Gallic acid disruption of A beta(1-42) aggregation rescues cognitive decline of APP/PS1 double transgenic mouse
Gallic acid disruption of A beta(1-42) aggregation rescues cognitive decline of APP/PS1 double transgenic mouse
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没食子酸破坏 A beta(1-42) 聚集可挽救 APP/PS1 双转基因小鼠的认知衰退
DOI：
10.1016/j.nbd.2018.11.009
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发表时间：
2019
影响因子：
6.1
通讯作者：
Hou Sheng Tao
中科院分区：
文献类型：
--
作者：
Yu Mei;Chen Xuwei;Liu Jihong;Ma Quan;Zhuo Zhan;Chen Hao;Zhou Lin;Yang Sen;Zheng Lifeng;Ning Chengqing;Xu Jing;Gao Tianming;Hou Sheng Tao
阿尔茨海默病（AD）治疗是最大的未满足的医疗需求之一。开发靶向Aβ聚集的小分子药物是预防和治疗AD的有效途径。我们发现没食子酸（gallic acid，GA）是一种天然存在的多酚类小分子，富含于葡萄籽和葡萄果实中，能够通过减少Aβ1- 42聚集和神经毒性来减轻APP/PS1转基因小鼠的认知功能下降。口服GA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，而且还显著减轻了9月龄APP/PS1小鼠在空间学习、参考记忆、短时识别和空间工作记忆方面出现的更严重的缺陷。GA处理的9月龄APP/PS1小鼠的海马长时程增强（LTP）也显著升高，突触标记蛋白的表达增加。原子力显微镜（AFM）、动态光散射（DLS）和硫代黄素T（ThT）荧光密度分析表明，GA能显著降低Aβ1- 42在体内外的聚集。此外，GA与寡聚体Aβ1- 42预孵育可降低Aβ1-42介导的细胞内钙内流和神经毒性。分子对接研究表明，GA的3，4，5-羟基在非共价稳定GA与Lys 28-Ala 42盐桥的结合中是必不可少的，而-COOH基团对于破坏Aβ1-42的盐桥至关重要。通过氧化产物的羰基与Lys 16的ε-氨基之间的席夫碱形成的预期共价相互作用也是破坏Aβ1- 42 S形三β基序和毒性的关键。总之，这些研究表明GA可以进一步开发为通过破坏Aβ1- 42聚集的形成来治疗AD的药物。
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 Aβ1–42aggregation 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 Aβ1–42aggregation bothin vitroandin vivo. Further, pre-incubating GA with oligomeric Aβ1–42reduced Aβ1–42-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 Aβ1–42. 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 Aβ1–42S-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 Aβ1–42aggregation.