Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

Previously, we reported that Alzheimer’s disease (AD) epitope vaccines (EVs) composed of N-terminal β-amyloid (Aβ42) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Aβ42 is a target. Here, we directly compare the efficacy of anti-Aβ42 antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6–6.5 months for preventive vaccinations and 16–19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Aβ antibodies, significantly reducing pathologic forms of Aβ in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11–11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Aβ antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance. Petrushina et al. show that Alzheimer’s disease epitope vaccine generated high titers of anti-Aβ antibodies and reduced brain pathology in young, but not middle-age and old, Tg2576 mice. Pre-existing memory Th cells augmented antibody titers in middle-age Tg2576 mice, decreasing Aβ pathology and improving novel object recognition performance.