School of Chemical Science and Engineering, Tongji University, Shanghai 200092, China.
School of Medicine, Tongji University, Shanghai 200092, China.
ACS Chem Neurosci. 2020 Nov 4;11(21):3623-3634. doi: 10.1021/acschemneuro.0c00508. Epub 2020 Oct 13.
Inhibition of Tau protein aggregation is an attractive therapeutic target for Alzheimer's disease. However, most of the inhibitors have failed in clinical trials due to the superficial understanding of inhibition mechanism and drug-transfer pharmacokinetics. Innovation of design strategy has become a top priority. To afford a hairpinlike molecular inhibitor, we introduced tannic acid, a multibranched polyphenol molecule, and its moiety, gallic acid. We showed that tannic acid could effectively inhibit Tau aggregation through a multidentate chelation mode. We then encapsulated tannic acid in a non-neurotoxic liposome by lecithin/β-sitosterol, overcoating with Tween 80. Using transwell devices, we cytologically demonstrated that tannic acid liposome can successfully be transferred across the model of a blood-brain barrier made up of mouse brain microvascular endothelial cell bEnd.3 and effectively reduce Tau aggregation induced by fibrils of Tau peptide R3 in human neuroblastoma cell SK-N-SH. This result indicates the potential therapeutic effect of tannic acid liposome on Alzheimer's disease.
抑制 Tau 蛋白聚集是治疗阿尔茨海默病的一个有吸引力的治疗靶点。然而，由于对抑制机制和药物传递药代动力学的肤浅理解，大多数抑制剂在临床试验中都失败了。设计策略的创新已成为当务之急。为了提供一种发夹状的分子抑制剂，我们引入了单宁酸，一种多支化的多酚分子，及其部分成分没食子酸。我们表明，单宁酸可以通过多齿螯合模式有效地抑制 Tau 聚集。然后，我们通过卵磷脂/β-谷甾醇将单宁酸包裹在非神经毒性的脂质体中，并用吐温 80 覆盖。通过 Transwell 装置，我们细胞学地证明了单宁酸脂质体可以成功地穿过由小鼠脑微血管内皮细胞 bEnd.3 组成的血脑屏障模型，并有效地减少由 Tau 肽 R3 纤维诱导的人神经母细胞瘤细胞 SK-N-SH 中的 Tau 聚集。这一结果表明单宁酸脂质体对阿尔茨海默病具有潜在的治疗作用。
