Licoflavonol Reduces Aβ Secretion by Increasing BACE1 Phosphorylation to Facilitate BACE1 Degradation

Scope In the 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 corresponds to the same mechanism as GUE, but LF has a different mechanism. In this study, the mechanism underlying inhibition of Aβ by LF is investigated. Methods and results The effects of LF on Aβ, sAPPα, and sAPPβ secretion are evaluated by ELISA, and the effect of LF on BACE1 expression is detected by western blotting. It is found that the effect of LF on Aβ secretion is due to promotion of BACE1 protein degradation, and that the effect of LF on Aβ and BACE1 expression is attenuated after cotreatment with the lysosome inhibitor chloroquine. In a subsequent mechanistic study, it is found that LF increases 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.