Multiple Antigenic Peptide System Coupled with Amyloid Beta Protein Epitopes As An Immunization Approach to Treat Alzheimer’s Disease

Abstract

Latest studies suggest that Alzheimer's disease (AD) is one of the "four big killers" that threaten the health of the elderly. AD affects about 46 million people across the world, and there is a critical need for research on new therapies for treating AD. The purpose of the present study was to develop and evaluate immunogens to elicit antibodies against the formation of amyloid beta protein (Aβ), a pathological hallmark of AD, as a therapeutic strategy in AD. In this study, serial potential immunogenic epitopes were screened according to the Aβ sequence. The screened linear epitopes on the Aβ C-terminal fragment were coupled with either the carrier protein keyhole limpet hemocyanin (KLH) or the synthesized 4-branch peptide (MAP 4 ). MAP 4 immunogens could effectively elicit immunogenicity against Aβ 1−42 monomer and fiber in Balb/C mice. Furthermore, MAP 4 sera could also effectively inhibit the formation of the Aβ 1−42 fiber. Interestingly, one of the MAP 4 sera was able to depolymerize the Aβ 1−42 fibers that had aggregated. The monoclonal antibody, 1H7, was shown to inhibit the formation of Aβ 1−42 fiber. MAP 4 carrier may provide benefits over current immunization strategies, as it does not induce inflammation. In conclusion, the MAP 4 -Aβ conjugates offer a promising approach for the development of a safe and effective AD vaccine.

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

“…More specifically (Table 1), Aβ(3-10) [70][71][72] and Aβ(1-6) were among the peptide epitopes used [73]; different copy numbers of the latter were used in another attempt to develop new Aβ-vaccines [74]. In addition, Aβ(1-6) and Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) were used for the synthesis of 4-branched multiple-antigen peptides (MAP) 4 and subsequently administered to mice to develop Aβ specific antibodies [75]. Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) was also used in a cholera toxin B subunit/silkworm pupa vaccine [76] as well as in a yeast-based vaccine (Y-5A15) [77].…”

“…The so-called multiple antigen peptides (MAPs), i.e., synthetic peptide dendrimers which contain two functional structures, a branched oligo-lysine core, and multiple copies of peptide epitopes (often, B-and T-cell ones), have been used as immunogens instead of the conventional peptide/carrier protein conjugates. In a recent study, a four-branched MAP [(MAP) 4 ] was covalently coupled with Aβ linear epitopes, i.e., Aβ (1)(2)(3)(4)(5)(6) or Aβ(1-15), via 6-aminohexanoic acid to enhance epitope flexibility, and the products were used for animal immunization with promising results [75].…”

“…Usage of CFA in vaccine formulation has been associated with undesirable side effects, such as weight loss, leucocytosis, and granulomatous peritonitis in mice [118,120]. Nevertheless, CFA has been used in the formulation of candidate AD vaccines tested in animal preclinical studies, often in combination with IFA [70][71][72]75,82] or in combination with Bordetella pertussis toxin (PT), in order to induce a proinflammatory CNS milieu resembling disease background [95].…”

“…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).…”

A literature review of MRI techniques used to detect amyloid-beta plaques in Alzheimer’s disease patients

“…have been conducted with small sample sizes, using Aβ plaque biomarkers to confirm the therapeutic targets and effects (72). Currently, MR images (in vivo and ex vivo) and histological sections have still not been unequivocally matched to the display of plaques, and there are still some plaques that can only be seen histologically.…”