A vaccine with Aβ oligomer-specific mimotope attenuates cognitive deficits and brain pathologies in transgenic mice with Alzheimer’s disease

Wang et al. Alzheimer's Research & Therapy (2017) 9:41 DOI 10.1186/s13195-017-0267-5 RESEARCH ARTICLE Open Access A vaccine with Aβ oligomer-specific mimotope attenuates cognitive deficits and brain pathologies in transgenic mice with Alzheimer’s disease Shao-wei Wang1†, Dong-qun Liu1†, Ling-xiao Zhang1†, Mei Ji1, Yang-xin Zhang1,2, Quan-xiu Dong1, Shu-ying Liu1,3, Xi-xiu Xie1 and Rui-tian Liu1* Abstract Background: β-Amyloid peptide (Aβ) oligomers are initial factors used to induce Alzheimer’s disease (AD) development, and Aβ monomers have normal physiological function. The antibodies or vaccines against Aβ monomers have serious problems, such as side effects and low curative effects. Therefore, it is essential to specifically target Aβ oligomers rather than monomers for the treatment of AD. Methods: The mimotopes of Aβ oligomers were obtained by panning the phage-displayed random peptide libraries using oligomer-specific antibodies as targets and expressed on the surface of EBY100 Saccharomyces cerevisiae to generate yeast cell base vaccines. One vaccine (AOE1) induced antibodies specifically against Aβ oligomers and was selected for further study. The APP/PS1 mice were subcutaneously immunized with AOE1 eight times. The levels and characteristics of antibodies induced by AOE1 were determined by enzyme-linked immunosorbent assay. The effect of AOE1 on the cognitive deficits of AD mice was tested by novel object recognition (NOR) and Y-maze. Dot blot analysis, Western blot analysis, and immunohistochemistry were applied to measure the effects of AOE1 on Aβ pathologies, neuroinflammation, and microhemorrhages in the brains of AD mice. Results: Eight mimotope candidates of Aβ oligomers were selected and expressed on EBY100 S. cerevisiae. Only AOE1 vaccine containing mimotope L2 induced antibodies that specifically recognized Aβ42 oligomers rather than monomers. AOE1 immunization significantly increased the AD mice’s exploration times for the novel object in the NOR test and the choices for new arms in the Y-maze test, and it reduced levels of Aβ oligomers and glial activation in the AD mouse brains. No activation of Aβ-specific T cells and microhemorrhages was observed in their brains following AOE1 vaccination. Conclusions: AOE1 is the first vaccine applying the oligomer-specific mimotope as an immunogen, which could induce antibodies with high specificity to Aβ oligomers. AOE1 immunization attenuated Aβ pathologies and cognitive deficits in AD mice, decreased the overactivation of glial cells, and did not induce microhemorrhage in the brains of AD mice. These findings suggest that AOE1 may be a safer and more effective vaccine for AD treatment. Keywords: Alzheimer’s disease, β-amyloid oligomer, Mimotope, Saccharomyces cerevisiae, Vaccine * Correspondence: † Equal contributors 1 National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Haidian District, Beijing 100190, China Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Alzheimer's Research & Therapy (2017) 9:41 Background Alzheimer’s disease (AD) is the most prevalent dementia that seriously threatens the health and life of the elderly [1]. The hallmark pathologies of AD are neuronal extracellular senile plaques consisting of β-amyloid peptide (Aβ) aggregates and intracellular neurofibrillary tangles consisting of abnormally hyperphosphorylated tau protein [2]. Aβ oligomers, aggregated from Aβ monomers, are considered to be the initial cause of AD by inducing tau hyperphosphorylation, oxidative stress, inflammatory response, synaptic dysfunction, and subsequent neurodegeneration that underlie the progression of AD [3, 4]. Aβ is a proteolytic fragment of the amyloid precursor protein (APP) by the sequential enzymatic actions of βsecretase and γ-secretase [5]. APP and Aβ play trophic roles in the development of neurons and synapses [6, 7]. Aβ may exist in several forms, including monomers, oligomers, and fibrils, whereas only the oligomeric forms were considered to be more neurotoxic [8]. Anti-Aβ immunotherapy is an efficient way to clear the Aβ burden and has promising applications in AD treatment. However, the risk of autoimmunity and notable side effects, as well as uncertain therapeutic effects, have restricted the development of immunotherapy against Aβ [9]. The first Aβ vaccine, AN1792 using Aβ42 fibrils as an immunogen, significantly reduced the amyloid burden in AD transgenic mice after vaccination [10]. Unfortunately, AN1792 was terminated in clinical trials because of meningoencephalitis that occurred in 6% of immunized patients with AD [11]. Subsequent research indicated that T-cell-mediated autoimmunity induced by the self-antigen Aβ1–42 was the main cause of this serious adverse effect [12]. To avoid T-cell autoimmunity, the second generation of Aβ vaccines was developed by conjugating a B-cell epitope of Aβ42 with a carrier [13]. However, the antibodies elicited by these vaccines bound to Aβ monomers, oligomers, fibrils, and even APP [14, 15], also leading to cerebral edema and microvascular hemorrhage in the brains of patients with AD, and they did not show remarkably therapeutic effects in the clinical trials [16–18]. Passive immunotherapy using antibodies against Aβ monomers, such as bapineuzumab [19] and solanezumab [20], was also unsuccessful in AD clinical trials. However, aducanumab, an antibody recently developed by Biogen (Cambridge, MA, USA), selectively targeted aggregated Aβ, reduced Aβ levels in brains, and inhibited the clinical decline of recognition in patients with prodromal or mild AD in a phase I clinical trial. Aducanumab entered phase III clinical trials directly without a phase II clinical study [4]. Another phase III clinical study demonstrated that intravenous immunoglobulin (IVIG) exhibited beneficial effects on the subgroup of moderate and apolipoprotein E ε4 allele carrier patients with AD [21]. The antibodies against Aβ Page 2 of 14 oligomers in IVIG were considered to contribute to these beneficial effects on AD treatment [22]. Consistently, our Aβ oligomer-specific antibodies (AβO) purified from IVIG (IVIG-AβO) attenuated the cognitive deficits and Aβ pathologies in APPswe/PS1dE9-transgenic mice [23]. These studies suggest that antibodies targeting Aβ oligomers may exert more (...truncated)