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Background: Adjuvants are important components of vaccines and effectively enhance the immune response of specific antigens. However, the role of adjuvants or combinations of adjuvants in stimulating immunogenicity of the amyloid-β (Aβ) vaccine, as well as molecular mechanisms underlying such stimulation still remain unclear. A previous study of ours developed a norovirus P particle-based active Aβ epitope vaccine, PP-3copy-Aβ1-6-loop123, which stimulates a high titer of Aβ-specific antibodies in mouse Alzheimer's disease (AD) models.Objective: The most effective and safe adjuvant that maximizes the immunogenicity of our protein vaccine was determined.Methods: We investigated four adjuvants (CpG, AS02, AS03, and MF59), and combinations of those, for capacity to enhance immunogenicity, and performed transcriptome analysis to explore mechanisms underlying the role of these in AD immunotherapy.Results: Addition of the adjuvant, AS02, remarkably improved the immunogenicity of the PP-3copy-Aβ1-6-loop123 vaccine without triggering an Aβ-specific T-cell response. Combinations of adjuvants, particularly CpG +  AS02 and CpG + AS03, elicited a significantly elevated and prolonged Aβ-specific antibody response. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that a combination of two adjuvants was more effective in activating immune-related pathways, thereby enhancing the immunogenicity of PP-3copy-Aβ1-6-loop123.Conclusion: These findings demonstrated that adjuvants can be used as enhancers in AD protein vaccination, and that a combination of CpG and AS-related adjuvants may be a very effective adjuvant candidate suitable for further clinical trials of the PP-3copy-Aβ1-6-loop123 vaccine. Our studies also revealed potential mechanisms underlying the stimulation of immune response of protein vaccines by adjuvants. [ABSTRACT FROM AUTHOR]

The abnormal deposition of amyloid- β (A β) peptides in the brain is the main neuropathological hallmark of Alzheimer's disease (AD). Amyloid deposits are formed by a heterogeneous mixture of A β peptides, among which the most studied are A β40 and A β42. A β40 is abundantly produced in the human brain, but the level of A β42 is remarkably increased in the brain of AD patients. Aside from A β40 and A β42, recent data have raised the possibility that A β43 peptides may be instrumental in AD pathogenesis. Besides its length, whether the A β aggregated form accounts for the neurotoxicity is also particularly controversial. A β fibrils are generally considered as key pathogenic substances in AD pathogenesis. Nevertheless, recent data implicated soluble A β oligomers as the main cause of synaptic dysfunction and memory loss in AD. To further address this uncertainty, we analyzed the neurotoxicity of different A β species and A β forms at the cellular level. The results showed that A β42 could form oligomers significantly faster than A β40 and A β43 and A β42 oligomers showed the greatest level of neurotoxicity. Regardless of the length of A β peptides, A β oligomers induced significantly higher cytotoxicity compared with the other two A β forms. Surprisingly, the neurotoxicity of fibrils in PC12 cells was only marginally but not significantly stronger than monomers, contrary to previous reports. Altogether, our findings demonstrate the high pathogenicity of A β42 among the three A β species and support the idea that A β42 oligomers contribute to the pathological events leading to neurodegeneration in AD. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Highlights • Alzheimer’s disease vaccine using the Aβ1–6 epitope is safe and effective. • The BLP-based AD vaccine induced antibodies against Aβ42 without T-cell activation. • A suitable epitope copy number improved the immunogenicity of the vaccine. • Antibodies effectively blocked toxicity of Aβ42 oligomer at the cellular level. Abstract Amyloid-beta (Aβ) plaque accumulation in the brain is one of the hallmarks of Alzheimer’s disease (AD). Immunotherapy against Aβ was considered a potential strategy for reducing the Aβ load in the brain. However, none of the Aβ immunotherapies have produced clinically meaningful results to date, due to poor safety or lack of efficacy. Thus, we aimed to design a safe and effective vaccine against AD. In this study, we used bacterium-like particles (BLPs) as carriers and different copy numbers of the Aβ 1-6 peptide as epitopes to design four Aβ active immunization vaccines. The epitopes containing different copy numbers of the Aβ 1-6 peptide were specifically loaded on the surface of BLPs via fusion with a peptidoglycan anchoring domain. These four BLP-based Aβ vaccines successfully induced high levels of Aβ42-specific antibodies in mice. However, none of the vaccines induced a T-cell-mediated immune response. Importantly, the antibodies induced by these four vaccines were effective in blocking Aβ42 oligomer toxicity at the cellular level. Among the four vaccines, 6copy-Aβ 1-6 -PA-BLP was the most effective in inducing Aβ-specific antibodies, indicating that a suitable epitope copy number is critical for high immunogenicity of the BLP-based vaccine. Furthermore, high levels of serum Aβ-specific antibodies could still be detected 3 months after the final administration of 6copy-Aβ 1-6 -PA-BLP. Thus, 6copy-Aβ 1-6 -PA-BLP may be a potential therapeutic treatment for AD. [ABSTRACT FROM AUTHOR]

Active vaccination against amyloid β (Aβ42) is considered a potential therapeutic approach for Alzheimer’s disease (AD). However, immunization with synthetic human Aβ1–42 has resulted in meningoencephalitis in 6% of patients and generated only low-titer anti-Aβ42 antibodies. In order to develop a safe and effective vaccine against Alzheimer’s disease, the Aβ1–6 peptide was used as the novel immunogen and Norovirus P particles as the vaccine platform in this study. By inserting and presenting Aβ1–6 on the outermost surface of the P particle, we showed that the chimeric P particle-based AD protein vaccine could elicit a strong immune response, inducing highly specific antibody titers against Aβ42 without causing T-cell activation. Furthermore, antibodies induced by the AD protein vaccines were demonstrated to be effective at the cellular level. In addition, we also compared the immunogenicity of the chimeric P particles with different insertional loci in the loop structure domain and demonstrated that insertion of the antigen into all three loops of the P particle at the same time could significantly improve immune responses to the vaccine. In conclusion, the Norovirus P particle is an excellent vaccine platform for stimulating Aβ42 antibody production, and chimeric P particles may be developed as an effective therapy for AD. [ABSTRACT FROM AUTHOR]