Tanshinone IIA ameliorates Aβ transendothelial transportation through SIRT1-mediated endoplasmic reticulum stress.
Tanshinone IIA ameliorates Aβ transendothelial transportation through SIRT1-mediated endoplasmic reticulum stress.
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DOI：
10.1186/s12967-023-03889-y
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发表时间：
2023-01-20
影响因子：
7.4
通讯作者：
Zhang, Shi-Jie
中科院分区：
文献类型：
--
作者：
Wan, Can;Liu, Xiao-Qi;Chen, Mei;Ma, Hui-Han;Wu, Guang-Liang;Qiao, Li-Jun;Cai, Ye-Feng;Zhang, Shi-Jie
关键词：
以脑微血管内皮细胞（BMEC）为主要成分的血脑屏障（BBB）的破坏是阿尔茨海默病（AD）的特征之一。因此，改善BMEC功能可能对AD治疗有益。丹参酮IIA（Tan IIA）已被证明能改善AD的认知功能障碍。在此，我们探讨了Tan IIA如何影响AD中BMEC的功能。采用Aβ1-42处理的脑源性内皮细胞3（bEnd.3细胞）进行体外实验。并通过分子对接和qPCR方法确定了Tan IIA在Sirtuins家族中的靶分子。应用APPswe/PSdE 9（APP/PS1）小鼠进行体内实验。在行为测试之后，通过蛋白质印迹和免疫荧光测定蛋白质表达。用生化试剂盒分析氧化应激相关酶的活性。Nissl染色和ThioflavinT染色分别反映神经元变性和Aβ沉积。分子对接和qPCR结果表明，Tan IIA主要作用于Sirtuins家族中的Sirtuin 1（SIRT 1）。采用SIRT 1抑制剂（EX 527）进一步证实Tan IIA可减弱SIRT 1介导的BMEC内质网应激（ER应激）。行为学测试表明，Tan IIA可以改善APP/PS1小鼠的认知缺陷。Tan IIA给药增加APP/PS1小鼠SIRT 1表达并减轻ER应激。此外，在动物和细胞中，Tan IIA给药后LRP 1表达增加，Tan IIA表达降低。Tan IIA可通过减轻SIRT 1介导的ER应激，促进BMEC内Aβ的转运，从而改善APP/PS1小鼠的认知功能障碍。在线版本包含补充材料，可通过10.1186/s12967-023-03889-y获得。
The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer’s disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD. Aβ1–42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aβ deposition respectively. Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells. Tan IIA could promote Aβ transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice. The online version contains supplementary material available at 10.1186/s12967-023-03889-y.
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影响因子：
4.2
作者：
Devi L;Ohno M
通讯作者：
Ohno M
影响因子：
5.6
作者：
Ghemrawi R;Khair M
通讯作者：
Khair M
影响因子：
9.3
作者：
Ding B;Lin C;Liu Q;He Y;Ruganzu JB;Jin H;Peng X;Ji S;Ma Y;Yang W
通讯作者：
Yang W
DOI：
10.1016/j.jalz.2017.02.006
发表时间：
2017-04-01
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Karlawish, Jason;Jack, Clifford R Jr;Carrillo, Maria C
通讯作者：
Carrillo, Maria C
影响因子：
1.8
作者：
Eftekhari, Aziz;Azarmi, Yadollah;Eghbal, Mohammad Ali
通讯作者：
Eghbal, Mohammad Ali