Yeast-Based Aβ1-15 Vaccine Elicits Strong Immunogenicity and Attenuates Neuropathology and Cognitive Deficits in Alzheimer's Disease Transgenic Mice.

Dong-Qun Liu,Mei Ji,Ya-Ru Huang,Lun Zhang,Xiao-Ge Liu,Rui-Tian Liu,Shuai Lu,Xiao-Ying Sun

doi:10.3390/vaccines8030351

Abstract

Immunotherapy focusing on reducing the amyloid-beta (Aβ) burden is a promising treatment strategy for Alzheimer’s disease (AD). Many clinical studies on AD immunotherapies have failed due to low safety and efficacy, calling for a highly potent AD vaccine which induces sufficient antibody titer while avoiding side effects. Here, we designed a yeast-based vaccine Y-5A15 comprising five copies of Aβ1-15 displayed on the surface of yeast cell wall, and we subcutaneously immunized APP/PS1 mice three times. Our results demonstrated that the Y-5A15 remarkably enhanced the Aβ epitope immunogenicity and elicited high antibody titers against Aβ in AD mice. Importantly, Y-5A15 vaccination successfully reduced Aβ levels, plaque burden and glial activation, rescued synaptic deficits and significantly ameliorated memory and cognitive decline in APP/PS1 transgenic mice, suggesting that the yeast-based Aβ epitope vaccine has a promising potency for the treatment of AD.

Highlights

The neuropathologies of Alzheimer’s disease (AD) are characterized by deposition of β-amyloid (Aβ) peptide in senile plaques and the formation of intracellular neurofibrillary tangles (NFT) [1,2].Aβ peptides have been confirmed to play a central role in the onset and progression of AD for over20 years, and the soluble Aβ oligomers and protofibrils, which are considered to be the most toxic forms of Aβ, responsible for synaptic destruction [3,4,5,6]
To further test the exhibition of 5 × Aβ1-15 epitope on the surface, the yeast cells were incubated with anti-c-Myc antibody, incubated with secondary antibody labelled with FITC, and detected by flow cytometer and confocal microscope, respectively
The results showed that 6E10 and the sera induced by Y-5A15 vaccine bound to Aβ plaques in the brains of APP/PS1 mice, whereas no positive induced by Y-5A15 vaccine bound to Aβ plaques in the brains of APP/PS1 mice, whereas no positive signal was observed with the addition of the sera from yeast vehicle (YEVC)-treated mice, indicating that the induced signal was observed with the addition of the sera from YEVC-treated mice, indicating that the antibodies recognized Aβ plaques (Figure 2e)

Summary

Introduction

The neuropathologies of Alzheimer’s disease (AD) are characterized by deposition of β-amyloid (Aβ) peptide in senile plaques and the formation of intracellular neurofibrillary tangles (NFT) [1,2].Aβ peptides have been confirmed to play a central role in the onset and progression of AD for over20 years, and the soluble Aβ oligomers and protofibrils, which are considered to be the most toxic forms of Aβ, responsible for synaptic destruction [3,4,5,6]. The first vaccine clinical trial in AD patients (AN-1792) failed due to meningoencephalitis in 6% of immunized AD patients, which was associated with autoreactive T cell infiltration into the brains of immunized subjects in combination with a strong, Th1-based adjuvant, QS21 [7,8,9]. Another major issue with the AN-1792 vaccine was insufficient antibody titer due to the weak immunogenicity of Aβ, which limited the therapeutic effect [10,11,12]. An expanded dataset from the phase 3 EMERGE trial on patients receiving high-dose aducanumab reported statistically significant changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores [14], suggesting that a potential Aβ-based vaccine should be administered preventatively and induce robust antibody

Methods

Results

Discussion

Conclusion