Activating transcription factor 6 reduces Aβ1–42 and restores memory in Alzheimer’s disease model mice

Abstract

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 β-site APP-cleaving enzyme 1 (BACE1) and Aβ1–42 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 Aβ1–42. 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.

Keywords:

• Activating transcription factor 6
• BACE1
• β-Amyloid
• Alzheimer’s disease

Acknowledgements

We are thankful to grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-1-004).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-1-004).