Abstract
Active immunotherapy for Alzheimer’s disease (AD) is aimed to induce antibodies specific to amyloid-beta (Aβ) that are capable to reduce the level of Aβ in the CNS of Alzheimer’s disease patients. First clinical trial AN-1792 that was based on vaccination with full-length Aβ42 showed that safe and effective AD vaccine should induce high titers of anti-Aβ antibodies without activation of harmful autoreactive T cells. Replacement of self-T cell epitope with foreign epitope, keeping self-B cell epitope intact, may allow to induce high titers of anti-Aβ antibodies while avoiding the activation of T cells specific to Aβ.
Here we describe the protocols for evaluation of AD DNA- or multiple antigenic peptide (MAP)-based epitope vaccines composed of Aβ1–11 B cell epitope fused to synthetic T cell epitope PADRE (Aβ1–11-PADRE). All protocols could be used for testing any epitope vaccine constructed in your lab and composed of other T cell epitopes using the appropriate peptides in tests for evaluation of humoral and cellular immune responses.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Price DL, Sisodia SS (1994) Cellular and molecular biology of Alzheimer's disease and animal models. Annu Rev Med 45:435–446
Selkoe DJ (1991) The molecular pathology of Alzheimer's disease. Neuron 6:487–498
Hardy JA, Higgins GA (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256:184–185
Schenk DJ, Barbour R, Dunn W et al (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177
Morgan D, Diamond DM, Gottschall PE et al (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408:982–985
Bard F, Cannon C, Barbour R (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
DeMattos RB, Bales KR, Cummins DJ (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 98:8850–8855
Dodart JC, Bales KR, Gannon KS et al (2002) Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci 5:452–457
Nicoll JA, Wilkinson D, Holmes C et al (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–452
Ferrer I, Rovira MB, Guerra MLS et al (2004) Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol 14:11–20
Masliah E, Hansen L, Adame A et al (2005) Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64:129–131
Nicoll JA, Barton E, Boche D et al (2006) Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol 65:1040–1048
Patton RL, Kalback WM, Esh CL (2006) Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients: a biochemical analysis. Am J Pathol 169:1048–1063
Holmes C, Boche D, Wilkinson D et al (2008) Long-term effects of Abeta42 immunization in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372: 216–223
Gilman S, Koller M, Black RS et al (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64:1553–1562
Bayer AJ, Bullock R, Jones RW et al (2005) Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 64:94–101
Cribbs DH, Ghochikyan A, Tran M et al (2003) Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. Int Immunol 15:505–514
Bard F, Barbour R, Cannon C et al (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 100:2023–2028
Lee M, Bard F, Johnson-Wood K (2005) Abeta42 immunization in Alzheimer's disease generates Abeta N-terminal antibodies. Ann Neurol 58:430–435
McLaurin J, Cecal R, Kierstead ME et al (2002) Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nat Med 8:1263–1269
Town T, Tan J, Sansone N et al (2001) Characterization of murine immunoglobulin G antibodies against human amyloid-b 1–42. Neurosci Lett 307:101–104
Dickey CA, Morgan DG, Kudchodkar S et al (2001) Duration and specificity of humoral immune responses in mice vaccinated with the Alzheimer's disease-associated beta-amyloid 1–42 peptide. DNA Cell Biol 20(11):723–729
Lemere CA, Maron R, Selkoe DJ et al (2001) Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer's disease. DNA Cell Biol 20:705–711
Lemere CA, Maron R, Spooner ET et al (2000) Nasal Aß treatment induces anti-Aß antibody production and decreases cerebral amyloid burden in PD-APP mice. Ann N Y Acad Sci 920:328–331
Monsonego A, Zota V, Karni A (2003) Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest 112(3):415–422
Sigurdsson EM, Knudsen E, Asuni A et al (2004) An attenuated immune response is sufficient to enhance cognition in an Alzheimer's disease mouse model immunized with amyloid-beta derivatives. J Neurosci 24:6277–6282
Singh H, Raghava GP (2001) ProPred: prediction of HLA-DR binding sites. Bioinformatics 17:1236–1237
Singh H, Raghava GP (2003) ProPred1: prediction of promiscuous MHC Class-I binding sites. Bioinformatics 19:1009–1014
Das P, Chapoval S, Howard V et al (2003) Immune responses against Abeta1-42 in HLA class II transgenic mice: implications for Abeta1-42 immune-mediated therapies. Neurobiol Aging 24:969–996
Petrushina I, Ghochikyan A, Mktrichyan M et al (2007) Alzheimer's disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric A{beta} species in amyloid precursor protein transgenic mice. J Neurosci 27:12721–12731
Movsesyan N, Ghochikyan A, Mkrtichyan M et al (2008) Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine- a novel immunotherapeutic strategy. PLos One 3:e21
Ghochikyan A, Davtyan H, Petrushina I et al (2013) Refinement of a DNA based Alzheimer's disease epitope vaccine in rabbits. Hum Vaccin Immunother 9:1002–1010
Davtyan H, Ghochikyan A, Petrushina I et al (2013) Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial. J Neurosci 33:4923–4934
Evans CF, Davtyan H, Petrushina I et al (2013) Epitope-based DNA vaccine for Alzheimer's disease: translational study in macaques. Alzheimer’s Dement. [Epub ahead of print]
Alexander J, del Guercio MF, Maewal A (2000) Linear PADRE T helper epitope and carbohydrate B cell epitope conjugates induce specific high titer IgG antibody responses. J Immunol 164:1625–1633
Ghochikyan A (2009) Rationale for peptide and DNA based epitope vaccines for Alzheimer's disease immunotherapy. CNS Neurol Disord Drug Targets 8:128–143
Babiuk LA, Pontarollo R, Babiuk S et al (2003) Induction of immune responses by DNA vaccines in large animals. Vaccine 21:649–658
Gregersen JP (2001) DNA vaccines. Naturwissenschaften 88:504–513
Cribbs DH, Agadjanyan MG (2005) Immunotherapy for Alzheimer's disease: potential problems and possible solutions. Curr Immunol Rev 1:139–155
Acknowledgments
This work was supported by NIH grants AG20241, NS50895, NS057395, and NS065518 and from the Alzheimer’s Association IIRG12239626.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Davtyan, H., Petrushina, I., Ghochikyan, A. (2014). Immunotherapy for Alzheimer’s Disease: DNA- and Protein-Based Epitope Vaccines. In: Rinaldi, M., Fioretti, D., Iurescia, S. (eds) DNA Vaccines. Methods in Molecular Biology, vol 1143. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0410-5_16
Download citation
DOI: https://doi.org/10.1007/978-1-4939-0410-5_16
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-0409-9
Online ISBN: 978-1-4939-0410-5
eBook Packages: Springer Protocols