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Inhibition of amyloid Aβ aggregation by high pressures or specific d-enantiomeric peptides†
Chemical Communications ( IF 4.3 ) Pub Date : 2018-03-02 00:00:00 , DOI: 10.1039/c8cc01458b Italo A. Cavini 1, 2, 3, 4, 5 , Claudia E. Munte 1, 2, 3, 4, 5 , Markus Beck Erlach 5, 6, 7, 8 , Thomas van Groen 9, 10, 11 , Inga Kadish 9, 10, 11 , Tao Zhang 8, 12, 13, 14, 15 , Tamar Ziehm 8, 15, 16, 17, 18 , Luitgard Nagel-Steger 8, 12, 13, 14, 15 , Janine Kutzsche 8, 15, 16, 17, 18 , Werner Kremer 5, 6, 7, 8 , Dieter Willbold 8, 12, 13, 14, 15 , Hans Robert Kalbitzer 5, 6, 7, 8
Chemical Communications ( IF 4.3 ) Pub Date : 2018-03-02 00:00:00 , DOI: 10.1039/c8cc01458b Italo A. Cavini 1, 2, 3, 4, 5 , Claudia E. Munte 1, 2, 3, 4, 5 , Markus Beck Erlach 5, 6, 7, 8 , Thomas van Groen 9, 10, 11 , Inga Kadish 9, 10, 11 , Tao Zhang 8, 12, 13, 14, 15 , Tamar Ziehm 8, 15, 16, 17, 18 , Luitgard Nagel-Steger 8, 12, 13, 14, 15 , Janine Kutzsche 8, 15, 16, 17, 18 , Werner Kremer 5, 6, 7, 8 , Dieter Willbold 8, 12, 13, 14, 15 , Hans Robert Kalbitzer 5, 6, 7, 8
Affiliation
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Pressure can shift the polymer–monomer equilibrium of Aβ, increasing pressure first leads to a release of Aβ-monomers, surprisingly at pressures higher than 180 MPa repolymerization is induced. By high pressure NMR spectroscopy, differences of partial molar volumes ΔV0 and compressibility factors Δβ′ of polymerization were determined at different temperatures. The D-enantiomeric peptides RD2 and RD2D3 bind to monomeric Aβ with affinities substantially higher than those determined for fibril formation. By reducing the Aβ concentration below the critical concentration for polymerization they inhibit the formation of toxic oligomers. Chemical shift perturbation allows the identification of the binding sites. The D-peptides are candidates for drugs preventing Alzheimer's disease. We show that RD2D3 has a positive effect on the cognitive behaviour of transgenic (APPSwDI) mice prone to Alzheimer's disease. The heterodimer complexes have a smaller Stokes radius than Aβ alone indicating the recognition of a more compact conformation of Aβ identified by high pressure NMR before.
中文翻译：
高压或特定的d-对映体肽对淀粉样蛋白Aβ聚集的抑制作用†
压力会改变Aβ的聚合物-单体平衡，首先增加压力会导致Aβ单体的释放，令人惊讶的是，在高于180 MPa的压力下引发了再聚合。通过高压NMR谱，偏摩尔体积的差异Δ V 0和压缩因子Δ β聚合的“在不同温度下进行了测定。的d -对映体肽RD2和RD2D3结合单体Aβ与亲和力比原纤维形成测定显着更高。通过将Aβ浓度降低到聚合反应的临界浓度以下，它们可抑制有毒低聚物的形成。化学位移扰动允许鉴定结合位点。该d-肽是预防阿尔茨海默氏病的药物的候选物。我们显示RD2D3对易患阿尔茨海默氏病的转基因（APPSwDI）小鼠的认知行为具有积极影响。异二聚体复合物的斯托克斯半径比单独的Aβ小，表明先前已通过高压NMR鉴定出了更紧凑的Aβ构象。
更新日期：2018-03-02
中文翻译：
高压或特定的d-对映体肽对淀粉样蛋白Aβ聚集的抑制作用†
压力会改变Aβ的聚合物-单体平衡，首先增加压力会导致Aβ单体的释放，令人惊讶的是，在高于180 MPa的压力下引发了再聚合。通过高压NMR谱，偏摩尔体积的差异Δ V 0和压缩因子Δ β聚合的“在不同温度下进行了测定。的d -对映体肽RD2和RD2D3结合单体Aβ与亲和力比原纤维形成测定显着更高。通过将Aβ浓度降低到聚合反应的临界浓度以下，它们可抑制有毒低聚物的形成。化学位移扰动允许鉴定结合位点。该d-肽是预防阿尔茨海默氏病的药物的候选物。我们显示RD2D3对易患阿尔茨海默氏病的转基因（APPSwDI）小鼠的认知行为具有积极影响。异二聚体复合物的斯托克斯半径比单独的Aβ小，表明先前已通过高压NMR鉴定出了更紧凑的Aβ构象。
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