Development of a New DNA Vaccine for Alzheimer Disease Targeting a Wide Range of Ab Species and

It has recently been determined that not only Ab oligomers, but also other Ab species and amyloidogenic peptides are neurotoxic in Alzheimer disease (AD) and play a pivotal role in AD pathogenesis. In the present study, we attempted to develop new DNA vaccines targeting a wide range of Ab species. For this purpose, we first performed in vitro assays with newly developed vaccines to evaluate Ab production and Ab secretion abilities and then chose an IgL-Abx4-Fc-IL-4 vaccine (designated YM3711) for further studies. YM3711 was vaccinated to mice, rabbits and monkeys to evaluate anti-Ab species antibody-producing ability and Ab reduction effects. It was found that YM3711 vaccination induced significantly higher levels of antibodies not only to Ab1-42 but also to AD-related molecules including AbpE3-42, Ab oligomers and Ab fibrils. Importantly, YM3711 significantly reduced these Ab species in the brain of model mice. Binding and competition assays using translated YM3711 protein products clearly demonstrated that a large part of antibodies induced by YM3711 vaccination are directed at conformational epitopes of the Ab complex and oligomers. Taken together, we demonstrate that YM3711 is a powerful DNA vaccine targeting a wide range of AD-related molecules and is worth examining in preclinical and clinical trials