Wang Shao-Wei, Liu Dong-Qun, Zhang Ling-Xiao, Ji Mei, Zhang Yang-Xin, Dong Quan-Xiu, Liu Shu-Ying, Xie Xi-Xiu, Liu Rui-Tian
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Haidian District, Beijing, 100190, China.
School of Life Science, Anhui Agricultural University, Hefei, 230036, China.
Alzheimers Res Ther. 2017 Jun 7;9(1):41. doi: 10.1186/s13195-017-0267-5.
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.
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.
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.
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.
β淀粉样肽（Aβ）寡聚体是诱导阿尔茨海默病（AD）发展的起始因素，而Aβ单体具有正常的生理功能。针对Aβ单体的抗体或疫苗存在严重问题，如副作用和疗效低。因此，针对AD治疗，特异性靶向Aβ寡聚体而非单体至关重要。
以寡聚体特异性抗体为靶点，通过淘选噬菌体展示随机肽库获得Aβ寡聚体的模拟表位，并在EBY100酿酒酵母表面表达以制备酵母细胞基础疫苗。筛选出一种能诱导特异性针对Aβ寡聚体抗体的疫苗（AOE1）进行进一步研究。将AOE1皮下免疫APP/PS1小鼠8次。通过酶联免疫吸附测定法测定AOE1诱导的抗体水平和特性。通过新物体识别（NOR）和Y迷宫试验检测AOE1对AD小鼠认知缺陷的影响。采用斑点印迹分析、蛋白质印迹分析和免疫组织化学方法检测AOE1对AD小鼠脑内Aβ病变、神经炎症和微出血的影响。
筛选出8个Aβ寡聚体的模拟表位候选物并在EBY100酿酒酵母上表达。只有含有模拟表位L2的AOE1疫苗诱导的抗体能特异性识别Aβ42寡聚体而非单体。AOE1免疫显著增加了AD小鼠在NOR试验中对新物体的探索时间以及在Y迷宫试验中对新臂的选择次数，并降低了AD小鼠脑内Aβ寡聚体水平和胶质细胞活化。AOE1疫苗接种后，未在其脑内观察到Aβ特异性T细胞活化和微出血。
AOE1是第一种将寡聚体特异性模拟表位作为免疫原的疫苗，可诱导对Aβ寡聚体具有高特异性的抗体。AOE1免疫减轻了AD小鼠的Aβ病变和认知缺陷，降低了胶质细胞的过度活化，且未在AD小鼠脑内诱导微出血。这些发现表明AOE1可能是一种更安全、更有效的AD治疗疫苗。
Zotero 插件