Analysis of three plasmid systems for use in DNA Aβ42 immunization as therapy for Alzheimer's disease

Abstract

In an effort to optimize DNA immunization-elicited antibody production responses against Aβ1–42 (Aβ42) as a therapy for Alzheimer's disease (AD), comparisons were made between three distinct plasmid systems using gene gun delivery. Plasmids encoding Aβ42 monomer and a novel Aβ42 trimeric fusion protein were evaluated in conjunction with CMV or Gal4/UAS promoter elements. It was found that vaccination Aβ42 trimer under the Gal4/UAS promoter elicited high levels of anti-Aβ42 antibody production. Serum antibody levels from Gal4/UAS-Aβ42 trimer immunized mice were found to be 16.6±5.5μg/ml compared to 6.5±2.5μg/ml with Gal4/UAS-Aβ42 monomer or even less with CMV-Aβ42 trimer. As compared to monomeric Aβ42 or Aβ42 trimer expressed under the CMV promoter, injection of the Gal4/UAS-Aβ42 trimer induced high levels of Aβ42 antigen expression in tissue suggesting a mechanism for the increase in anti-Aβ42 antibody. Antibodies were found to be primarily IgG1 suggesting a predominant Th2 response (IgG1/IgG2a ratio of 9). Serum from Aβ42 trimer-vaccinated mice was also found to identify amyloid plaques in the brains of APP/PS1 transgenic mice. These results demonstrate the potential therapeutic use of Gal4/UAS DNA Aβ42 trimer immunization in preventing Alzheimer's disease.