Strikingly Reduced Amyloid Burden and Improved Behavioral Performance in Alzheimer's Disease Mice Immunized with Recombinant Chimeric Vaccines by Hexavalent Foldable A beta(1-15) Fused to Toxin-Derived Carrier Proteins

摘要

Targeting on the amyloid-beta (A beta) is a promising immunotherapeutic strategy for Alzheimer's disease (AD). However, A beta(1-15) sequence alone induces low antibody response and poor protection against AD. We describe here the immunological characterization and protective efficacy of several recombinant chimeric vaccines with hexavalent foldable A beta(1-15) (6A beta 15) fused to PADRE or toxin-derived carrier proteins. Immunization with these chimeric antigens generated robust Th2 immune responses with high anti-A beta(42) antibody titers in different mice, which recognized neurotoxic A beta(42) oligomers, but did not stimulate A beta(42)-specific T cell responses. These 6A beta 15 chimeric vaccines markedly reduced A beta pathology and prevented development of behavioral deficits in immunized older AD mice. Importantly, toxin-derived carrier proteins as molecular adjuvants of chimeric vaccines could substantially boost immune responses and overcome A beta -and old age-associated hypo-responsiveness, and elicit long-term A beta-specific antibody response, which in turn inhibited A beta-mediated pathology and improved acquisition and retention of spatial memory in immunized AD mice. These data indicate that toxin fragments as molecular adjuvants are promising new tools for the rational design and development of prototype chimeric vaccines for AD and this type of chimeric vaccine design has the added advantage of overcoming hypo-responsiveness in elderly AD patients with pre-existing memory Th cells from tetanus toxin.