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

Biochim Biophys Acta. 2012 Apr;1820(4):453-60. doi: 10.1016/j.bbagen.2011.12.005. Epub 2011 Dec 11.


Background: The pathogenic accumulation of amyloid β peptide (Aβ), 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 α (sAPPα), enhanced α-secretase activity and decreased extracellular release of Aβ. 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 sAPPα, increase of α-secretase activity, and activation of ERK and Akt signaling. In addition, Rg1 promoted phosphorylation of ERα at Ser118 residue. The in vivo study demonstrated that 8-week Rg1 treatment of OVX rats increased sAPPα levels and decreased Aβ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Cell Line, Tumor
  • Central Nervous System Agents / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Ginsenosides / pharmacology*
  • Humans
  • MAP Kinase Signaling System
  • Memory / drug effects*
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Receptors, Estrogen / metabolism*
  • Serum Amyloid A Protein / metabolism*
  • Signal Transduction


  • Amyloid beta-Protein Precursor
  • Central Nervous System Agents
  • Ginsenosides
  • Receptors, Estrogen
  • Serum Amyloid A Protein
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Amyloid Precursor Protein Secretases
  • ginsenoside Rg1