Reduced oligomeric and vascular amyloid-beta following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine.
Immunization with amyloid-beta (Abeta) peptide reduces amyloid load in animal studies and in humans; however clinical trials resulted in the development of a pro-inflammatory cellular response to Abeta. Apoptosis has been employed to stimulate humoral and Th2-biased cellular immune responses. Thus, we sought to investigate whether immunization using a DNA vaccine encoding Abeta in conjunction with an attenuated caspase generates therapeutically effective antibodies. Plasmids encoding Abeta and an attenuated caspase were less effective in reducing amyloid pathology than those encoding Abeta alone. Moreover, use of Abeta with an Arctic mutation (E22G) as an immunogen was less effective than wild-type Abeta in terms of improvements in pathology. Low levels of IgG and IgM were generated in response to immunization with a plasmid encoding wild-type Abeta. These antibodies decreased plaque load by as much as 36+/-8% and insoluble Abeta42 levels by 56+/-3%. Clearance of Abeta was most effective when antibodies were directed against N-terminal epitopes of Abeta. Moreover, immunization reduced CAA by as much as 69+/-12% in TgCRND8 mice. Finally, high-molecular-weight oligomers and Abeta trimers were significantly reduced with immunization. Thus, immunization with a plasmid encoding Abeta alone drives an attenuated immune response that is sufficient to clear amyloid pathology in a mouse model of Alzheimer's disease.
DaSilva
Kevin A
KA
Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Brown
Mary E
ME
McLaurin
JoAnne
J
D000544:Alzheimer Disease / Q000097:blood / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D000818:Animals; D000917:Antibody Formation; D015704:CD4 Antigens / Q000276:immunology; D003001:Cloning, Molecular; D017931:DNA Primers; D000229:Dependovirus / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015183:Restriction Mapping; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D015704:CD4 Antigens; D017931:DNA Primers; D019444:Vaccines, DNA