Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice.
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.
Muhs
Andreas
A
AC Immune, PSE-B, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Hickman
David T
DT
Pihlgren
Maria
M
Chuard
Nathalie
N
Giriens
Valérie
V
Meerschman
Carine
C
van der Auwera
Ingrid
I
van Leuven
Fred
F
Sugawara
Masae
M
Weingertner
Marie-Catherine
MC
Bechinger
Burkhard
B
Greferath
Ruth
R
Kolonko
Nadine
N
Nagel-Steger
Luitgard
L
Riesner
Detlev
D
Brady
Roscoe O
RO
Pfeifer
Andrea
A
Nicolau
Claude
C
D000544:Alzheimer Disease / Q000517:prevention & control*; D023582:Alzheimer Vaccines / Q000276:immunology* / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000941:Antigens / Q000276:immunology*; D001921:Brain / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D008081:Liposomes / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology; D021641:Recognition, Psychology / Q000187:drug effects*
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000941:Antigens; D016207:Cytokines; D008081:Liposomes; D009842:Oligopeptides; C449186:PS1 antigen; D010446:Peptide Fragments