Wang Teng, Xie Xi-Xiu, Ji Mei, Wang Shao-Wei, Zha Jun, Zhou Wei-Wei, Yu Xiao-Lin, Wei Chen, Ma Shan, Xi Zhi-Ying, Pang Guang-Li, Liu Rui-Tian
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China; School of Life Science, AnHui Agricultural University, HeFei 230036, China.
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
Neuropharmacology. 2016 Jun;105:561-576. doi: 10.1016/j.neuropharm.2016.02.015. Epub 2016 Feb 18.
Alzheimer's disease (AD) is characterized by memory loss, intracellular neurofibrillary tangles, and extracellular plaque deposits composed of β-amyloid (Aβ). Previous reports showed that naturally occurring autoantibodies, such as intravenous immunoglobulin (IVIG), benefited patients with moderate-stage AD who carried an APOE-ε4 allele. However, the mechanism underlying the role of IVIG remains unclear. In this study, we identified naturally occurring autoantibodies against Aβ oligomers (NAbs-Aβo), which were purified by Aβ42 oligomer or Cibacron Blue affinity chromatography from IVIG and termed as Oli-NAbs and Blue-NAbs, respectively. Oli-NAbs and Blue-NAbs recognized Aβ42 oligomers or both Aβ40 and 42 oligomers, differently. Both antibodies inhibited Aβ42 aggregation and attenuated Aβ42-induced cytotoxicity. Compared with vehicles, Oli-NAbs, Blue-NAbs and IVIG significantly improved the memory and cognition, and reduced the soluble and oligomeric Aβ levels in APPswe/PS1dE9 transgenic mice. Further investigation showed that Blue-NAbs at increased doses effectively decreased plaque burden and insoluble Aβ levels, whereas Oli-NAbs significantly declined the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines in vivo. Therefore, high levels of these antibodies against oligomeric Aβ40 or Aβ42 were required, correspondingly, to achieve the optimal effect. NAbs-Aβo could be condensed to a high concentration by affinity chromatography and its isolation from IVIG may not interfere with the normal function of conventional IVIG as its concentration is very low. Thus, the isolated NAbs-Aβo as an extra product of plasma required low cost and the enriched NAbs-Aβo may be more feasible than IVIG for the treatment of AD.
阿尔茨海默病（AD）的特征是记忆力丧失、细胞内神经原纤维缠结以及由β-淀粉样蛋白（Aβ）组成的细胞外斑块沉积。先前的报告显示，天然存在的自身抗体，如静脉注射免疫球蛋白（IVIG），对携带APOE-ε4等位基因的中度AD患者有益。然而，IVIG发挥作用的潜在机制仍不清楚。在本研究中，我们鉴定出了针对Aβ寡聚体的天然存在的自身抗体（NAbs-Aβo），它们通过Aβ42寡聚体或汽巴克隆蓝亲和色谱法从IVIG中纯化得到，分别称为Oli-NAbs和Blue-NAbs。Oli-NAbs和Blue-NAbs对Aβ42寡聚体或Aβ40和42寡聚体两者的识别方式不同。两种抗体均抑制Aβ42聚集并减轻Aβ42诱导的细胞毒性。与载体相比，Oli-NAbs、Blue-NAbs和IVIG显著改善了APPswe/PS1dE9转基因小鼠的记忆力和认知能力，并降低了可溶性和寡聚体Aβ水平。进一步研究表明，剂量增加的Blue-NAbs有效降低了斑块负荷和不溶性Aβ水平，而Oli-NAbs显著降低了体内的小胶质细胞增生和星形胶质细胞增生以及促炎细胞因子的产生。因此，相应地需要高水平的这些针对寡聚体Aβ40或Aβ42的抗体才能达到最佳效果。NAbs-Aβo可以通过亲和色谱法浓缩至高浓度，并且从IVIG中分离它可能不会干扰传统IVIG的正常功能，因为其浓度非常低。因此，分离出的NAbs-Aβo作为血浆的额外产物成本低廉，并且富集的NAbs-Aβo在治疗AD方面可能比IVIG更可行。
