Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment
Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment
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DOI：
10.1073/pnas.1206433109
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发表时间：
2012-07-31
影响因子：
11.1
通讯作者：
Faendrich, Marcus
中科院分区：
文献类型：
--
作者：
Morgado, Isabel;Wieligmann, Karin;Faendrich, Marcus
寡聚体是β-淀粉样蛋白（A β）肽纤维形成途径的中间体，是阿尔茨海默病（AD）的假定致病元凶。在这里，我们报告的寡聚体特异性抗体片段，KW 1的生物技术生成和生化表征。KW 1不仅区分低聚物和其他A β构象，如原纤维或解聚肽;它还区分不同类型的A β低聚物，如A β（1-40）和A β（1-42）肽形成的低聚物。这种结合的高选择性与许多其他构象抗体形成鲜明对比，这些构象抗体与大量结构类似但顺序不同的抗原相互作用。X射线晶体学，NMR光谱，和肽阵列测量意味着，KW 1识别寡聚体通过疏水性和显着的芳香族表面基序，包括A β残基18-20。KW 1阳性寡聚体出现在人类AD脑样品中，并诱导活脑组织中的突触功能障碍。二价KW 1有效地中和这种效应并干扰A β组装。通过改变原纤维形成级联的特定步骤，它阻止成熟A β原纤维的形成并诱导非原纤维聚集体的积累。我们的数据阐明了寡聚体和原纤维识别的显著机制差异，并表明KW 1在未来研究中检测或抑制特定类型的A β构象异构体的巨大潜力。
Oligomers are intermediates of the beta-amyloid (A beta) peptide fibrillogenic pathway and are putative pathogenic culprits in Alzheimer's disease (AD). Here we report the biotechnological generation and biochemical characterization of an oligomer-specific antibody fragment, KW1. KW1 not only discriminates between oligomers and other A beta conformations, such as fibrils or disaggregated peptide; it also differentiates between different types of A beta oligomers, such as those formed by A beta (1-40) and A beta (1-42) peptide. This high selectivity of binding contrasts sharply with many other conformational antibodies that interact with a large number of structurally analogous but sequentially different antigens. X-ray crystallography, NMR spectroscopy, and peptide array measurements imply that KW1 recognizes oligomers through a hydrophobic and significantly aromatic surface motif that includes A beta residues 18-20. KW1-positive oligomers occur in human AD brain samples and induce synaptic dysfunctions in living brain tissues. Bivalent KW1 potently neutralizes this effect and interferes with A beta assembly. By altering a specific step of the fibrillogenic cascade, it prevents the formation of mature A beta fibrils and induces the accumulation of nonfibrillar aggregates. Our data illuminate significant mechanistic differences in oligomeric and fibril recognition and suggest the considerable potential of KW1 in future studies to detect or inhibit specific types of A beta conformers.