Activating transcription factor 6 reduces Aβ1-42 and restores memory in Alzheimer's disease model mice
Activating transcription factor 6 reduces Aβ1-42 and restores memory in Alzheimer's disease model mice
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DOI：
10.1080/00207454.2020.1715977
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发表时间：
2020-01-21
影响因子：
2.2
通讯作者：
Wu, Xiaopan
中科院分区：
文献类型：
--
作者：
Du, Yayun;Liu, Xiaoli;Wu, Xiaopan
目的：淀粉样斑块是阿尔茨海默病最重要的病理标志。淀粉样斑块的沉积会引起内质网应激。转录激活因子6（Activating Transcription Factor 6，ATF 6）是内质网应激的感受器。然而，ATF 6在阿尔茨海默病中的作用尚未报道。方法：采用Western blot、ELISA和硫磺素S染色法检测β-APP裂解酶1（BACE 1）和A β 1-42的表达。采用Y迷宫和Morris水迷宫实验检测大鼠的学习记忆功能。双荧光素酶法检测BACE 1和ADAM 17的启动子活性。结果如下：在我们的研究中，我们发现与野生型小鼠相比，ATF 6在APPswe/PSNdE 9（APP/PS1）阿尔茨海默病模型小鼠中的表达降低。在LN 229细胞中，我们发现ATF 6在蛋白水平上降低了全长淀粉样前体蛋白（APP）的表达。同时，ATF 6的过表达显著降低了A β 1-42的水平。有趣的是，ATF 6也下调了BACE 1的启动子活性。Y迷宫和Morris水迷宫实验表明ATF 6对APP/PS1小鼠的空间记忆保持有保护作用。结论：我们的研究结果表明，ATF 6通过下调BACE 1挽救淀粉样病变。因此，我们认为ATF 6可能是阿尔茨海默病靶向治疗的潜在枢纽。
Objectives: Amyloid plaques are the most important pathological hallmarks of Alzheimer's disease. The deposition of amyloid plaques will cause ER Stress. Activating Transcription Factor 6(ATF6) is a sensor of ER Stress. However, the role of ATF6 in Alzheimer's disease has not been reported yet. Methods: The levels of beta-site APP-cleaving enzyme 1 (BACE1) and A beta 1-42 were detected by Western blot, ELISA and Thioflavin S staining. Y maze and Morris water maze tests were used to detect the learning and memory functions. Dual luciferase assay was used to test the promoter activity of BACE1 and ADAM17. Results: In our study, we found that the expression of ATF6 was reduced in APPswe/PSNdE9 (APP/PS1) Alzheimer's disease model mice compared with wild type mice. Furthermore, in LN229 cell, we found that ATF6 reduced the expression of full length amyloid precursor protein (APP) in protein level. At the same time, the overexpression of ATF6 strikingly reduced the level of A beta 1-42. Interestingly, ATF6 also downregulated the promoter activity of BACE1. And some behavioral experiments like Y maze and Morris water maze test indicated that ATF6 could protect retention of spatial memory in APP/PS1 mice. Conclusion: Our findings indicated that ATF6 rescued the amyloid pathology by downregulating BACE1. Therefore, we suggest that ATF6 could be a potential hub for targeting treatment of the Alzheimer's disease.