Physics Institute of São Carlos, University of São Paulo, São Carlos, SP, Brazil.
Chem Commun (Camb). 2018 Mar 27;54(26):3294-3297. doi: 10.1039/c8cc01458b.
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.
压力可以改变 Aβ 的聚合物单体平衡，增加压力首先会导致 Aβ-单体释放，但令人惊讶的是，在高于 180 MPa 的压力下会引发聚合反应。通过高压 NMR 光谱法，在不同温度下测定了聚合的偏摩尔体积差 ΔV0 和压缩系数差 Δβ'。D-对映体肽 RD2 和 RD2D3 与单体 Aβ 的结合亲和力明显高于测定的纤维形成亲和力。通过将 Aβ 浓度降低到聚合的临界浓度以下，它们可以抑制有毒寡聚物的形成。化学位移扰动允许鉴定结合位点。D-肽是预防阿尔茨海默病的药物候选物。我们表明，RD2D3 对易患阿尔茨海默病的转基因（APPSwDI）小鼠的认知行为有积极影响。杂二聚体复合物的 Stokes 半径比单独的 Aβ 小，这表明通过高压 NMR 之前鉴定的 Aβ 更紧凑构象的识别。
