardridge WM (2013) Pharmacokinetics and brain uptake in the rhesus monkey of a fusion protein of arylsulfatase a and a monoclonal antibody against the human insulin receptor. Biotechnol Bioeng 110(5):1456–1465PubMedCentralPubMedCrossRefGoogle Scholar
  15. Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, Rauchenberger R, Richter WF, Rothe C, Urban M, Bardroff M, Winter M, Nordstedt C, Loetscher H (2012) Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J Alzheimers Dis 28(1):49–69PubMedGoogle Scholar
  16. Brody DL, Holtzman DM (2008) Active and passive immunotherapy for neurodegenerative disorders. Annu Rev Neurosci 31:175–193PubMedCentralPubMedCrossRefGoogle Scholar
  17. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 3(3):186–191PubMedCrossRefGoogle Scholar
  18. Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S, Daeron M (2009) Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood 113(16):3716–3725PubMedCrossRefGoogle Scholar
  19. Cai Z, Hussain MD, Yan LJ (2014) Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int J Neurosci 124(5):307–321PubMedCrossRefGoogle Scholar
  20. Chang KA, Suh YH (2010) Possible roles of amyloid intracellular domain of amyloid precursor protein. BMB Rep 43(10):656–663PubMedCrossRefGoogle Scholar
  21. Das P, Murphy MP, Younkin LH, Younkin SG, Golde TE (2001) Reduced effectiveness of Abeta1-42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiol Aging 22(5):721–727PubMedCrossRefGoogle Scholar
  22. De Strooper B, Vassar R, Golde T (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6(2):99–107PubMedCentralPubMedCrossRefGoogle Scholar
  23. Deane R, Yan SD, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9(7):907–913PubMedCrossRefGoogle Scholar
  24. Deane R, Sagare A, Hamm K, Parisi M, LaRue B, Guo H, Wu Z, Holtzman DM, Zlokovic BV (2005) IgG-assisted age-dependent clearance of Alzheimer’s amyloid beta peptide by the blood-brain barrier neonatal Fc receptor. J Neurosci 25(50):11495–11503PubMedCrossRefGoogle Scholar
  25. Delrieu J, Ousset PJ, Caillaud C, Vellas B (2012a) ‘Clinical trials in Alzheimer’s disease’: immunotherapy approaches. J Neurochem 120(Suppl 1):186–193PubMedCrossRefGoogle Scholar
  26. Delrieu J, Ousset PJ, Vellas B (2012b) Gantenerumab for the treatment of Alzheimer’s disease. Expert Opin Biol Ther 12(8):1077–1086PubMedCrossRefGoogle Scholar
  27. 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 U S A 98(15):8850–8855PubMedCentralPubMedCrossRefGoogle Scholar
  28. 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(5):452–457PubMedGoogle Scholar
  29. Dodel R, Hampel H, Depboylu C, Lin S, Gao F, Schock S, Jackel S, Wei X, Buerger K, Hoft C, Hemmer B, Moller HJ, Farlow M, Oertel WH, Sommer N, Du Y (2002) Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer’s disease. Ann Neurol 52(2):253–256PubMedCrossRefGoogle Scholar
  30. Dodel RC, Du Y, Depboylu C, Hampel H, Frolich L, Haag A, Hemmeter U, 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(10):1472–1474PubMedCentralPubMedCrossRefGoogle Scholar
  31. Doody RS, Farlow M, Aisen PS, A. Alzheimer’s Disease Cooperative Study Data, C. Publication (2014a) Phase 3 trials of solanezumab and bapineuzumab for Alzheimer’s disease. N Engl J Med 370(15):1460PubMedGoogle Scholar
  32. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R, C. Alzheimer’s Disease Cooperative Study Steering, G. Solanezumab Study (2014b) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4):311–321PubMedCrossRefGoogle Scholar
  33. Doraiswamy PM, Xiong GL (2006) Pharmacological strategies for the prevention of Alzheimer’s disease. Expert Opin Pharmacother 7(1):1–10PubMedCrossRefGoogle Scholar
  34. Duran-Aniotz C, Morales R, Moreno-Gonzalez I, Hu PP, Soto C (2013) Brains from non-Alzheimer’s individuals containing amyloid deposits accelerate Abeta deposition in vivo. Acta Neuropathol Commun 1(1):76PubMedCentralPubMedCrossRefGoogle Scholar
  35. Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Aspects Med 29(5):258–289PubMedCrossRefGoogle Scholar
  36. Englund H, Sehlin D, Johansson AS, Nilsson LN, Gellerfors P, Paulie S, Lannfelt L, Pettersson FE (2007) Sensitive ELISA detection of amyloid-beta protofibrils in biological samples. J Neurochem 103(1):334–345PubMedGoogle Scholar
  37. Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, Friedrich S, Dean RA, Gonzales C, Sethuraman G, DeMattos RB, Mohs R, Paul SM, Siemers ER (2012) Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement 8(4):261–271PubMedCrossRefGoogle Scholar
  38. 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(1):11–20PubMedCrossRefGoogle Scholar
  39. Fillit H, Hess G, Hill J, Bonnet P, Toso C (2009) IV immunoglobulin is associated with a reduced risk of Alzheimer disease and related disorders. Neurology 73(3):180–185PubMedCrossRefGoogle Scholar
  40. Freeman GB, Lin JC, Pons J, Raha NM (2012) 39-week toxicity and toxicokinetic study of ponezumab (PF-04360365) in cynomolgus monkeys with 12-week recovery period. J Alzheimers Dis 28(3):531–541PubMedGoogle Scholar
  41. Frenkel D, Katz O, Solomon B (2000) Immunization against Alzheimer’s beta -amyloid plaques via EFRH phage administration. Proc Natl Acad Sci U S A 97(21):11455–11459PubMedCentralPubMedCrossRefGoogle Scholar
  42. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM, Team ANS (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64(9):1553–1562PubMedCrossRefGoogle Scholar
  43. Golde TE, Koo EH, Felsenstein KM, Osborne BA, Miele L (2013) Gamma-secretase inhibitors and modulators. Biochim Biophys Acta 1828(12):2898–2907PubMedCrossRefGoogle Scholar
  44. Gowing E, Roher AE, Woods AS, Cotter RJ, Chaney M, Little SP, Ball MJ (1994) Chemical characterization of A beta 17-42 peptide, a component of diffuse amyloid deposits of Alzheimer disease. J Biol Chem 269(15):10987–10990PubMedGoogle Scholar
  45. Guan X, Zou J, Gu H, Yao Z (2012) Short amyloid-beta immunogens with spacer-enhanced immunogenicity without junctional epitopes for Alzheimer’s disease immunotherapy. Neuroreport 23(15):879–884PubMedCrossRefGoogle Scholar
  46. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185PubMedCrossRefGoogle Scholar
  47. Jellinger KA (2006) Challenges in neuronal apoptosis. Curr Alzheimer Res 3(4):377–391PubMedCrossRefGoogle Scholar
  48. Jia Q, Deng Y, Qing H (2014) Potential therapeutic strategies for Alzheimer’s disease targeting or beyond beta-amyloid: insights from clinical trials. Biomed Res Int 2014:837157PubMedCentralPubMedGoogle Scholar
  49. Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ (2011) Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A 108(14):5819–5824PubMedCentralPubMedCrossRefGoogle Scholar
  50. Kakimura J, Kitamura Y, Takata K, Umeki M, Suzuki S, Shibagaki K, Taniguchi T, Nomura Y, Gebicke-Haerter PJ, Smith MA, Perry G, Shimohama S (2002) Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. FASEB J 16(6):601–603PubMedGoogle Scholar
  51. Khorassani F, Hilas O (2013) Bapineuzumab, an investigational agent for Alzheimer’s disease. P T 38(2):89–91PubMedCentralPubMedGoogle Scholar
  52. Kingwell K (2012) Alzheimer disease: amyloid-beta immunotherapy CAD106 passes first safety test in patients with Alzheimer disease. Nat Rev Neurol 8(8):414PubMedGoogle Scholar
  53. Kirkitadze MD, Condron MM, Teplow DB (2001) Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. J Mol Biol 312(5):1103–1119PubMedCrossRefGoogle Scholar
  54. Landen JW, Zhao Q, Cohen S, Borrie M, Woodward M, Billing CB Jr, Bales K, Alvey C, McCush F, Yang J, Kupiec JW, Bednar MM (2013) Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clin Neuropharmacol 36(1):14–23PubMedCrossRefGoogle Scholar
  55. Lannfelt L, Moller C, Basun H, Osswald G, Sehlin D, Satlin A, Logovinsky V, Gellerfors P (2014a) Perspectives on future Alzheimer therapies: amyloid-beta protofibrils – a new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res Ther 6(2):16PubMedCentralPubMedCrossRefGoogle Scholar
  56. Lannfelt L, Relkin NR, Siemers ER (2014b) Amyloid-ss-directed immunotherapy for Alzheimer’s disease. J Intern Med 275(3):284–295PubMedCentralPubMedCrossRefGoogle Scholar
  57. Lansbury PT Jr (1997) Structural neurology: are seeds at the root of neuronal degeneration? Neuron 19(6):1151–1154PubMedCrossRefGoogle Scholar
  58. Legleiter J, Czilli DL, Gitter B, DeMattos RB, Holtzman DM, Kowalewski T (2004) Effect of different anti-Abeta antibodies on Abeta fibrillogenesis as assessed by atomic force microscopy. J Mol Biol 335(4):997–1006PubMedCrossRefGoogle Scholar
  59. Lemere CA (2013) Immunotherapy for Alzheimer’s disease: hoops and hurdles. Mol Neurodegener 8:36PubMedCentralPubMedCrossRefGoogle Scholar
  60. Lemere CA, Masliah E (2010) Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol 6(2):108–119PubMedCentralPubMedCrossRefGoogle Scholar
  61. Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Desai R, Hancock WW, Weiner HL, Selkoe DJ (2000) Nasal A beta treatment induces anti-A beta antibody production and decreases cerebral amyloid burden in PD-APP mice. Ann N Y Acad Sci 920:328–331PubMedCrossRefGoogle Scholar
  62. Leuner K, Muller WE, Reichert AS (2012) From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer’s disease. Mol Neurobiol 46(1):186–193PubMedCrossRefGoogle Scholar
  63. Levy JB, Pusey CD (2000) Nephrotoxicity of intravenous immunoglobulin. QJM 93(11):751–755PubMedCrossRefGoogle Scholar
  64. Lleo A, Greenberg SM, Growdon JH (2006) Current pharmacotherapy for Alzheimer’s disease. Annu Rev Med 57:513–533PubMedCrossRefGoogle Scholar
  65. Lobello K, Ryan JM, Liu E, Rippon G, Black R (2012) Targeting Beta amyloid: a clinical review of immunotherapeutic approaches in Alzheimer’s disease. Int J Alzheimers Dis 2012:628070PubMedCentralPubMedGoogle Scholar
  66. Loeffler DA (2013) Intravenous immunoglobulin and Alzheimer’s disease: what now? J Neuroinflammation 10(1):70PubMedCentralPubMedCrossRefGoogle Scholar
  67. Lord A, Gumucio A, Englund H, Sehlin D, Sundquist VS, Soderberg L, Moller C, Gellerfors P, Lannfelt L, Pettersson FE, Nilsson LN (2009) An amyloid-beta protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer’s disease. Neurobiol Dis 36(3):425–434PubMedCrossRefGoogle Scholar
  68. Madeo J, Frieri M (2013) Alzheimer’s disease and immunotherapy. Aging Dis 4(4):210–220PubMedCentralPubMedGoogle Scholar
  69. Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C, Lemere CA (2006) Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer’s disease mouse model in the absence of an Abeta-specific cellular immune response. J Neurosci 26(18):4717–4728PubMedCrossRefGoogle Scholar
  70. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M (2010) Alzheimer’s disease: clinical trials and drug development. Lancet Neurol 9(7):702–716PubMedCrossRefGoogle Scholar
  71. 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(1):129–131PubMedCrossRefGoogle Scholar
  72. Mayeux R, Schupf N (2011) Blood-based biomarkers for Alzheimer’s disease: plasma Abeta40 and Abeta42, and genetic variants. Neurobiol Aging 32(Suppl 1):S10–S19PubMedCentralPubMedCrossRefGoogle Scholar
  73. McElhaney JE, Effros RB (2009) Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 21(4):418–424PubMedCentralPubMedCrossRefGoogle Scholar
  74. Menendez-Gonzalez M, Perez-Pinera P, Martinez-Rivera M, Muniz AL, Vega JA (2011) Immunotherapy for Alzheimer’s disease: rational basis in ongoing clinical trials. Curr Pharm Des 17(5):508–520PubMedCrossRefGoogle Scholar
  75. Michaelis ML (2003) Drugs targeting Alzheimer’s disease: some things old and some things new. J Pharmacol Exp Ther 304(3):897–904PubMedCrossRefGoogle Scholar
  76. Moreth J, Mavoungou C, Schindowski K (2013) Passive anti-amyloid immunotherapy in Alzheimer’s disease: what are the most promising targets? Immun Ageing 10(1):18PubMedCentralPubMedCrossRefGoogle Scholar
  77. Muhs A, Hickman DT, Pihlgren M, Chuard N, Giriens V, Meerschman C, van der Auwera I, van Leuven F, Sugawara M, Weingertner MC, Bechinger B, Greferath R, Kolonko N, Nagel-Steger L, Riesner D, Brady RO, Pfeifer A, Nicolau C (2007) Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci U S A 104(23):9810–9815PubMedCentralPubMedCrossRefGoogle Scholar
  78. 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(4):448–452PubMedCrossRefGoogle Scholar
  79. Novakovic D, Feligioni M, Scaccianoce S, Caruso A, Piccinin S, Schepisi C, Errico F, Mercuri NB, Nicoletti F, Nistico R (2013) Profile of gantenerumab and its potential in the treatment of Alzheimer’s disease. Drug Des Devel Ther 7:1359–1364PubMedCentralPubMedGoogle Scholar
  80. O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34:185–204PubMedCentralPubMedCrossRefGoogle Scholar
  81. Okura Y, Matsumoto Y (2009) Recent advance in immunotherapies for Alzheimer disease: with special reference to DNA vaccination. Hum Vaccin 5(6):373–380PubMedCrossRefGoogle Scholar
  82. 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 meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61(1):46–54PubMedCrossRefGoogle Scholar
  83. Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo K, Xu ZX, Loetscher H, Santarelli L (2012) Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 69(2):198–207PubMedCrossRefGoogle Scholar
  84. Panza F, Frisardi V, Imbimbo BP, D’Onofrio G, Pietrarossa G, Seripa D, Pilotto A, Solfrizzi V (2010) Bapineuzumab: anti-beta-amyloid monoclonal antibodies for the treatment of Alzheimer’s disease. Immunotherapy 2(6):767–782PubMedCrossRefGoogle Scholar
  85. 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(5597):1379PubMedCrossRefGoogle Scholar
  86. Pietri M, Dakowski C, Hannaoui S, Alleaume-Butaux A, Hernandez-Rapp J, Ragagnin A, Mouillet-Richard S, Haik S, Bailly Y, Peyrin JM, Launay JM, Kellermann O, Schneider B (2013) PDK1 decreases TACE-mediated alpha-secretase activity and promotes disease progression in prion and Alzheimer’s diseases. Nat Med 19(9):1124–1131PubMedCrossRefGoogle Scholar
  87. Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S (2009) Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A 106(14):5907–5912PubMedCentralPubMedCrossRefGoogle Scholar
  88. Poduslo JF, Gilles EJ, Ramakrishnan M, Howell KG, Wengenack TM, Curran GL, Kandimalla KK (2010) HH domain of Alzheimer’s disease Abeta provides structural basis for neuronal binding in PC12 and mouse cortical/hippocampal neurons. PLoS One 5(1):e8813PubMedCentralPubMedCrossRefGoogle Scholar
  89. Pohanka M (2011) Cholinesterases, a target of pharmacology and toxicology. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 155(3):219–229PubMedCrossRefGoogle Scholar
  90. Prins ND, Scheltens P (2013) Treating Alzheimer’s disease with monoclonal antibodies: current status and outlook for the future. Alzheimers Res Ther 5(6):56PubMedCentralPubMedCrossRefGoogle Scholar
  91. 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(3):629–636PubMedCrossRefGoogle Scholar
  92. 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(11):1728–1736PubMedCrossRefGoogle Scholar
  93. Robinson SR, Bishop GM, Lee HG, Munch G (2004) Lessons from the AN 1792 Alzheimer vaccine: lest we forget. Neurobiol Aging 25(5):609–615PubMedCrossRefGoogle Scholar
  94. Ryan JM, Grundman M (2009) Anti-amyloid-beta immunotherapy in Alzheimer’s disease: ACC-001 clinical trials are ongoing. J Alzheimers Dis 17(2):243PubMedGoogle Scholar
  95. Savage JM, Wu G, McCampbell A, Wessner RK, Citron M, Liang X, Hsieh S, Kinney G, Wolfe AL, Rosen BL, Renger JJ (2010) A novel multivalent Aβ peptide vaccine with preclinical evidence of a central immune response that generates antisera recognizing a wide range of abeta peptide species [abstract]. Alzheimers Dement 6:S142CrossRefGoogle Scholar
  96. 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(6740):173–177PubMedCrossRefGoogle Scholar
  97. Schneeberger A, Mandler M, Otawa O, Zauner W, Mattner F, Schmidt W (2009) Development of AFFITOPE vaccines for Alzheimer’s disease (AD) – from concept to clinical testing. J Nutr Health Aging 13(3):264–267PubMedCrossRefGoogle Scholar
  98. Sehlin D, Englund H, Simu B, Karlsson M, Ingelsson M, Nikolajeff F, Lannfelt L, Pettersson FE (2012) Large aggregates are the major soluble Abeta species in AD brain fractionated with density gradient ultracentrifugation. PLoS One 7(2), e32014PubMedCentralPubMedCrossRefGoogle Scholar
  99. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766PubMedGoogle Scholar
  100. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27(11):2866–2875PubMedCrossRefGoogle Scholar
  101. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B et al (1992) Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258(5079):126–129PubMedCrossRefGoogle Scholar
  102. Siemers ER, Friedrich S, Dean RA, Gonzales CR, Farlow MR, Paul SM, Demattos RB (2010) Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol 33(2):67–73PubMedCrossRefGoogle Scholar
  103. Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T (2001) Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am J Pathol 159(2):439–447PubMedCentralPubMedCrossRefGoogle Scholar
  104. 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(1):452–455PubMedCentralPubMedCrossRefGoogle Scholar
  105. Solomon B, Koppel R, Frankel D, Hanan-Aharon E (1997) Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci U S A 94(8):4109–4112PubMedCentralPubMedCrossRefGoogle Scholar
  106. Spencer B, Masliah E (2014) Immunotherapy for Alzheimer’s disease: past, present and future. Front Aging Neurosci 6:114PubMedCentralPubMedCrossRefGoogle Scholar
  107. Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M (2012) Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol 11(3):241–249PubMedCentralPubMedCrossRefGoogle Scholar
  108. Takano K, Endo S, Mukaiyama A, Chon H, Matsumura H, Koga Y, Kanaya S (2006) Structure of amyloid beta fragments in aqueous environments. FEBS J 273(1):150–158PubMedCrossRefGoogle Scholar
  109. Tucker S, Moller C, Tegerstedt K, Lord A, Laudon H, Sjodahl J, Soderberg L, Spens E, Sahlin C, Waara ER, Satlin A, Gellerfors P, Osswald G, Lannfelt L (2015) The murine version of BAN2401 (mAb158) selectively reduces amyloid-beta protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis 43(2):575–588PubMedGoogle Scholar
  110. van der Zee JS, van Swieten P, Aalberse RC (1986) Inhibition of complement activation by IgG4 antibodies. Clin Exp Immunol 64(2):415–422PubMedCentralPubMedGoogle Scholar
  111. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416(6880):535–539PubMedCrossRefGoogle Scholar
  112. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe DJ (2000) Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol 48(4):567–579PubMedCrossRefGoogle Scholar
  113. Wiessner C, Wiederhold KH, Tissot AC, Frey P, Danner S, Jacobson LH, Jennings GT, Luond R, Ortmann R, Reichwald J, Zurini M, Mir A, Bachmann MF, Staufenbiel M (2011) The second-generation active Abeta immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J Neurosci 31(25):9323–9331PubMedCrossRefGoogle Scholar
  114. 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(1):11–20PubMedCrossRefGoogle Scholar
  115. Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, Blennow K, Lundmark J, Staufenbiel M, Orgogozo JM, Graf A (2012) Safety, tolerability, and antibody response of active Abeta immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 11(7):597–604PubMedCrossRefGoogle Scholar
  116. Winblad B, Graf A, Riviere ME, Andreasen N, Ryan JM (2014) Active immunotherapy options for Alzheimer’s disease. Alzheimers Res Ther 6(1):7PubMedCentralPubMedCrossRefGoogle Scholar
  117. Wolfe MS (2006) Shutting down Alzheimer’s. Sci Am 294(5):72–79PubMedCrossRefGoogle Scholar
  118. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12(9):1005–1015PubMedGoogle Scholar
  119. Zhang H, Ma Q, Zhang YW, Xu H (2012) Proteolytic processing of Alzheimer’s beta-amyloid precursor protein. J Neurochem 120(Suppl 1):9–21PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  1. 1.Center for Neuro-MedicineBrain Science Institute, Korea Institute of Science and TechnologySeoulRepublic of Korea
  2. 2.Biological Chemistry ProgramKorea University of Science and TechnologyDaejeonRepublic of Korea

Personalised recommendations