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

Abstract

Backgroundβ-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.MethodsThe 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.ResultsEight 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.ConclusionsAOE1 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.

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

“…In previous studies, Aβ42 and AOE1 vaccination effectively induced the production of anti‐Aβ antibodies and improved cognitive performance in AD transgenic mice (Schenk et al, 1999; Wang et al, 2017). In this study, we compared the efficacy of Aβ42 and AOE1 vaccines in EAE/AD mice in parallel.…”

“…Numerous reports have indicated that the antibodies induced by Aβ vaccines contribute to Aβ clearance by promoting microglial activation (Heneka et al, 2015; Xiang et al, 2016). Indeed, our previous reports also demonstrated that the AOE1 vaccine significantly decreased the levels of soluble and fibrillar Aβ and attenuated neuroinflammation in APP/PS1 mice (Wang et al, 2017). However, immunization with Aβ42 promoted inflammation and enhanced Aβ burden in the brains of EAE/AD mice, suggesting that the immune responses triggered by the vaccine induced further microglial activation, promoted neuroinflammation, and suppressed Aβ clearance.…”

“…The AOE1 vaccine was prepared according to a previously described method (Wang et al, 2017). Briefly, a DNA fragment encoding the oligomer‐specific mimotope peptide was inserted into a modified vector of pCTCON2, transfected into EBY100 ( S accharomyces cerevisiae ), and expressed on the yeast cell surface.…”

“…EAE/AD, EAE, and APP/PS1 control mice were injected with CFA/IFA alone (n = 8). For AOE1 immunization, 6‐month‐old male EAE/AD mice were immunized with 6 × 10 7 yeast cells of the AOE1 vaccine (n = 8) five times at biweekly intervals as described previously (Wang et al, 2017). Blood samples (300 μl ) were collected from the tail vein before the immunization protocol was initiated (pre‐bleed) and 10 days after each immunization.…”

“…The AOE1 vaccine is a yeast cell‐based vaccine developed by our group, in which Aβ oligomer‐specific mimotopes are displayed on the yeast cell surface. This vaccine has been shown to effectively attenuate cognitive deficits and neuropathology in APP/PS1 mice (Wang et al, 2017).…”