Immunotherapy for alzheimer's disease: Rational basis in ongoing clinical trials

Current Pharmaceutical Design

Volumn 17, Issue 5, 2011, Pages 508-520

  Menéndez González, Manuel ^a,b   Pérez Piñera, Pablo ^a   Martínez Rivera, Marta ^b   Muñiz, Alfonso López ^a   Vega, Jose A ^a  

^a UNIVERSITY OF OVIEDO   (Spain)

^b HOSPITAL ÁLVAREZ BUYLLA   (Spain)

Author keywords

Alzheimer; Amyloid; Clinical trial; Immunotherapy; Vaccine

Indexed keywords

ADJUVANT; ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-42]; ANTIGEN; BAPINEUZUMAB; BIOLOGICAL MARKER; CAD 105; CAD 106; DNA VACCINE; EPITOPE; GANTENERUMAB; IMMUNOGLOBULIN G; PF 04360365; SOLANEZUMAB; UB 311; UNCLASSIFIED DRUG; V 950; VANUTIDE CRIDIFICAR;

ACTIVE IMMUNIZATION; ALZHEIMER DISEASE; AMINO TERMINAL SEQUENCE; ARTICLE; CEREBROSPINAL FLUID; HUMAN; IMMUNE RESPONSE; IMMUNOTHERAPY; INNATE IMMUNITY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; T LYMPHOCYTE; TH1 CELL; VACCINATION;

ALZHEIMER DISEASE; ALZHEIMER VACCINES; AMYLOID BETA-PEPTIDES; ANIMALS; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; HUMANS; IMMUNIZATION, PASSIVE; IMMUNOTHERAPY, ACTIVE; MODELS, IMMUNOLOGICAL;

EID: 79953295579     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161211795164112     Document Type: Article

References (126)

1. Winklhofer KF, Tatzelt J, Haass C. The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. EMBO J 2008; 27: 336-49.
2. Knobloch M, Farinelli M, Konietzko U, Nitsch RM, Mansuy IM. Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms. J Neurosci 2007; 27: 7648-53.
3. Shankar GM, Li S, Mehta TH, et al. Amyloid-beta protein dimmers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008; 14: 837-42.
4. Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 2009; 457: 981-9.
5. Chiba T, Yamada M, Sasabe J, et al. Amyloid-beta causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons. Mol Psychiatry 2009; 14: 206-22.
6. Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci 2000; 924: 17-25.
7. Braak H, Braak E, Bohl J. Staging of Alzheimer-related cortical destruction. Eur Neurol 1993; 33: 403-8.
8. Jellinger KA, Bancher C. AD neuropathology. Neurology 1996; 46: 1186-7.
9. Selkoe DJ. Alzheimer's disease: a central role for amyloid. J Neuropathol Exp Neurol 1994; 53: 438-47.
10. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002; 297: 353-6.
11. Gouras GK, Almeida CG, Takahashi RH. Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease. Neurobiol Aging 2005; 26: 1235-44.
12. Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995; 373: 523-7.
13. Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996; 274: 99-102.
14. Routtenberg A. Measuring memory in a mouse model of Alzheimer's disease. Science 1997; 277: 839-41.
15. Sturchler-Pierrat C, Abramowski D, Duke M, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 1997; 94: 13287-92.
16. Bronfman FC, Moechars D, Van Leuven F. Acetylcholinesterase-positive fiber deafferentation and cell shrinkage in the septohippocampal pathway of aged amyloid precursor protein london mutant transgenic mice. Neurobiol Dis 2000; 7: 152-68.
17. Dewachter I, van Dorpe J, Spittaels K, et al. Modeling Alzheimer's disease in transgenic mice: effect of age and of presenilin1 on amyloid biochemistry and pathology in APP/London mice. Exp Gerontol 2000; 35: 831-41.
18. Kuo YM, Kokjohn TA, Beach TG, et al. Comparative analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer's disease brains. J Biol Chem 2001; 276: 12991-8.
19. Janus C, Pearson J, McLaurin J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 2000; 408: 979-82.
20. Morgan D, Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 2000; 408: 982-5.
21. McGeer PL, McGeer EG. Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging 2001; 22: 799-809.
22. Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000; 21: 383-421.
23. Togo T, Akiyama H, Iseki E, et al. Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J Neuroimmunol 2002; 124: 83-92.
24. McGeer EG, McGeer PL. Innate immunity in Alzheimer's disease: a model for local inflammatory reactions. Mol Interv 2001; 1: 22-9.
25. Rogers J, Cooper NR, Webster S, et al. Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci USA 1992; 89: 10016-20.
26. Hafer-Macko CE, Dyck PJ, Koski CL. Complement activation in acquired and hereditary amyloid neuropathy. J Peripher Nerv Syst 2000; 5: 131-9.
27. Minghetti L. Role of inflammation in neurodegenerative diseases. Curr Opin Neurol 2005; 18: 315-21.
28. Meda L, Baron P, Scarlato G. Glial activation in Alzheimer's disease: the role of Abeta and its associated proteins. Neurobiol Aging 2001; 22: 885-93.
29. Kitazawa M, Yamasaki TR, LaFerla FM. Microglia as a potential bridge between the amyloid beta-peptide and tau. Ann N Y Acad Sci 2004; 1035: 85-103.
30. DeWitt DA, Perry G, Cohen M, Doller C, Silver J. Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease. Exp Neurol 1998; 149: 329-40.
31. Dolev I, Michaelson DM. A nontransgenic mouse model shows inducible amyloid-beta (Abeta) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade. Proc Natl Acad Sci U S A 2004; 101: 13909-14.
32. Aderinwale OG, Ernst HW, Mousa SA. Current therapies and new strategies for the management of Alzheimer's disease. Am J Alzheimers Dis Other Demen 2010; 25: 414-24.
33. Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol 2004; 14: 11-20.
34. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003; 9: 448-52.
35. Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003; 61: 46-54.
36. Neumann H. Control of glial immune function by neurons. Glia 2001; 36: 191-9.
37. Hanisch UK. Microglia as a source and target of cytokines. Glia 2002; 40: 140-55.
38. Yang MS, Park EJ, Sohn S, et al. Interleukin-13 and -4 induce death of activated microglia. Glia 2002; 38: 273-80.
39. Shin WH, Lee DY, Park KW, et al. Microglia expressing interleukin-13 undergo cell death and contribute to neuronal survival in vivo. Glia 2004; 46: 142-52.
40. Monsonego A, Imitola J, Zota V, Oida T, Weiner HL. Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid beta-peptide presentation to Th1 cells. J Immunol 2003; 171: 2216-24.
41. Yamamoto M, Kiyota T, Walsh SM, Liu J, Kipnis J, Ikezu T. Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes. J Immunol 2008; 181: 3877-86.
42. Sigurdsson EM, Knudsen E, Asuni A, et al. An attenuated immune response is sufficient to enhance cognition in an Alzheimer's disease mouse model immunized with amyloid-beta derivatives. J Neurosci 2004; 24: 6277-82.
43. Singh H, Raghava GP. ProPred1: prediction of promiscuous MHC Class-I binding sites. Bioinformatics 2003; 19: 1009-14.
44. Monsonego A, Zota V, Karni A, et al. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest 2003; 112: 415-22.
45. Das P, Chapoval S, Howard V, David CS, Golde TE. Immune responses against Abeta1-42 in HLA class II transgenic mice: implications for Abeta1-42 immune-mediated therapies. Neurobiol Aging 2003; 24: 969-76.
46. Town T, Tan J, Sansone N, Obregon D, Klein T, Mullan M. Characterization of murine immunoglobulin G antibodies against human amyloid-beta1-42. Neurosci Lett 2001; 307: 101-4.
47. Lemere CA, Maron R, Selkoe DJ, Weiner HL. Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer's disease. DNA Cell Biol 2001; 20: 705-11.
48. Lemere CA, Maron R, Spooner ET, et al. Nasal A beta treatment induces anti-A beta antibody production and decreases cerebral amyloid burden in PD-APP mice. Ann N Y Acad Sci 2000; 920: 328-31.
49. Cribbs DH, Ghochikyan A, Vasilevko V, et al. Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. Int Immunol 2003; 15: 505-14.
50. Dickey CA, Morgan DG, Kudchodkar S, et al. Duration and specificity of humoral immune responses in mice vaccinated with the Alzheimer's disease-associated beta-amyloid 1-42 peptide. DNA Cell Biol 2001; 20: 723-9.
51. Miller DL, Currie JR, Mehta PD, et al. Humoral immune response to fibrillar beta-amyloid peptide. Biochemistry 2003; 42: 11682-92.
52. McLaurin J, Cecal R, Kierstead ME, et al. Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis. Nat Med 2002; 8: 1263-9.
53. Solomon B, Koppel R, Hanan E, Katzav T. Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci U S A 1996; 93: 452-5.
54. Mamikonyan G, Necula M, Mkrtichyan M, et al. Anti-A beta 1-11 antibody binds to different beta-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligomers. J Biol Chem 2007; 282: 22376-86.
55. Bard F, Barbour R, Cannon C, et al. 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 2003; 100: 2023-8.
56. Nikolich-Zugich J, Rudd BD. Immune memory and aging: an infinite or finite resource? Curr Opin Immunol 2010; 22: 535-40.
57. Siegrist CA, Aspinall R. B-cell responses to vaccination at the extremes of age. Nat Rev Immunol 2009; 9: 185-94.
58. Panda A, Arjona A, Sapey E, et al. Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 2009; 30: 325-33.
59. Lynch HE, Goldberg GL, Chidgey A, Van den Brink MR, Boyd R, Sempowski GD. Thymic involution and immune reconstitution. Trends Immunol 2009; 30: 366-73.
60. Kohler S, Thiel A. Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. Blood 2009; 113: 769-74.
61. Candore G, Balistreri CR, Colonna-Romano G, et al. Immunosenescence and anti-immunosenescence therapies: the case of probiotics. Rejuvenation Res 2008; 11: 425-32.
62. Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis 2008; 46: 1078-84.
63. Franceschi C, Olivieri F, Marchegiani F, et al. Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians. Mech Ageing Dev 2005; 126: 351-61.
64. Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 2007; 64: 343-9.
65. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004; 55: 306-19.
66. Wisniewski T, Boutajangout A. Vaccination as a therapeutic approach to Alzheimer's disease. Mt Sinai J Med 2010; 77: 17-31.
67. Patton RL, Kalback WM, Esh CL, et al. Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients: a biochemical analysis. Am J Pathol 2006; 169: 1048-63.
68. de Jong D, Jansen RW, Kremer BP, Verbeek MM. Cerebrospinal fluid amyloid beta42/phosphorylated tau ratio discriminates between Alzheimer's disease and vascular dementia. J Gerontol A Biol Sci Med Sci 2006; 61: 755-8.
69. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007; 6: 734-46.
70. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000; 6: 916-9.
71. Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J Neurosci 2003; 23: 8532-8.
72. Lemere CA, Spooner ET, LaFrancois J, et al. Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP mice. Neurobiol Dis 2003; 14: 10-8.
73. Klyubin I, Walsh DM, Lemere CA, et al. Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat Med 2005; 11: 556-61.
74. Yamada K, Yabuki C, Seubert P, et al. Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta. J Neurosci 2009; 29: 11393-8.
75. Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol 2010; 6: 108-19.
76. Wilcock DM, Colton CA. Anti-amyloid-beta immunotherapy in Alzheimer's disease: relevance of transgenic mouse studies to clinical trials. J Alzheimers Dis 2008; 15: 555-69.
77. Agadjanyan MG, Ghochikyan A, Petrushina I, et al. Prototype Alzheimer's disease vaccine using the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J Immunol 2005; 174: 1580-6.
78. Maier M, Seabrook TJ, Lazo ND, et al. 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 2006; 26: 4717-28.
79. Alexander J, Sidney J, Southwood S, et al. Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. Immunity 1994; 1: 751-61.
80. Alexander J, Fikes J, Hoffman S, et al. The optimization of helper T lymphocyte (HTL) function in vaccine development. Immunol Res 1998; 18: 79-92.
81. del Guercio MF, Alexander J, Kubo RT, et al. Potent immunogenic short linear peptide constructs composed of B cell epitopes and Pan DR T helper epitopes (PADRE) for antibody responses in vivo. Vaccine 1997; 15: 441-8.
82. Weber JS, Hua FL, Spears L, Marty V, Kuniyoshi C, Celis E. A phase I trial of an HLA-A1 restricted MAGE-3 epitope peptide with incomplete Freund's adjuvant in patients with resected high-risk melanoma. J Immunother 1999; 22: 431-40.
83. Alexander J, del Guercio MF, Maewal A, et al. Linear PADRE T helper epitope and carbohydrate B cell epitope conjugates induce specific high titer IgG antibody responses. J Immunol 2000; 164: 1625-33.
84. Panina-Bordignon P, Tan A, Termijtelen A, Demotz S, Corradin G, Lanzavecchia A. Universally immunogenic T cell epitopes: promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur J Immunol 1989; 19: 2237-42.
85. Wei WZ, Ratner S, Shibuya T, Yoo G, Jani A. Foreign antigenic peptides delivered to the tumor as targets of cytotoxic T cells. J Immunol Methods 2001; 258: 141-50.
86. Moore A, McCarthy L, Mills KH. The adjuvant combination monophosphoryl lipid A and QS21 switches T cell responses induced with a soluble recombinant HIV protein from Th2 to Th1. Vaccine 1999; 17: 2517-27.
87. Zamora E, Handisurya A, Shafti-Keramat S, et al. Papillomavirus- like particles are an effective platform for amyloid-beta immunization in rabbits and transgenic mice. J Immunol 2006; 177: 2662-70.
88. Chackerian B, Rangel M, Hunter Z, Peabody DS. Virus and virus- like particle-based immunogens for Alzheimer's disease induce antibody responses against amyloid-beta without concomitant T cell responses. Vaccine 2006; 24: 6321-31.
89. Jennings GT, Bachmann MF. The coming of age of virus-like particle vaccines. Biol Chem 2008; 389: 521-36.
90. Donnelly JJ, Liu MA, Ulmer JB. Antigen presentation and DNA vaccines. Am J Respir Crit Care Med 2000; 162: S190-3.
91. Liu MA. Immunologic basis of vaccine vectors. Immunity 2010; 33: 504-15.
92. Becker PD, Noerder M, Guzman CA. Genetic immunization: bacteria as DNA vaccine delivery vehicles. Hum Vaccin 2008; 4: 189-202.
93. Choo AY, Broderick KE, Kim JJ, Sardesai NY. DNA-based influenza vaccines: evaluating their potential to provide universal protection. IDrugs 2010; 13: 707-12.
94. Ingolotti M, Kawalekar O, Shedlock DJ, Muthumani K, Weiner DB. DNA vaccines for targeting bacterial infections. Expert Rev Vaccines 2010; 9: 747-63.
95. Carvalho JA, Rodgers J, Atouguia J, Prazeres DM, Monteiro GA. DNA vaccines: a rational design against parasitic diseases. Expert Rev Vaccines 2010; 9: 175-91.
96. Gardlik R, Fruehauf JH. Bacterial vectors and delivery systems in cancer therapy. IDrugs 2010; 13: 701-6.
97. Barrett AJ, Le Blanc K. Immunotherapy prospects for acute myeloid leukaemia. Clin Exp Immunol 2010; 161: 223-32.
98. van den Berg JH, Oosterhuis K, Beijnen JH, Nuijen B, Haanen JB. DNA vaccination in oncology: current status, opportunities and perspectives. Curr Clin Pharmacol 2010; 5: 218-25.
99. Johnson MC, Wang B, Tisch R. Genetic vaccination for reestablishing T cell tolerance in type 1 diabetes. Hum Vaccin 2011; 7.
100. Fissolo N, Montalban X, Comabella M. DNA-based vaccines for multiple sclerosis: Current status and future directions. Clin Immunol 2010.
101. Stuve O, Cravens PD, Eagar TN. DNA-based vaccines: the future of multiple sclerosis therapy? Expert Rev Neurother 2008; 8: 351-60.
102. Wang YJ, Zhou HD, Zhou XF. Modified Immunotherapies Against Alzheimer's Disease: Toward Safer and Effective Amyloid-beta Clearance. J Alzheimers Dis 2010.
103. Okura Y, Matsumoto Y. Recent advance in immunotherapies for Alzheimer disease: with special reference to DNA vaccination. Hum Vaccin 2009; 5: 373-80.
104. Tang DC, DeVit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature 1992; 356: 152-4.
105. Boyer JD, Ugen KE, Wang B, et al. Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination. Nat Med 1997; 3: 526-32.
106. Petrushina I, Ghochikyan A, Mktrichyan M, et al. Alzheimer's disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Abeta species in amyloid precursor protein transgenic mice. J Neurosci 2007; 27: 12721-31.
107. Bonecchi R, Bianchi G, Bordignon PP, et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 1998; 187: 129-34.
108. Imai T, Nagira M, Takagi S, et al. Selective recruitment of CCR4- bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int Immunol 1999; 11: 81-8.
109. Biragyn A, Belyakov IM, Chow YH, et al. DNA vaccines encoding human immunodeficiency virus-1 glycoprotein 120 fusions with proinflammatory chemoattractants induce systemic and mucosal immune responses. Blood 2002; 100: 1153-9.
110. Zou J, Yao Z, Zhang G, Wang H, Xu J, Yew DT, Forster EL. Vaccination of Alzheimer's model mice with adenovirus vector containing quadrivalent foldable Abeta(1-15) reduces Abeta burden and behavioral impairment without Abeta-specific T cell response. J Neurol Sci 2008; 272: 87-98.
111. Kim HD, Jin JJ, Maxwell JA, Fukuchi K. Enhancing Th2 immune responses against amyloid protein by a DNA prime-adenovirus boost regimen for Alzheimer's disease. Immunol Lett 2007; 112: 30-8.
112. Ghochikyan A. Rationale for peptide and DNA based epitope vaccines for Alzheimer's disease immunotherapy. CNS Neurol Disord Drug Targets 2009; 8: 128-43.
113. Ghochikyan A, Petrushina I, Lees A, et al. Abeta-immunotherapy for Alzheimer's disease using mannan-amyloid-Beta peptide immunoconjugates. DNA Cell Biol 2006; 25: 571-80.
114. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. 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 2001; 98: 8850-5.
115. Levites Y, Das P, Price RW, et al. Anti-Abeta42- and anti-Abeta40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J Clin Invest 2006; 116: 193-201.
116. Dodel R, Neff F, Noelker C, et al. Intravenous immunoglobulins as a treatment for Alzheimer's disease: rationale and current evidence. Drugs 2010; 70: 513-28.
117. Dodart JC, Bales KR, Gannon KS, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci 2002; 5: 452-7.
118. Wilcock DM, Rojiani A, Rosenthal A, et al. Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci 2004; 24: 6144-51.
119. Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Abel T, Lee VM. 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 2006; 281: 4292-9.
120. Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 2004; 43: 321-32.
121. Spires-Jones TL, Mielke ML, Rozkalne A, et al. Passive immunotherapy rapidly increases structural plasticity in a mouse model of Alzheimer disease. Neurobiol Dis 2009; 33: 213-20.
122. Pfeifer M, Boncristiano S, Bondolfi L, et al. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 2002; 298: 1379.
123. Wilcock DM, Rojiani A, Rosenthal A, et al. Passive immuno-therapy 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 2004; 1: 24.
124. Solomon B. Intravenous immunoglobulin and Alzheimer's disease immunotherapy. Curr Opin Mol Ther 2007; 9: 79-85.
125. Magga J, Puli L, Pihlaja R, et al. Human intravenous immunoglobulin provides protection against Abeta toxicity by multiple mechanisms in a mouse model of Alzheimer's disease. J Neuroinflammation 2010; 7: 90.
126. Istrin G, Bosis E, Solomon B. Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-beta peptide. J Neurosci Res 2006; 84: 434-43.