Planta Med 2014; 80 - P1L35
DOI: 10.1055/s-0034-1394692

Justicidin A reduces β-amyloid peptide by O-GlcNAcylation of β-amyloid precursor protein

S Chung 1, YS Chun 1, YY Cho 1, J Kim 2, HO Yang 2
  • 1Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, Korea
  • 2Natural Medicine Center, Korea Institute of Science and Technology, Gangneung, Korea

β-amyloid precursor protein (APP) is transported to the plasma membrane, where it is sequentially cleaved by α-secretase and γ-secretase. This pathway is called non-amyloidogenic pathway, since it precludes the production of hydrophobic β-amyloid peptide (Aβ), the main culprit of Alzheimer's disease (AD). Alternatively, once APP undergoes clathrin-dependent endocytosis, it can be sequentially cleaved by β-secretase and γ-secretase at endosomes, producing Aβ (amyloidogenic pathway). O-GlcNAcylation is a novel type of O-linked glycosylation attaching the monosaccharide β-N-acetylglucosamine (GlcNAc) to serine and threonine residues. Recently, we found that O-GlcNAcylation of APP increases the non-amyloidogenic processing of APP and decreases the production of Aβ. In this study, we identified specific increase of O-GlcNAcylation of APP by Justicidin A, which is one of lignin derivatives. Justicidin A increased the level of APP in the plasma membrane. We also found that Justicidin A selectively attenuated the endocytosis of APP, but not that of transferrin receptor. The level of sAPPα increased, while the level of sAPPβ and Aβ was concomitantly decreased by Justicidin A as shown in figure below. Blocking the clathrin-dependent endocytosis by inhibitor prevented the effect of Justicidin A, suggesting that the effect of Justicidin A on Aβ production was mainly mediated through the decrease of APP endocytosis. These results strongly indicate that O-GlcNAcylation by Justicidin A increases the plasma membrane targeting of APP and selectively decreases endocytosis rate of APP, thereby enhancing non-amyloidogenic processing of APP. Thus, O-GlcNAcylation of APP could be a new novel therapeutic target for AD.

Fig. 1: The levels of sAPPα, and sAPPβ-sw were measured from the conditioned media treated with indicated concentrations of Justicidin A for 8h by using ELISA methods. (A) sAPPα level was increased by incubating cells with Justicidin A. (B) Justicidin A decreased the level of sAPP-sw.

Keywords: Amyloid-β protein precursor, Alzheimer's disease, O-GlcNAcylation, endocytosis