An imbalance between production and clearance of soluble amyloid-β (Aβ) initiates the pathological process in sporadic Alzheimer's disease (AD). Aβ-specific antibodies seemed promising as therapeutic option in AD mouse models. In patients, however, vascular side-effects and Aβ-antibody complex-induced microglial and/or perivascular macrophage inflammatory responses were encountered.

To prevent inflammatory reactions, we designed a single chain variable fragment (scFv-h3D6), based on monoclonal antibody bapineuzumab (mAb-h3D6), but lacking the Fc region. ScFv-h3D6 reduced Aβ-oligomer burden and prevented AD-associated behavioral and cellular changes in 3xTg-AD mice. As scFv-h3D6 lacks the Fc-tail, it cannot enhance Fc-receptor mediated Aβ clearance by microglia and probably exerts its beneficial effects in 3xTg-AD mice through other mechanisms. ScFv-h3D6 restored the increased apoE and apoJ levels in 3xTg-AD brains back to normal. ApoE and apoJ influence cholesterol transport, Aβ aggregation and clearance, and their genetic variants are risk factors for sporadic AD. Astrocytes are constitutive scavengers of soluble Aβ from the CNS. We previously found apoE and apoJ to inhibit Aβ uptake by adult human astrocytes, in vitro, and thus to potentially protect astrocytes from Aβ cytotoxicity.

In the present study, scFv-h3D6 and mAb-h3D6 inhibited Aβ-oligomer uptake by adult human astrocytes. ApoE- and apoJ- mimetic peptides (MP) affected Aβ uptake as well as Aβ-induced cytokine release similar to intact apoE and apoJ, without interfering with the strong inhibitory effects of scFv-h3D6 on Aβ-oligomer uptake. These results suggest that combining Aβ-specific scFv and apoE-MP, that inhibits Aβ oligomer-induced cytokine release by astrocytes, could offer advantages over currently used therapeutics.

可溶性淀粉样β（Aβ）的产生与清除之间的不平衡引发了偶发性阿尔茨海默氏病（AD）的病理过程。Aβ特异性抗体似乎有望在AD小鼠模型中作为治疗选择。然而，在患者中，遇到了血管副作用和Aβ-抗体复合物诱导的小胶质细胞和/或血管周围巨噬细胞的炎症反应。

为防止炎症反应，我们基于单克隆抗体bapineuzumab（mAb-h3D6）设计了一个单链可变片段（scFv-h3D6），但缺少Fc区。ScFv-h3D6减少了3xTg-AD小鼠的Aβ-寡聚体负担并防止了AD相关的行为和细胞变化。由于scFv-h3D6缺少Fc尾巴，因此它无法增强小胶质细胞介导的Fc受体介导的Aβ清除，并可能通过其他机制在3xTg-AD小鼠中发挥其有益作用。ScFv-h3D6使3xTg-AD脑中增加的apoE和apoJ水平恢复正常。ApoE和apoJ影响胆固醇转运，Aβ聚集和清除，其遗传变异是散发性AD的危险因素。星形胶质细胞是来自CNS的可溶性Aβ的组成型清除剂。我们先前发现apoE和apoJ抑制成年人类星形胶质细胞摄取Aβ，在体外，从而潜在地保护星形胶质细胞免受Aβ细胞毒性作用。

在本研究中，scFv-h3D6和mAb-h3D6抑制成人星形胶质细胞摄取Aβ-寡聚体。与完整的apoE和apoJ相似，ApoE和apoJ模拟肽（MP）影响Aβ摄取以及Aβ诱导的细胞因子释放，而不会干扰scFv-h3D6对Aβ低聚物摄取的强烈抑制作用。这些结果表明，抑制Aβ寡聚体诱导的星形胶质细胞释放的Aβ特异性scFv和apoE-MP相结合，可以提供优于目前使用的治疗剂的优势。