Generation and characterization of the humoral immune response to DNA immunization with a chimeric β‐amyloid‐interleukin‐4 minigene

Active immunization with fibrillar β–amyloid peptide (Aβ42) as well as passive transfer of anti‐Aβ antibodies significantly reduces Aβ plaque deposition, neuritic dystrophy, and astrogliosis in the brain of mutant amyloid precursor protein (APP)‐transgenic mice. Although the mechanism(s) of clearance of Aβ from the brain following active or passive immunization remains to be determined, it is clear that anti‐Aβ antibodies are critical for clearance. DNA immunization provides an attractive alternative to direct peptide and adjuvant approaches for inducing a humoral response to Aβ. We constructed a DNA minigene with Aβ fused to mouse interleukin‐4 (pAβ42‐IL‐4) as a molecular adjuvant to generate anti‐Aβ antibodies and enhance the Th2‐type of immune responses. Gene gun immunizations induced primarily IgG1 and IgG2b anti‐Aβ antibodies. Fine epitope analysis with overlapping peptides of the Aβ42 sequence identified the 1–15 region as a dominant B cell epitope. The DNA minigene‐induced anti‐Aβ antibodies bound to Aβ plaques in brain tissue from an Alzheimer's disease patient demonstrating functional activity of the antibodies and the potential for therapeutic efficacy.