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Experimental Genetics Group

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

Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9810-5.

Muhs A1, Hickman DT1, Pihlgren M1, Chuard N1, Giriens V1, Meerschman C1, van der Auwera I2, van Leuven F3, Sugawara M4, Weingertner MC4, Bechinger B4, Greferath R1, Kolonko N1, Nagel-Steger L5, Riesner D5, Brady RO6*, Pfeifer A1, Nicolau C1,7*.

1AC Immune, Lausanne, Switzerland.
2reMYND nv, Leuven, Belgium.
3Experimental Genetics Group, K.U.Leuven, Leuven, Belgium.
4Institut de Science et d'Ingénierie Supramoléculaires, Université Louis Pasteur, Strasbourg, France.
5Institut für Biophysikalische Chemie, Heinrich-Heine Universität, Düsseldorf, Germany.
6Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD.
7Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA.
*Corresponding authors.

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.

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