Dataset Information

Norovirus P particle-based active A? immunotherapy elicits sufficient immunogenicity and improves cognitive capacity in a mouse model of Alzheimer's disease.

ABSTRACT: Disease-modifying immunotherapies focusing on reducing amyloid-beta (A?) deposition are the main treatment for Alzheimer's disease (AD). However, none of the A? immunotherapies has produced clinically meaningful results to date. The main reason for this lack of efficacy is that the vaccine induces insufficiently high antibody titers, as it contains small B-cell epitope of A? to avoid A?42-specific T-cell activation. With the aim of generating a potent AD vaccine, we designed the protein PP-3copy-A?1-6-loop123, comprising three copies of A?1-6 inserted into three loops of a novel vaccine platform, the norovirus P particle, which could present A? at its surface and remarkably enhance the immunogenicity of the vaccine. We demonstrated that PP-3copy-A?1-6-loop123 was able to elicit high antibody titers against A?42, without causing T-cell activation, in AD mice regardless of their age. Importantly, PP-3copy-A?1-6-loop123 treatment successfully reduced amyloid deposition, rescued memory loss, and repaired hippocampus damage in AD mice. The A? antibodies induced by this active immunotherapy reacted with and disrupted aggregated A?, reducing its cellular toxicity. In addition, our results suggested PP-3copy-A?1-6-loop123 immunization could restore A?42 homeostasis in both the serum and brain. Thus, the P particle-based A? epitope vaccine is a sufficiently immunogenic and safe immunotherapeutic intervention for Alzheimer's disease.

SUBMITTER: Fu L

PROVIDER: S-EPMC5247735 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Norovirus P particle-based active Aβ immunotherapy elicits sufficient immunogenicity and improves cognitive capacity in a mouse model of Alzheimer's disease.

Fu Lu L Li Yingnan Y Hu Yue Y Zheng Yayuan Y Yu Bin B Zhang Haihong H Wu Jiaxin J Wu Hui H Yu Xianghui X Kong Wei W

Scientific reports 20170120

Disease-modifying immunotherapies focusing on reducing amyloid-beta (Aβ) deposition are the main treatment for Alzheimer's disease (AD). However, none of the Aβ immunotherapies has produced clinically meaningful results to date. The main reason for this lack of efficacy is that the vaccine induces insufficiently high antibody titers, as it contains small B-cell epitope of Aβ to avoid Aβ42-specific T-cell activation. With the aim of generating a potent AD vaccine, we designed the protein PP-3copy ...[more]

PMID: 28106117

Similar Datasets

Project description:Brain-directed immunotherapy is a promising strategy to target amyloid-β (Aβ) deposits in Alzheimer's disease (AD). In the present study, we compared the therapeutic efficacy of the Aβ protofibril targeting antibody RmAb158 with its bispecific variant RmAb158-scFv8D3, which enters the brain by transferrin receptor-mediated transcytosis. AppNL-G-F knock-in mice received RmAb158, RmAb158-scFv8D3, or PBS in three treatment regimens. First, to assess the acute therapeutic effect, a single antibody dose was given to 5 months old AppNL-G-F mice, with evaluation after 3 days. Second, to assess the antibodies' ability to halt the progression of Aβ pathology, 3 months old AppNL-G-F mice received three doses during a week, with evaluation after 2 months. Reduction of RmAb158-scFv8D3 immunogenicity was explored by introducing mutations in the antibody or by depletion of CD4+ T cells. Third, to study the effects of chronic treatment, 7-month-old AppNL-G-F mice were CD4+ T cell depleted and treated with weekly antibody injections for 8 weeks, including a final diagnostic dose of [125I]RmAb158-scFv8D3, to determine its brain uptake ex vivo. Soluble Aβ aggregates and total Aβ42 were quantified with ELISA and immunostaining. Neither RmAb158-scFv8D3 nor RmAb158 reduced soluble Aβ protofibrils or insoluble Aβ1-42 after a single injection treatment. After three successive injections, Aβ1-42 was reduced in mice treated with RmAb158, with a similar trend in RmAb158-scFv8D3-treated mice. Bispecific antibody immunogenicity was somewhat reduced by directed mutations, but CD4+ T cell depletion was used for long-term therapy. CD4+ T cell-depleted mice, chronically treated with RmAb158-scFv8D3, showed a dose-dependent increase in blood concentration of the diagnostic [125I]RmAb158-scFv8D3, while concentration was low in plasma and brain. Chronic treatment did not affect soluble Aβ aggregates, but a reduction in total Aβ42 was seen in the cortex of mice treated with both antibodies. Both RmAb158 and its bispecific variant RmAb158-scFv8D3 achieved positive effects of long-term treatment. Despite its ability to efficiently enter the brain, the benefit of using the bispecific antibody in chronic treatment was limited by its reduced plasma exposure, which may be a result of interactions with TfR or the immune system. Future research will focus in new antibody formats to further improve Aβ immunotherapy.

Dataset Information

Norovirus P particle-based active A? immunotherapy elicits sufficient immunogenicity and improves cognitive capacity in a mouse model of Alzheimer's disease.

Publications

Norovirus P particle-based active Aβ immunotherapy elicits sufficient immunogenicity and improves cognitive capacity in a mouse model of Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets