A liposome-based therapeutic vaccine against beta -amyloid plaques on the pancreas of transgenic NORBA mice.
Immune tolerance to beta-amyloid (Abeta) was broken in NORBA transgenic mice presenting Abeta plaques on their pancreases. Vaccination of Black C57, BALB/c, and NORBA mice with the synthetic Abeta(1-16) sequence modified by covalently attaching two palmitoyl residues at each end of the peptide, subsequently reconstituted in liposomes-Lipid A elicited titers of 1:5,000 of anti-Abeta(1-16) antibodies within 10 weeks after the first inoculation. On direct interaction, sera with antibody titers of 1:5,000 solubilized in vitro up to 80% of preformed Abeta(1-42) aggregates. Cryosections of pancreases of unvaccinated NORBA mice show, on staining with Thioflavin T, extensive areas of high-intensity fluorescence in the acinar cell fields. Quantitation of the average fluorescence intensity in each section indicated that: (i) whereas nonvaccinated NORBA mice develop plaques within 45-60 days after birth, vaccinated 8-week-old NORBA mice did not develop amyloid plaques on their pancreases over a period of 7 months; (ii) cryosections from pancreases of 9- and 15-month-old vaccinated NORBA mice showed less than 50% of the fluorescence shown by cryosections from unvaccinated animals of the same age. The results indicate that palmitoylated Abeta peptides, reconstituted in liposomes-lipid A, are highly immunogenic, eliciting "therapeutic" antibody titers within 3 months of the first inoculation and preventing amyloid plaque formation in young animals or significantly reducing existing plaques in older transgenic mice. Possible implications for the therapy of Alzheimer's disease are discussed.
Nicolau
Claude
C
Ecole Supérieure de Biotechnologie de Strasbourg, Université Louis Pasteur, 67091 Strasbourg, France. claude.nicolau@caregroup.harvard.edu
Greferath
Ruth
R
Balaban
Teodor Silviu
TS
Lazarte
Jaime E
JE
Hopkins
Robert J
RJ
D000544:Alzheimer Disease / Q000517:prevention & control; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D004797:Enzyme-Linked Immunosorbent Assay; D007106:Immune Sera; D007109:Immunity; D008081:Liposomes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019308:Palmitic Acid / Q000378:metabolism; D010179:Pancreas / Q000166:cytology* / Q000473:pathology*; D010455:Peptides / Q000737:chemistry; D013045:Species Specificity; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014612:Vaccines
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D007106:Immune Sera; D008081:Liposomes; D010455:Peptides; D013844:Thiazoles; D014612:Vaccines; C009462:thioflavin T; D019308:Palmitic Acid