A monoclonal antibody against synthetic Aβ dimer assemblies neutralizes brain-derived synaptic plasticity-disrupting Aβ.
A monoclonal antibody against synthetic Aβ dimer assemblies neutralizes brain-derived synaptic plasticity-disrupting Aβ.
复制标题
针对合成 Aβ 二聚体组件的单克隆抗体中和脑源性突触可塑性破坏 Aβ。
DOI：
10.1111/j.1471-4159.2011.07389.x
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发表时间：
2011
影响因子：
4.7
通讯作者：
Walsh,DominicM
中科院分区：
文献类型：
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作者：
O'Nuallain,Brian;Klyubin,Igor;McDonald,JessicaM;Foster,JamesS;Welzel,Alfred;Barry,Andrew;Dykoski,RichardK;Cleary,JamesP;Gebbink,MartijnFBG;Rowan,MichaelJ;Walsh,DominicM
J. Neurochem.(2011)119, 189–201.摘要不同的证据表明，β-淀粉样蛋白 (Aβ) 的纤维前扩散组装在阿尔茨海默病的发病机制中发挥着重要作用。尽管这些可溶性毒素的精确分子身份仍未确定，但最近的实验表明，十二烷基硫酸钠 (SDS) 稳定的 Aβ 二聚体可能是阿尔茨海默病相关突触毒性组件的基本组成部分，因此为治疗干预提供了一个有吸引力的目标。在缺乏足够量的高纯度脑 Aβ 二聚体的情况下，我们使用合成的二硫键交联二聚体（不含 Aβ 单体或原纤维）来生成构象特异性单克隆抗体。这些二聚体聚集形成动力学捕获的原纤维，但不容易形成原纤维。我们鉴定了两种抗体 3C6 和 4B5，它们优先结合由共价 Aβ 二聚体形成的组装体，但不结合 Aβ 单体、淀粉样蛋白前体蛋白或由其他淀粉样蛋白形成的聚集体。单克隆抗体 3C6（而非 IgM 同种型匹配的对照抗体）改善了从阿尔茨海默氏病大脑水相中提取的 Aβ 的可塑性破坏作用，因此表明 3C6 靶向致病相关的 Aβ 组装体。这些数据证明了共价二聚体及其组装体作为免疫原的有用性，并建议进一步研究针对此类组装体产生的单克隆抗体的治疗和诊断效用。
J. Neurochem.(2011)119, 189–201.AbstractDiverse lines of evidence indicate that pre‐fibrillar, diffusible assemblies of the amyloid β‐protein (Aβ) play an important role in Alzheimer’s disease pathogenesis. Although the precise molecular identity of these soluble toxins remains unsettled, recent experiments suggest that sodium dodecyl sulfate (SDS)‐stable Aβ dimers may be the basic building blocks of Alzheimer’s disease‐associated synaptotoxic assemblies and as such present an attractive target for therapeutic intervention. In the absence of sufficient amounts of highly pure cerebral Aβ dimers, we have used synthetic disulfide cross‐linked dimers (free of Aβ monomer or fibrils) to generate conformation‐specific monoclonal antibodies. These dimers aggregate to form kinetically trapped protofibrils, but do not readily form fibrils. We identified two antibodies, 3C6 and 4B5, which preferentially bind assemblies formed from covalent Aβ dimers, but do not bind to Aβ monomer, amyloid precursor protein, or aggregates formed by other amyloidogenic proteins. Monoclonal antibody 3C6, but not an IgM isotype‐matched control antibody, ameliorated the plasticity‐disrupting effects of Aβ extracted from the aqueous phase of Alzheimer’s disease brain, thus suggesting that 3C6 targets pathogenically relevant Aβ assemblies. These data prove the usefulness of covalent dimers and their assemblies as immunogens and recommend further investigation of the therapeutic and diagnostic utility of monoclonal antibodies raised to such assemblies.