Brain Research Centre and Department of Biology, Southern University of Science and Technology, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, Guangdong Province 518055, PR China.
Key Laboratory of Psychiatric Disorders of Guangdong Province, Southern Medical University, Guangzhou 510515, PR China.
Neurobiol Dis. 2019 Apr;124:67-80. doi: 10.1016/j.nbd.2018.11.009. Epub 2018 Nov 14.
Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing small molecules targeting Aβ aggregation is an effective approach to prevent and treat AD. Here, we show that gallic acid (GA), a naturally occurring polyphenolic small molecule rich in grape seeds and fruits, has the capacity to alleviate cognitive decline of APP/PS1 transgenic mouse through reduction of Aβ aggregation and neurotoxicity. Oral administration of GA not only improved the spatial reference memory and spatial working memory of 4-month-old APP/PS1 mice, but also significantly reduced the more severe deficits developed in the 9-month-old APP/PS1 mice in terms of spatial learning, reference memory, short-term recognition and spatial working memory. The hippocampal long-term-potentiation (LTP) was also significantly elevated in the GA-treated 9-month-old APP/PS1 mice with increased expression of synaptic marker proteins. Evidence from atomic force microscopy (AFM), dynamic light scattering (DLS) and thioflavin T (ThT) fluorescence densitometry analyses showed that GA significantly reduces Aβ aggregation both in vitro and in vivo. Further, pre-incubating GA with oligomeric Aβ reduced Aβ-mediated intracellular calcium influx and neurotoxicity. Molecular docking studies identified that the 3,4,5-hydroxyle groups of GA were essential in noncovalently stabilizing GA binding to the Lys28-Ala42 salt bridge and the -COOH group is critical for disrupting the salt bridge of Aβ. The predicated covalent interaction through Schiff-base formation between the carbonyl group of the oxidized product and ε-amino group of Lys16 is also critical for the disruption of Aβ S-shaped triple-β-motif and toxicity. Together, these studies demonstrated that GA can be further developed as a drug to treat AD through disrupting the formation of Aβ aggregation.
阿尔茨海默病（AD）的治疗是最大的未满足的医疗需求之一。开发针对 Aβ聚集的小分子是预防和治疗 AD 的有效方法。在这里，我们表明，没食子酸（GA），一种天然存在的多酚小分子，富含葡萄籽和水果，具有通过减少 Aβ聚集和神经毒性来减轻 APP/PS1 转基因小鼠认知下降的能力。GA 的口服给药不仅改善了 4 月龄 APP/PS1 小鼠的空间参考记忆和空间工作记忆，而且还显著降低了 9 月龄 APP/PS1 小鼠在空间学习、参考记忆、短期识别和空间工作记忆方面更严重的缺陷。GA 还显著提高了 GA 治疗的 9 月龄 APP/PS1 小鼠的海马长时程增强（LTP），同时增加了突触标记蛋白的表达。原子力显微镜（AFM）、动态光散射（DLS）和硫黄素 T（ThT）荧光密度分析的证据表明，GA 显著减少了体外和体内的 Aβ聚集。此外，GA 与寡聚体 Aβ预先孵育可减少 Aβ介导的细胞内钙流入和神经毒性。分子对接研究表明，GA 的 3,4,5-羟基是 GA 与 Lys28-Ala42 盐桥非共价稳定结合的必需基团，-COOH 基团对于破坏 Aβ的盐桥是至关重要的。预测的通过氧化产物的羰基与 Lys16 的 ε-氨基形成席夫碱的共价相互作用对于破坏 Aβ S 形三-β基序和毒性也是至关重要的。总的来说，这些研究表明，GA 可以通过破坏 Aβ聚集的形成，进一步开发为治疗 AD 的药物。
