Justicidin A Reduces beta-Amyloid via Inhibiting Endocytosis of beta-Amyloid Precursor Protein

Abstract

beta-amyloid precursor protein (APP) can be cleaved by alpha-, and gamma-secretase at plasma membrane producing soluble ectodomain fragment (sAPP alpha). Alternatively, following endocytosis, APP is cleaved by beta-, and gamma-secretase at early endosomes generating beta-amyloid (A beta), the main culprit in Alzheimer's disease (AD). Thus, APP endocytosis is critical for A beta production. Recently, we reported that Monsonia angustifolia, the indigenous vegetables consumed in Tanzania, improved cognitive function and decreased A beta production. In this study, we examined the underlying mechanism of justicidin A, the active compound of M. angustifolia, on A beta production. We found that justicidin A reduced endocytosis of APP, increasing sAPPa level, while decreasing A beta level in HeLa cells overexpressing human APP with the Swedish mutation. The effect of justicidin A on A beta production was blocked by endocytosis inhibitors, indicating that the decreased APP endocytosis by justicidin A is the underlying mechanism. Thus, justicidin A, the active compound of M. angustifolia, may be a novel agent for AD treatment.