Just as immunotherapy for Alzheimer's disease has encountered its first problems in the clinic (see Live Chat discussion), new approaches are emerging in the research pipeline. In yesterday's Early Online edition of PNAS, Claude Nicolau of Universite Louis Pasteur in Strasbourg and Beth Israel Deaconess Medical Center in Boston, and colleagues, describe an alternative that aims to boost the ability of an Aβ peptide vaccine to generate a potent antibody response by embedding the peptide in fatty droplets called liposomes.
Nicolau et al. used the first 16 amino acids of the Aβ peptide, which researchers led by Beka Solomon, now at Tel Aviv University, had shown to dissolve A1-42 fibrils (Solomon et al, 1997.) They attached to its ends palmitoylated lysine residues that enabled them to anchor the peptide in the lipid bilayer of a liposome adjuvant. Then they immunized Balb/c, C57BL, and transgenic NORBA mice with this experimental Aβ1-16 vaccine and tested the mice's sera for its ability to disaggregate amyloid in vitro. NORBA mice have Aβ-derived amyloid deposits on their pancreas, not in their brains, (Shoji et al. 1996.)
The scientists report that their vaccine generated significant antibody titers within 10 weeks after the first inoculation, much faster than was reported for previous Aβ vaccines. They also present data suggesting that the sera from the vaccinated mice dissolve fibrillar amyloid and prevent or slow plaque buildup in the pancreas of NORBA mice.
The study implies that its anti-Aβ1-16 antibody dissolves amyloid more potently than does a previous antibody by Elan Pharmaceuticals, 6C6. However, Figure 4b, which refers to Aβ1-16, 6C6, and a control antibody in the caption, does not actually present all the data necessary to directly compare anti-Aβ1-16 and 6C6 in a single experiment. The paper also does not contain a statistical analysis of the mice's reaction to inoculation with Aβ1-16.
This study does not include tests of the Aβ1-16 vaccine in more standard AD models that overproduce Aβ in the brain, and therefore also does not address whether the vaccine can prevent or improve the behavioral effects seen in these mice, as shown for other experimental vaccines (Janus et al. 2000; Morgan et al. 2000). However, it points to a possible method to improve the antigenicity of Aβ. In general, self-peptides do not generate high antibody titers because the immune system tolerates the body's own proteins.—Gabrielle Strobel
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- Nicolau C, Greferath R, Balaban TS, Lazarte JE, Hopkins RJ. A liposome-based therapeutic vaccine against beta -amyloid plaques on the pancreas of transgenic NORBA mice. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2332-7. PubMed.