Low concentrations of anti-Aβ antibodies generated in Tg2576 mice by DNA epitope vaccine fused with 3C3d molecular adjuvant do not affect AD pathology.
It has been demonstrated that an active vaccination strategy with protein- or DNA-based epitope vaccines composed of the immunodominant self B cell epitope of amyloid-β₄₂ (Aβ₄₂) and a non-self T helper (Th) cell epitope is an immunotherapeutic approach to preventing or treating Alzheimer's disease (AD). As a DNA-based epitope vaccine, we used a plasmid encoding three copies of Aβ(1-11) and Th cell epitope, PADRE (p3Aβ(1-11)-PADRE). We have previously reported that three copies of component of complement C3d (3C3d) acts as a molecular adjuvant significantly enhancing immune responses in wild-type mice of the H2(b) haplotype immunized with p3Aβ(1-11)-PADRE. Here, we tested the efficacy of p3Aβ(1-11)-PADRE and the same vaccine fused with 3C3d (p3Aβ(1-11)-PADRE-3C3d) in a transgenic (Tg) mouse model of AD (Tg2576) of the H2(bxs) immune haplotype. The overall responses to both vaccines were very weak in Tg2576 mice despite the fact that the 3C3d molecular adjuvant significantly enhanced the anti-Aβ response to 3Aβ(1-11)-PADRE. Importantly, generation of low antibody responses was associated with the strain of amyloid precursor protein Tg mice rather than with a molecular adjuvant, as a p3Aβ(1-11)-PADRE-3C3d vaccine induced significantly higher antibody production in another AD mouse model, 3xTg-AD of the H2(b) haplotype. Finally, this study demonstrated that low concentrations of antibodies generated by both DNA vaccines were not sufficient for the reduction of Aβ pathology in the brains of vaccinated Tg2576 animals, confirming previous reports from preclinical studies and the AN-1792 clinical trials, which concluded that the concentration of anti-Aβ antibodies may be essential for the reduction of AD pathology.
Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA 92647, USA.
Nina
N
Movsesyan
Hayk
H
Davtyan
Mikayel
M
Mkrtichyan
Irina
I
Petrushina
Tigran
T
Tiraturyan
Ted
T
Ross
Michael G
MG
Agadjanyan
Anahit
A
Ghochikyan
David H
DH
Cribbs
D000276:Adjuvants, Immunologic; D000544:Alzheimer Disease / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy; D023582:Alzheimer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D015933:Complement C3d / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D019444:Vaccines, DNA; C115195:amyloid beta-protein (1-11); D015933:Complement C3d