Fukuchi Ken-ichiro, Accavitti-Loper Mary Ann, Kim Hong-Duck, Tahara Kazuki, Cao Yunpeng, Lewis Terry L, Caughey Robert C, Kim Helen, Lalonde Robert
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Box 1649, Peoria, IL 61656, USA.
Biochem Biophys Res Commun. 2006 May 26;344(1):79-86. doi: 10.1016/j.bbrc.2006.03.145.
Parenteral immunization of transgenic mouse models of Alzheimer disease (AD) with synthetic amyloid beta-peptide (Abeta) prevented or reduced Abeta deposits and attenuated their memory and learning deficits. A clinical trial of immunization with synthetic Abeta, however, was halted due to brain inflammation, presumably induced by a toxic Abeta, T-cell- and/or Fc-mediated immune response. Another issue relating to such immunizations is that some AD patients may not be able to raise an adequate immune response to Abeta vaccination due to immunological tolerance or age-associated decline. Because peripheral administration of antibodies against Abeta also induced clearance of amyloid plaques in the model mice, injection of humanized Abeta antibodies has been proposed as a possible therapy for AD. By screening a human single-chain antibody (scFv) library for Abeta immunoreactivity, we have isolated a scFv that specifically reacts with oligomeric Abeta as well as amyloid plaques in the brain. The scFv inhibited Abeta amyloid fibril formation and Abeta-mediated cytotoxicity in vitro. We have tested the efficacy of the human scFv in a mouse model of AD (Tg2576 mice). Relative to control mice, injections of the scFv into the brain of Tg2576 mice reduced Abeta deposits. Because scFvs lack the Fc portion of the immunoglobulin molecule, human scFvs against Abeta may be useful to treat AD patients without eliciting brain inflammation.
用合成淀粉样β肽（Aβ）对阿尔茨海默病（AD）转基因小鼠模型进行肠胃外免疫可预防或减少Aβ沉积，并减轻其记忆和学习缺陷。然而，一项用合成Aβ进行免疫的临床试验因脑部炎症而停止，推测这种炎症是由有毒的Aβ、T细胞和/或Fc介导的免疫反应所引发的。与这种免疫相关的另一个问题是，一些AD患者可能由于免疫耐受或年龄相关的免疫功能衰退而无法对Aβ疫苗接种产生足够的免疫反应。由于向模型小鼠外周注射抗Aβ抗体也能诱导淀粉样斑块的清除，因此有人提出注射人源化Aβ抗体可能是一种治疗AD的方法。通过筛选人单链抗体（scFv）文库以检测其对Aβ的免疫反应性，我们分离出了一种能与寡聚Aβ以及大脑中的淀粉样斑块特异性反应的scFv。该scFv在体外抑制了Aβ淀粉样原纤维的形成以及Aβ介导的细胞毒性。我们在AD小鼠模型（Tg2576小鼠）中测试了人scFv的疗效。相对于对照小鼠，向Tg2576小鼠脑内注射scFv减少了Aβ沉积。由于scFv缺乏免疫球蛋白分子的Fc部分，针对Aβ的人scFv可能有助于治疗AD患者而不引发脑部炎症。
