Papillomavirus-like particles are an effective platform for amyloid-β immunization in rabbits and transgenic mice

Immunization with amyloid-beta (A beta) prevents the deposition of A beta in the brain and memory deficits in transgenic mouse models of Alzheimer's disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of A beta vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an A beta vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1-9 aa of A beta protein repetitively on the viral capsid surface (A beta-VLP). This A beta peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with A beta-VLP were well tolerated and induced high-titer autoAb against A beta, that inhibited effectively assembly of A beta(1-42) peptides into neurotoxic fibrils in vitro. Following A beta-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced A beta deposits in the brain and increased numbers of activated microglia. Furthermore, A beta-VLP vaccinated mice also showed increased levels of A beta in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the A beta-VLP vaccine induces an effective humoral immune response to A beta and may thus form a basis to develop a safe and efficient immunotherapy for human AD.