TY - JOUR
T1 - Low concentrations of anti-Aβ antibodies generated in Tg2576 mice by DNA epitope vaccine fused with 3C3d molecular adjuvant do not affect AD pathology
AU - Movsesyan, Nina
AU - Davtyan, Hayk
AU - Mkrtichyan, Mikayel
AU - Petrushina, Irina
AU - Tiraturyan, Tigran
AU - Ross, Ted
AU - Agadjanyan, Michael G.
AU - Ghochikyan, Anahit
AU - Cribbs, David H.
PY - 2010/11/1
Y1 - 2010/11/1
N2 - 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 Aβ1-11 and Th cell epitope, PADRE (p3Aβ1-11-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 H2b haplotype immunized with p3Aβ1-11-PADRE. Here, we tested the efficacy of p3Aβ1-11-PADRE and the same vaccine fused with 3C3d (p3Aβ1-11-PADRE-3C3d) in a transgenic (Tg) mouse model of AD (Tg2576) of the H2bxs 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 3Aβ1-11-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 p3Aβ1-11-PADRE-3C3d vaccine induced significantly higher antibody production in another AD mouse model, 3xTg-AD of the H2b 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.
AB - 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 Aβ1-11 and Th cell epitope, PADRE (p3Aβ1-11-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 H2b haplotype immunized with p3Aβ1-11-PADRE. Here, we tested the efficacy of p3Aβ1-11-PADRE and the same vaccine fused with 3C3d (p3Aβ1-11-PADRE-3C3d) in a transgenic (Tg) mouse model of AD (Tg2576) of the H2bxs 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 3Aβ1-11-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 p3Aβ1-11-PADRE-3C3d vaccine induced significantly higher antibody production in another AD mouse model, 3xTg-AD of the H2b 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.
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U2 - 10.1089/hum.2009.219
DO - 10.1089/hum.2009.219
M3 - Article
C2 - 20528468
AN - SCOPUS:78649380771
SN - 1043-0342
VL - 21
SP - 1569
EP - 1576
JO - Human Gene Therapy
JF - Human Gene Therapy
IS - 11
ER -