Immunogenicity and therapeutic efficacy of phage-displayed beta-amyloid epitopes

In vitro and in vivo studies indicate that Alzheimer's Disease (AD) could be prevented or treated by active immunization against self-peptide beta-amyloid. In this study, we compared the immunogenicity of different regions of beta-amyloid, displayed on filamentous phages. We established that a filamentous phage displaying epitope 2-6 (AEFRH) of beta-amyloid at the N-terminus of Major Capside Protein (phage fdAD(2-6)) is more immunogenic than a phage displaying epitope 1-7 (DAEFRHD) that differs only in flanking residues. Monthly injections of fdAD(2-6) trigger a robust anti-beta-amyloid antibody response, and afford a significant reduction of plaque pathology in a mouse model of AD, whereas the same treatment, performed with phage fdAD(1-7), induces a lower anti-beta-amyloid titer and does not protect from amyloid deposition. "Memory" anti-amyloid antibodies induced by a single prime-boost cycle with vaccine fdAD(2-6), that have a lower titer compared to antibodies induced by monthly restimulations, do not prevent plaque pathology. Our data show that optimization of epitope display is essential in vaccine design, and suggest that the titer of the anti-amyloid response is the crucial parameter to obtain therapeutic efficacy in vivo.