MSU-College of Human Medicine. Department of Translational Science and Molecular Medicine, Grand Rapids, MI, USA.
J Alzheimers Dis. 2013;37(3):593-602. doi: 10.3233/JAD-131235.
The work presented herein addresses a specific portion of the tau pathology, pre-fibrillar oligomers, now thought to be important pathological components in Alzheimer's disease and other neurodegenerative tauopathies. In previous work, we generated an antibody against purified recombinant cross-linked tau dimers, called Tau Oligomeric Complex 1 (TOC1). TOC1 recognizes tau oligomers and its immunoreactivity is elevated in Alzheimer's disease brains. In this report, we expand upon the previous study to show that TOC1 selectively labels tau oligomers over monomers or polymers, and that TOC1 is also reactive in other neurodegenerative tauopathies. Using a series of deletion mutants spanning the tau molecule, we further demonstrate that TOC1 has one continuous epitope located within amino acids 209-224, in the so-called proline rich region. Together with the previous study, our data indicates that TOC1 is a conformation-dependent antibody whose epitope is revealed upon dimerization and oligomerization, but concealed again as polymers form. This characterization of the TOC1 antibody further supports its potential as a powerful biochemical tool that can be used to better investigate the involvement of tau in neurodegenerative diseases.
本文针对 tau 病理学的一个特定部分进行了研究，即预纤维寡聚物，目前认为它是阿尔茨海默病和其他神经退行性 tau 病的重要病理成分。在以前的工作中，我们针对纯化的重组交联 tau 二聚体生成了一种抗体，称为 Tau 寡聚复合物 1（TOC1）。TOC1 可识别 tau 寡聚物，并且在阿尔茨海默病脑中其免疫反应性升高。在本报告中，我们扩展了以前的研究，结果表明 TOC1 选择性标记 tau 寡聚物而不是单体或聚合物，并且 TOC1 在其他神经退行性 tau 病中也具有反应性。通过一系列跨越 tau 分子的缺失突变体，我们进一步证明 TOC1 在所谓的脯氨酸丰富区域内具有一个位于氨基酸 209-224 之间的连续表位。结合以前的研究，我们的数据表明 TOC1 是一种构象依赖性抗体，其表位在二聚化和寡聚化时暴露，但再次形成聚合物时又被掩盖。对 TOC1 抗体的这种特征描述进一步支持了其作为一种强大的生化工具的潜力，可用于更好地研究 tau 在神经退行性疾病中的作用。
