Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-06, Vol.104 (23), p.9810-9815
• Main Authors: Muhs, Andreas, Hickman, David T, Pihlgren, Maria, Chuard, Nathalie, Giriens, Valérie, Meerschman, Carine, van der Auwera, Ingrid, van Leuven, Fred, Sugawara, Masae, Weingertner, Marie-Catherine, Bechinger, Burkhard, Greferath, Ruth, Kolonko, Nadine, Nagel-Steger, Luitgard, Riesner, Detlev, Brady, Roscoe O, Pfeifer, Andrea, Nicolau, Claude
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - prevention & control; Alzheimer Vaccines - immunology; Alzheimer Vaccines - pharmacology; Alzheimer's disease; Amyloid beta-Peptides - immunology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloids; Analysis of Variance; Animals; Antibodies; Antigens; Antigens - immunology; Biological Sciences; Brain - immunology; Brain - metabolism; Clinical outcomes; Cytokines - metabolism; Enzyme linked immunosorbent assay; Epitope Mapping; Immune response; Immunization; Liposomes; Liposomes - immunology; Medical treatment; Memory; Mice; Mice, Transgenic; Nuclear Magnetic Resonance, Biomolecular; Oligopeptides - genetics; Peptide Fragments - immunology; Peptides; Recognition (Psychology) - drug effects; Vaccination; Vaccines
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0703137104

We investigated the therapeutic effects of two different versions of Aβ₁₋₁₅ ₍₁₆₎ liposome-based vaccines. Inoculation of APP-V717IxPS-1 (APPxPS-1) double-transgenic mice with tetra-palmitoylated amyloid 1-15 peptide (palmAβ₁₋₁₅), or with amyloid 1-16 peptide (PEG-Aβ₁₋₁₆) linked to a polyethyleneglycol spacer at each end, and embedded within a liposome membrane, elicited fast immune responses with identical binding epitopes. PalmAβ₁₋₁₅ liposomal vaccine elicited an immune response that restored the memory defect of the mice, whereas that of PEG-Aβ₁₋₁₆ had no such effect. Immunoglobulins that were generated were predominantly of the IgG class with palmAβ₁₋₁₅, whereas those elicited by PEG-Aβ₁₋₁₆ were primarily of the IgM class. The IgG subclasses of the antibodies generated by both vaccines were mostly IgG2b indicating noninflammatory Th2 isotype. CD and NMR revealed predominantly β-sheet conformation of palmAβ₁₋₁₅ and random coil of PEG-Aβ₁₋₁₆. We conclude that the association with liposomes induced a variation of the immunogenic structures and thereby different immunogenicities. This finding supports the hypothesis that Alzheimer's disease is a "conformational" disease, implying that antibodies against amyloid sequences in the β-sheet conformation are preferred as potential therapeutic agents.