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

Abstract

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.

Research trends in obesity & obesogenic environments in Korea

“…In particular, multicomponent multi-target technology and multi-omics-based systems biology were established for materials, markers, targets, and human testing on an integrated chemical biological basis in order to develop a low-cost, high-efficiency, bio-specialized support system. In addition, the establishment of a virtual human system to develop a technology to interpret and predict the efficacies of anti-obesity materials will provide a good model for future anti-obesity research [59][60][61].…”

Semilicoisoflavone B induces oral cancer cell apoptosis by targeting claspin and ATR‐Chk1 signaling pathways

“…Semilicoisoflavone B (SFB) is a natural bioactive isoprenoid‐substituted phenolic compound found in medicinal plants belonging to the genus Glycyrrhiza , including Glycyrrhiza glabra and Glycyrrhiza uralensis 12 . Recent evidence has shown that SFB acts as a peroxisome proliferator activated receptor γ agonist to suppress the expression of β‐secretase‐1, which in turn leads to reduction in amyloid beta secretion and improvement in Alzheimer's disease symptoms 13,14 . The compound has also been found to have potent inhibitory activity against aldose reductase, an enzyme that converts glucose into sorbitol and is associated with the pathogenesis of diabetic cataract and retinopathy 15 .…”

“…12 Recent evidence has shown that SFB acts as a peroxisome proliferator activated receptor γ agonist to suppress the expression of β-secretase-1, which in turn leads to reduction in amyloid beta secretion and improvement in Alzheimer's disease symptoms. 13,14 The compound has also been found to have potent inhibitory activity against aldose reductase, an enzyme that converts glucose into sorbitol and is associated with the pathogenesis of diabetic cataract and retinopathy. 15 In addition, one study has shown that SFB acts as a potent inhibitor of tyrosinase, a rate-limiting enzyme in the melanin synthesis pathway.…”