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

Muhs, A.; Weingertner, M.C.; Giriens, V.; Riesner, D.; Greferath, R.; Chuard, N.; van der Auwera, I.; Sugawara, M.; Bechinger, B.; Kolonko, N.; van Leuven, F.; Nicolau, C.; Meerschman, C.; Pfeifer, A.; Nagel-Steger, L.; Brady, R.O.; Pihlgren, M.; Hickmann, D.T.

doi:10.1073/pnas.0703137104

Journal Article

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

Muhs, A. ; Hickmann, D. T. ; Pihlgren, M. ; Chuard, N. ; Giriens, V. ; Meerschman, C. ; van der Auwera, I. ; van Leuven, F. ; Sugawara, M. ; Weingertner, M. C. ; Bechinger, B. ; Greferath, R. ; Kolonko, N. ; Nagel-Steger, L.FZJ* ; Riesner, D. ; Brady, R. O. ; Pfeifer, A. ; Nicolau, C.

2007
Academy Washington, DC

Proceedings of the National Academy of Sciences of the United States of America 104, 9810 - 9815 (2007) [10.1073/pnas.0703137104]

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Abstract: We investigated the therapeutic effects of two different versions of Abeta(1-15 (16)) liposome-based vaccines. Inoculation of APP-V717IxPS-1 (APPxPS-1) double-transgenic mice with tetra-palmitoylated amyloid 1-15 peptide (palmAbeta(1-15)), or with amyloid 1-16 peptide (PEG-Abeta(1-16)) linked to a polyethyleneglycol spacer at each end, and embedded within a liposome membrane, elicited fast immune responses with identical binding epitopes. PalmAbeta(1-15) liposomal vaccine elicited an immune response that restored the memory defect of the mice, whereas that of PEG-Abeta(1-16) had no such effect. Immunoglobulins that were generated were predominantly of the IgG class with palmAbeta(1-15), whereas those elicited by PEG-Abeta(1-16) 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 beta-sheet conformation of palmAbeta(1-15) and random coil of PEG-Abeta(1-16). 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 beta-sheet conformation are preferred as potential therapeutic agents.

Keyword(s): Alzheimer Disease: prevention & control (MeSH) ; Alzheimer Vaccines: immunology (MeSH) ; Alzheimer Vaccines: pharmacology (MeSH) ; Amyloid beta-Peptides: immunology (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Analysis of Variance (MeSH) ; Animals (MeSH) ; Antigens: immunology (MeSH) ; Brain: immunology (MeSH) ; Brain: metabolism (MeSH) ; Cytokines: metabolism (MeSH) ; Enzyme-Linked Immunosorbent Assay (MeSH) ; Epitope Mapping (MeSH) ; Liposomes: immunology (MeSH) ; Mice (MeSH) ; Mice, Transgenic (MeSH) ; Nuclear Magnetic Resonance, Biomolecular (MeSH) ; Oligopeptides: genetics (MeSH) ; Peptide Fragments: immunology (MeSH) ; Recognition (Psychology): drug effects (MeSH) ; Alzheimer Vaccines ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Antigens ; Cytokines ; Liposomes ; Oligopeptides ; PS1 antigen ; Peptide Fragments ; J ; Alzheimer's disease (auto) ; beta-amyloid (auto) ; vaccine (auto)