title: Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt.
abstract: 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.
  
  
  CONCLUSIONS
  Rg1 might be used to slow or prevent AD, in particular in postmenopausal females.
authors.affiliation: Department of Anatomy, Guangzhou Medical University, Guangzhou 510182, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Shi
authors.forename: Dong-dan
authors.initials: DD
authors.lastname: Zheng
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.forename: Fengming
authors.initials: F
authors.lastname: Wu
authors.forename: Wing Hang
authors.initials: WH
authors.lastname: Kwong
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002491:Central Nervous System Agents / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System; D008568:Memory / Q000187:drug effects*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016564:Amyloid beta-Protein Precursor; D002491:Central Nervous System Agents; D036145:Ginsenosides; D011960:Receptors, Estrogen; D000685:Serum Amyloid A Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases; C035054:ginsenoside Rg1