为什么绿茶对大脑有益? 来看化学学科顶级杂志揭秘
2017/10/16
近日,加拿大McMaster大学在JACS揭示了为什么绿茶提取物能作为神经毒性抑制剂,对抗阿尔茨海默氏症等疾病。研究人员会继续解决将其作为有效食品添加剂中的实际问题。


加拿大McMaster大学进行的这项研究揭示了绿茶对大脑有益的潜在机制。绿茶提取物的抗氧化和解毒特性,有助于对抗像阿尔茨海默氏症这样灾难性的疾病。然而,科学家们还没有完全理解它们在分子水平上的作用,以及如何利用它们来找到更好的治疗方法。

临床前证据表明,绿茶茶多酚的主要组成部分被称为EGCG(表没食子儿茶素没食子酸酯),能够干扰患阿尔兹海默症患者大脑中毒性低聚物的组装形成,在分子级联的早期步骤,这是导致患者认知能力下降的重要因素之一。

核磁共振的新方法解密分子机理

Giuseppe Melacini教授解释说,他们认为EGCG包裹毒性低聚物,并阻止它们发展和与健康细胞的作用。然而,EGCG诱导的分子机制尚不完全清楚。

结合15N和1H暗态交换饱和转移(DEST)——一种核磁共振的新方法,并与荧光化学位移投影核磁共振、动态光散射和电子显微镜的方法,来探讨EGCG对β淀粉样蛋白低聚物的影响。他们发现和EGCG 结合后,Aβ(1–40)的结构有了很大变化。这些明显的结构变化对于理解EGCG为什么是神经毒性抑制剂的分子机理提供了基础。


研究人员说,这项发现是核磁共振(NMR)方法发展的成果,也体现了DEST为基础的核磁共振新方法在发现低分子量淀粉样蛋白抑制剂方面的有效性。这一发现在化学学科的顶级杂志封面上发表,可能会带来新的治疗方法和进一步的药物发现。

实际实施还有问题有待解决

一旦出现症状,老年痴呆症就无法治愈,所以最好是能够进行早期干预。这可能意味可以在疾病发生的15到25年前,还没有任何症状的时候,使用绿茶提取物或其衍生物。

接下来,研究人员希望解决一些在实际实施中带来困难的问题,例如如何修饰EGCG和类似的分子,以便它们能有效地用作食品添加剂。EGCG在室温下是不稳定的,众所周知难以进入人体,尤其是大脑。

Melacini教授说“食品添加剂也许能作为一个关键或辅助性的治疗。除了运动和健康的生活方式,在人还年轻的时候利用起食品添加剂的价值对于增加健康老龄化的机会非常重要”。

参考资料

1) Molecular Mechanism for the(−)-Epigallocatechin Gallate-Induced Toxic to Nontoxic Remodeling of Aβ Oligomers

2) Green tea extract delivers molecular punch to disrupt formation of neurotoxic species

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  • Molecular Mechanism for the (−)-Epigallocatechin Gallate-Induced Toxic to Nontoxic Remodeling of Aβ Oligomers

    (−)-Epigallocatechin gallate (EGCG) effectively reduces the cytotoxicity of the Alzheimer’s disease β-amyloid peptide (Aβ) by remodeling seeding-competent Aβ oligomers into off-pathway seeding-incompetent Aβ assemblies. However, the mechanism of EGCG-induced remodeling is not fully understood. Here we combine 15N and 1H dark-state exchange saturation transfer (DEST), relaxation, and chemical shift projection NMR analyses with fluorescence, dynamic light scattering, and electron microscopy to elucidate how EGCG remodels Aβ oligomers. We show that the remodeling adheres to a Hill–Scatchard model whereby the Aβ(1–40) self-association occurs cooperatively and generates Aβ(1–40) oligomers with multiple independent binding sites for EGCG with a Kd ∼10-fold lower than that for the Aβ(1–40) monomers. Upon binding to EGCG, the Aβ(1–40) oligomers become less solvent exposed, and the β-regions, which are involved in direct monomer–protofibril contacts in the absence of EGCG, undergo a direct-to-tethered contact shift. This switch toward less engaged monomer–protofibril contacts explains the seeding incompetency observed upon EGCG remodeling and suggests that EGCG interferes with secondary nucleation events known to generate toxic Aβ assemblies. Unexpectedly, the N-terminal residues experience an opposite EGCG-induced shift from tethered to direct contacts, explaining why EGCG remodeling occurs without release of Aβ(1–40) monomers. We also show that upon binding Aβ(1–40) oligomers the relative positions of the EGCG B and D rings change with respect to that of ring A. These distinct structural changes occurring in both Aβ(1–40) oligomers and EGCG during remodeling offer a foundation for understanding the molecular mechanism of EGCG as a neurotoxicity inhibitor. Furthermore, the results reported here illustrate the effectiveness of DEST-based NMR approaches in investigating the mechanism of low-molecular-weight amyloid inhibitors.

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