title: Strikingly reduced amyloid burden and improved behavioral performance in Alzheimer's disease mice immunized with recombinant chimeric vaccines by hexavalent foldable Aβ₁₋₁₅ fused to toxin-derived carrier proteins.
abstract: Targeting on the amyloid-β (Aβ) is a promising immunotherapeutic strategy for Alzheimer's disease (AD). However, Aβ(1-15) sequence alone induces low antibody response and poor protection against AD. We describe here the immunological characterization and protective efficacy of several recombinant chimeric vaccines with hexavalent foldable Aβ(1-15) (6Aβ15) fused to PADRE or toxin-derived carrier proteins. Immunization with these chimeric antigens generated robust Th2 immune responses with high anti-Aβ42 antibody titers in different mice, which recognized neurotoxic Aβ42 oligomers, but did not stimulate Aβ42-specific T cell responses. These 6Aβ15 chimeric vaccines markedly reduced Aβ pathology and prevented development of behavioral deficits in immunized older AD mice. Importantly, toxin-derived carrier proteins as molecular adjuvants of chimeric vaccines could substantially boost immune responses and overcome Aβ- and old age-associated hypo-responsiveness, and elicit long-term Aβ-specific antibody response, which in turn inhibited Aβ-mediated pathology and improved acquisition and retention of spatial memory in immunized AD mice. These data indicate that toxin fragments as molecular adjuvants are promising new tools for the rational design and development of prototype chimeric vaccines for AD and this type of chimeric vaccine design has the added advantage of overcoming hypo-responsiveness in elderly AD patients with pre-existing memory Th cells from tetanus toxin.
authors.affiliation: Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Yun-Zhou
authors.initials: YZ
authors.lastname: Yu
authors.affiliation: Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Wang
authors.affiliation: Beijing Institute of Biotechnology, Beijing, China Pharmaceutical College, Henan University, Kaifeng, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Chen
authors.affiliation: Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Si
authors.initials: S
authors.lastname: Liu
authors.affiliation: Beijing Institute of Biotechnology, Beijing, China Institute of Life Science and Biotechnology, Beijing Jiaotong University, Beijing, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Qiu
authors.affiliation: Pharmaceutical College, Henan University, Kaifeng, China.
authors.forename: Xiao-Bin
authors.initials: XB
authors.lastname: Pang
authors.affiliation: Institute of Life Science and Biotechnology, Beijing Jiaotong University, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Beijing Institute of Biotechnology, Beijing, China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Sun
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D023582:Alzheimer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D019274:Botulinum Toxins, Type A / Q000276:immunology; D001921:Brain / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004926:Escherichia coli; D000922:Immunotoxins / Q000276:immunology; D017780:Malaria Vaccines / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D058225:Plaque, Amyloid / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D011897:Random Allocation; D065852:Spatial Memory / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use
chemical_list: D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000906:Antibodies; D000922:Immunotoxins; D017780:Malaria Vaccines; C401223:PADRE 45; D010446:Peptide Fragments; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; C480626:amyloid beta-protein (1-15); C075222:amyloid beta-protein (1-42); D019274:Botulinum Toxins, Type A
keywords: Alzheimer's disease; carrier protein; chimeric vaccines; immunotherapy; molecular adjuvant