Reduced oligomeric and vascular amyloid-β following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine

Immunization with amyloid-beta (A beta) peptide reduces amyloid load in animal studies and in humans; however clinical trials resulted in the development of a pro-inflammatory cellular response to A beta. 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 A beta in conjunction with an attenuated caspase generates therapeutically effective antibodies. Plasmids encoding A beta and an attenuated caspase were less effective in reducing amyloid pathology than those encoding A beta alone. Moreover, use of A beta with an Arctic mutation (E22G) as an immunogen was less effective than wild-type A beta in terms of improvements in pathology. Low levels of IgG and IgM were generated in response to immunization with a plasmid encoding wild-type A beta. These antibodies decreased plaque load by as much as 36 +/- 8% and insoluble A beta 42 levels by 56 +/- 3%. Clearance of A beta was most effective when antibodies were directed against N-terminal epitopes of A beta. Moreover, immunization reduced CAA by as much as 69 +/- 12% in TgCRND8 mice. Finally, high-molecular-weight oligomers and A beta trimers were significantly reduced with immunization. Thus, immunization with a plasmid encoding A beta alone drives an attenuated immune response that is sufficient to clear amyloid pathology in a mouse model of Alzheimer's disease. (C) 2009 Elsevier Ltd. All rights reserved.