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 β-secretase 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 Aβ
42 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 Aβ
1–42 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 Aβ
42 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 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 efficient therapeutic effects on AD treatment. To generate a vaccine that induces antibodies to specifically neutralize Aβ oligomers, we first obtained Aβ
42 oligomeric mimotopes by panning the phage-displayed random peptide libraries using IVIG-AβO as the target protein, then we expressed these mimotopes on EBY100
Saccharomyces cerevisiae to develop a novel Aβ oligomer-specific vaccine
.