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P1‐098: REPURPOSING OF FDA‐APPROVED DRUGS ON MULTIPLE ALZHEIMER DISEASE TARGETS
Author(s) -
Shrivastava Apeksha,
Akhter Mymoona
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.100
Subject(s) - pharmacology , drug repositioning , virtual screening , protein data bank (rcsb pdb) , docking (animal) , adme , drug , in silico , medicine , drug discovery , chemistry , biochemistry , nursing , gene
treatments are approved for AD therapy, while no disease-modifying therapies are currently available. The amyloid cascade hypothesis posits that the deposition of amyloid b (Ab) in the brain is the central pathological hallmark of AD. Thus, over the past 15 years, various disease-modifying immunotherapies focusing on reducing Ab deposition have progressed from preclinical studies in AD mouse models to clinical trials in humans. Unfortunately, until now, none of the Ab immunotherapies has produced clinically meaningful results. 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 Ab to avoid Ab42specific T-cell activation. Methods: With the aim of generating a potent AD vaccine that elicits sufficiently high immunogenicity and efficiently improves cognitive capacity, we designed the protein PP-3copy-Ab1-6-loop123, comprising three copies of Ab1-6 inserted into three loops of a novel vaccine platform, the norovirus P particle, which could present Ab at its surface and remarkably enhance the immunogenicity of the vaccine. We investigated the immunogenicity of PP-3copy-Ab1-6loop123 in three APP/PS1 transgenic mice cohorts of different ages and further determined if the vaccination using PP-3copyAb1-6-loop123 had beneficial functional consequences in AD mice. Afterwards, we examined the reduction in amyloid deposition following PP-3copy-Ab1-6-loop123 immunization in all three age cohorts and finally studied the mechanism of this novel Ab immunotherapy. Results: We demonstrated that PP-3copyAb1-6-loop123 was able to elicit high antibody titers against Ab42, without causing T-cell activation, in AD mice regardless of their age. Most importantly, PP-3copy-Ab1-6-loop123 treatment successfully reduced amyloid deposition, rescued memory loss, and repaired hippocampus damage in AD mice. The Ab antibodies induced by this active immunotherapy reacted with and disrupted aggregated Ab, reducing its cellular toxicity. In addition, our results indicated that PP-3copy-Ab1-6-loop123 immunization could restore Ab homeostasis in the brain via both the “direct-targeting” and “peripheral sink” pathways. Conclusions: Thus, the P particle-based Ab epitope vaccine, PP-3copy-Ab16-loop123, is a sufficiently immunogenic and safe immunotherapeutic intervention for Alzheimer’s disease.