Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt

Background: The pathogenic accumulation of amyloid beta peptide (A beta), a natural occurring peptide processed from beta-amyloid precursor protein (APP), is considered to play a key role in the development of Alzheimer's disease (AD). Ginsenoside Rg1, an active component in ginseng, has been identified as a phytoestrogen and also found to be neuroprotective. However, it is unknown whether Rg1-induced estrogenic activity intervenes in APP processing, and improves memory performance. Methods: Using HT22 cells and SH-SY5Y cells stably expressing the Swedish mutant APP (APPsw), this study investigated whether Rg1 intervened in APP metabolism through estrogenic activity. Using the ovariectomized (OVX) rats to mimic age-related changes in postmenopausal females, this study also tested the long-term effect of Rg1 on APP metabolism. Results: The in vitro study demonstrated that Rg1 increased extracellular secretion of soluble amyloid precursor protein a (sAPP alpha), enhanced alpha-secretase activity and decreased extracellular release of A beta. These effects of Rg1 could be prevented by inhibitors of protein kinase C (PKC), Extracellular-Signal Regulated Kinase/Mitogen-Activated Protein Kinase (ERK/MAPK) and Phosphoinositide-3 kinase (PI3K)/Akt pathways. Inhibition of endogenous estrogen receptor (ER) activity abrogated Rg1-triggered release of sAPP alpha, increase of alpha-secretase activity, and activation of ERK and Akt signaling. In addition, Rg1 promoted phosphorylation of ER alpha at Ser118 residue. The in vivo study demonstrated that 8-week Rg1 treatment of OVX rats increased sAPP alpha levels and decreased A beta content in the hippocampi, and improved the spatial learning and memory. General significance: Rg1 might be used to slow or prevent AD, in particular in postmenopausal females. (C) 2011 Elsevier B.V. All rights reserved.