Peripherally administered sera antibodies recognizing amyloid-β oligomers mitigate Alzheimer's disease-like pathology and cognitive decline in aged 3x Tg-AD mice

Active and passive immunotherapy targeting amyloid-beta (A beta) may be the most promising strategy to prevent or treat Alzheimer's disease (AD). Previously, immunization with the recombinant 6A beta 15-T antigen generated robust anti-A beta serum antibodies that strongly recognized A beta 42 oligomers in different mice, markedly reduced the amyloid burden, and improved behavioral performance of immunized older AD mice. Here, we further determined that these anti-6A beta 15-T serum antibodies from different strains of mice displayed anti-A beta antibody responses against the same epitopes in the A beta 1-15 region. Peripheral administration of anti-6A beta 15-T serum antibodies was also effective to mitigate AD-like pathology and cognitive decline in aged 3 x Tg-AD mice. Specifically, the levels of A beta and tau in the brains of 3x Tg-AD mice were significantly reduced after passive immunotherapy, which seemed necessary or beneficial to ameliorate memory impairment. In addition, our results showed that this immunotherapy also prevented presynaptic dynamin 1 degradation, which might help to further protect synaptic functions and allow functional recovery of cognition. Moreover, immunization with 6A beta 15-T in rabbits induced a similar antibody response as that in mice, and the rabbit serum antibodies reacted strongly with A beta 42 oligomers and inhibited oligomer-mediated neurotoxicity. We concluded that passive immunization with A beta 42 oligomer conformation-sensitive anti-6A beta 15-T serum antibodies is effective in providing potentially therapeutic effects in aged 3 x Tg-AD mice by reducing A beta and tau. (C) 2016 Elsevier Ltd. All rights reserved.