Mechanistic analyses of the suppression of amyloid β42 aggregation by apomorphine
Mechanistic analyses of the suppression of amyloid β42 aggregation by apomorphine
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DOI：
10.1016/j.bmc.2018.01.028
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发表时间：
2018-05-01
影响因子：
3.5
通讯作者：
Irie, Kazuhiro
中科院分区：
文献类型：
--
作者：
Hanaki, Mizuho;Murakami, Kazuma;Irie, Kazuhiro
(R)-阿朴吗啡(1)有可能减少淀粉样β蛋白(Aβ42)的积累，Aβ42是阿尔茨海默病(AD)的病原体。虽然1对Aβ42聚集的抑制作用归因于其苯酚部分的抗氧化作用，但其在分子水平上的抑制机制仍未完全阐明。LC-MS和UV分析表明，1在孵育过程中被自动氧化生成不稳定的邻苯二酮形式(2)，该形式与Aβ42的赖氨酸16和28形成Michael加合物。进一步自氧化形式的1(3)与邻苯二酚和菲部分可抑制与1相当的Aβ42聚集，而用还原剂三(2-羧乙基)膦处理1可降低其抑制活性。H-1-N-15 SOFAST-HMQC核磁共振研究表明，1与Aβ42单体的Arg5、His13、14、Gln15和Lys16相互作用。这些区域在AETA42聚集体中形成分子间的b-折叠。由于3不干扰单体Aβ42的化学位移，我们用1，1，1，3，3，3-六氟-2-丙醇处理的Aβ42进行了聚集实验，以研究3是否与Aβ42齐聚物有关。化合物1和3推迟了齐聚物驱动成核相的开始。尽管它们具有细胞毒性，但它们不会加重Aβ42介导的SH-SY5Y神经母细胞瘤细胞的神经毒性。这些结果表明，通过自氧化扩展1中的共轭体系可以促进其平面性，这是插入Aβ42核的β片层所必需的，从而抑制进一步的聚集。(C)2018爱思唯尔有限公司。保留所有权利。
(R)-Apomorphine (1) has the potential to reduce the accumulation of amyloid beta-protein (A beta 42), a causative agent of Alzheimer's disease (AD). Although the inhibition of A beta 42 aggregation by 1 is ascribable to the antioxidative effect of its phenol moiety, its inhibitory mechanism at the molecular level remains to be fully elucidated. LC-MS and UV analyses revealed that 1 is autoxidized during incubation to produce an unstable o-quinone form (2), which formed a Michael adduct with Lys 16 and 28 of A beta 42. A further autoxidized form of 1 (3) with o-quinone and phenanthrene moieties suppressed A beta 42 aggregation comparable to 1, whereas treating 1 with a reductant, tris(2-carboxyethyl) phosphine diminished its inhibitory activity. H-1-N-15 SOFAST-HMQC NMR studies suggested that 1 interacts with Arg5, His13,14, Gln15, and Lys16 of the A beta 42 monomer. These regions form intermolecular b-sheets in A eta 42 aggregates. Since 3 did not perturb the chemical shift of monomeric A beta 42, we performed aggregation experiments using 1,1,1,3,3,3-hexafluoro-2-propanol-treated A beta 42 to investigate whether 3 associates with A beta 42 oligomers. Compounds 1 and 3 delayed the onset of the oligomer-driven nucleation phase. Despite their cytotoxicity, they did not exacerbate A beta 42-mediated neurotoxicity in SH-SY5Y neuroblastoma cells. These results demonstrate that extension of the conjugated system in 1 by autoxidation can promote its planarity, which is required for intercalation into the beta-sheet of A beta 42 nuclei, thereby suppressing further aggregation. (C) 2018 Elsevier Ltd. All rights reserved.