Vaccines targeting the primary amino acid sequence and conformational epitope of amyloid‐β had distinct effects on neuropathology and cognitive deficits in EAE/AD mice

Abstract

Background and Purpose:Immunotherapeutic intervention is one of the most promising strategies for the prevention and treatment of Alzheimer's disease (AD). Although they showed great success in AD mouse models, the clinical trials of many immune approaches failed due to low efficacy and safety. Thus, an animal model which can show the potential side effects of vaccines or antibodies is urgently needed. In this study, we generated EAE/AD mice by crossing APP/PS1 mice with experimental autoimmune encephalomyelitis (EAE) mice. We then investigated the efficacy and safety of two vaccines: the immunogens of which were Aβ1-42 aggregates (Aβ42 vaccine) and an oligomer-specific conformational epitope (AOE1 vaccine), respectively.Experimental Approach: EAE/AD mice were immunized with the Aβ42 vaccine or AOE1 vaccine five times at biweekly intervals. After the final immunization, cognitive function was evaluated by the Morris water maze, Y maze, and object recognition tests.Neuropathological changes in the mouse brains were analysed by immunohistochemistry and ELISA. Key Results:In contrast to previous findings in conventional AD animal models, Aβ42 immunization promoted neuroinflammation, enhanced Aβ levels and plaque burden, and failed to restore cognitive deficits in EAE/AD mice. By contrast, AOE1 immunization dramatically attenuated neuroinflammation, reduced Aβ levels, and improved cognitive performance in EAE/AD mice. Conclusion and Implications:These results suggest that the EAE/AD mouse model can exhibit the potential side effects of AD immune approaches that conventional AD animal models fail to display. Furthermore, strategies specifically targeting Aβ oligomers may be safe and show clinical benefit for AD treatment.

Peptide-Based Vaccines for Neurodegenerative Diseases: Recent Endeavors and Future Perspectives

“…Formulation systems, in general, consist of factors that may greatly affect the final outcome of peptide-based vaccination; to support this, it is noteworthy mentioning that a new phase II clinical trial was announced for an optimized formulation of the α-syn peptide-based vaccine, PD01, a few months ago [108]. Concerning the pre-clinical in vivo animal studies, it should be noticed that specific parameters, such as the animal model, the specific vaccine excipients, and the vaccination schemes used [34,81,84,126] might have highly contributed to the overall outcome [70,72]. This issue may be responsible for the non-optimal results obtained in the subsequent trials with human subjects and should be carefully considered in future endeavors.…”

“…Moreover, a DNA vaccine based on Aβ(1-42) trimer and targeting amyloid plaques and tau protein was also reported [83]. Since soluble Aβ oligomers and protofibrils are now considered as the most toxic forms of Aβ and a discontinuous conformational epitope formed by soluble Aβ oligomers might be the ideal target of an Aβvaccine [18,61,68], one more vaccine (AOE1) based on specific conformational epitope(s) of Aβ oligomers as an immunogen has been recently described [84].…”

“…A yeast-based Aβ vaccine (Y-5A15) composed of five copies of Aβ(1-15) that had been displayed on the surface of a yeast cell's wall was tested in transgenic mice [77]. Another yeast-based Aβ vaccine (AOE1), in which Aβ oligomer-specific mimotope peptides had been displayed on the yeast cell surface, was tested in specific mouse models [84].…”

“…To this end, a series of animal models for AD or other neurodegenerative diseases have been created/selected and used. Focusing on studies recently reported, various transgenic mouse models including APP/PS1 [71,77]/APPswe/PS1dE9 co-expressing human APP with Swedish mutation and exon-9-deleted presenilin [72,76,95], TauP301S of AD and Frontotemporal dementia phenotype [40,94,97], 3xTg-AD involving both Aβ and p-tau pathology [70,80,82,83,100], EAE/AD deriving from APP/PS1 crossed with EAE (experimental autoimmune encephalomyelitis) [84], Tau22/5xFAD developing both pathological Aβ and tau aggregates [78], PS19 [92], J20 [81], SNCA-OVX [43], B6SJL [111], Tg2576 as well as Tg-SwDI [79], and Tg4510 [34,96] have been employed. On the other hand, a few studies have employed Balb/C or C57/BL6 mice, so as to preliminarily estimate the vaccine capability of eliciting high antibody titers [73][74][75] (Table 2).…”

Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model

“… 44 NOR test was performed as described previously with some modifications. 44 , 45 Briefly, mice were individually habituated to explore the behavioral arena for 5 min 24 h before testing, and then were allowed to explore for 5 min in the training session. After a 6 h retention period, mice were reintroduced to the box and allowed to explore for 5 min in the testing session.…”