Ming-Yao Gu1, 2, #, Yoon Sun Chun1,Ryu Shi Yong3, andHyun Ok Yang1, 2, *
1 Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25457, Gangwon-do, Republic of Korea
2Division of Bio-Medical Science &Technology, KIST School,Korea University of Science and Technology, Seoul 02792, Republic of Korea
3Research Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34113, Republic of Korea.
#Present address: Department of Cell Biology & Medical Genetics, School of Basic Medical Sciences,Shenzhen University Health Science Center, Shenzhen 518071, China
*Corresponding author: Hyun Ok Yang, Ph.D
Abstract
Scope
: In our previous study, Glycyrrhiza uralensis Fisch extract (GUE) inhibited Aβ secretion by inhibiting β?site APP?cleaving enzyme 1 (BACE1) transcription, and the active compounds semilicoisoflavone B (SB) and licoflavonol (LF) inhibited Aβ secretion. SB corresponded to the same mechanism as GUE, but LF had a different mechanism. In this study, we aimed to investigate the mechanism underlying inhibition of Aβ by LF.
Methods and results
: The effects of LF on Aβ, sAPPα and sAPPβ secretion were evaluated by ELISA, and the effect of LF on BACE1 expression was detected by western blotting. We found that the effect of LF on Aβ secretion was due to promotion of BACE1 protein degradation, and that the effect of LF on Aβ and BACE1 expression was attenuated after cotreatment with the lysosome inhibitor chloroquine. In a subsequent mechanistic study, we found that LF increased BACE1 phosphorylation to increase its interactions with ADP ribosylation factor?binding proteins 1 and 3 (GGA1 and GGA3, respectively) and eventually facilitate BACE1 delivery to lysosomes for degradation.
Conclusion
: This study is the first to demonstrate that the BACE1 phosphorylation inducer LF can modulate BACE1 trafficking and lead to facilitating degradation of BACE1, eventually decreasing Aβ secretion.
Key words: Alzheimer’s disease, Amyloid beta, BACE1, Licoflavonol