Abstract
IntroductionVaccination against amyloid-β protein (Aβ42) induces high levels of antibody, making it a promising strategy for treating Alzheimer’s disease (AD). One drawback in the past was that clinical trial approval was withheld because of speculation that the Aβ42 vaccine induces CD4+ T cell infiltrations into the central nervous system. To reduce T-cell activation while concomitantly maintaining high anti-Aβ42 titers is a great challenge in immunology.MethodsWe aimed to demonstrate that coimmunization with Aβ42 protein and expression plasmid can be beneficial in a mouse AD model and can prevent inflammation. We immunized the AD mice with the coimmunization vaccine and assessed behavior change and Aβ42 deposition. Furthermore, to determine the safety of the coimmunization vaccine, we used an induced Aβ42-EAE model to mimic the meningoencephalitis that happened in the AN-1792 vaccine clinical phase II trial and tested whether the coimmunization vaccine could ameliorate T-cell-mediated brain inflammation.ResultsThe coimmunization vaccination reduced Aβ plaques and significantly ameliorated cognitive deficit while inhibiting T-cell-mediated brain inflammation and infiltration. These studies demonstrate that the coimmunization strategy that we describe in this article can ameliorate AD pathology without notable adverse effects in mice.ConclusionsA coimmunization strategy leading to the development of a safe immunotherapeutic/preventive protocol against AD in humans is warranted.
Highlights
Vaccination against amyloid-β protein (Aβ42) induces high levels of antibody, making it a promising strategy for treating Alzheimer’s disease (AD)
The data derived from our study of the APP695 mice described in this article demonstrate that the coimmunization regimens with Aβ42 protein and Aβ42-coding DNA induced both high titers of antibody against Aβ42, which effectively reduced plaque formation in this AD mouse model, and induced Induction of antigen-specific regulatory T cell (iTreg) that strongly reduced brain inflammation and infiltration of T cells into the brain
Groups of C57BL/6 mice (n = 6) were immunized by coimmunization with protein/DNA at various ratios (100 μg/100 μg, 100 μg/200 μg, 100 μg/300 μg and 200 μg/100 μg), protein vaccine alone or DNA vaccine alone, or they were un-vaccinated as controls. (A) Total anti-Aβ immunoglobulin G (IgG) was analyzed by enzyme-linked immunosorbent assay (ELISA) on day 7 after the third immunization
Summary
Vaccination against amyloid-β protein (Aβ42) induces high levels of antibody, making it a promising strategy for treating Alzheimer’s disease (AD). Pathology reports indicated that the cases of meningoencephalitis were severe, which suggested that vaccine-induced T-cell infiltration might be the cause [11] This raised a critical question about how to develop a vaccine that can elicit a high level of antibody against Aβ42 antigen while preventing T-cell responses [12,13,14,15,16]. Liu et al [29] used a diphtheria toxoid (DT)-conjugated Aβ1–15 vaccine that deleted the T-cell epitope and found that it upregulated CD25+ Tregs Whether these regulatory T cells were specific for the Aβ peptide and had a major anti-inflammatory impact needs to be further investigated. This finding indicates that induction of antigen-specific regulatory T cells (iTregs), even when not directly against an Aβ antigen, may improve the safety of Aβ-based vaccines against inflammation
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