Ginsenoside Rd promotes non-amyloidogenic pathway of amyloid precursor protein processing by regulating phosphorylation of estrogen receptor alpha

Abstract Aims Previous study demonstrated that Ginsenoside Rd. (GS-Rd) could improve cognitive and memory function in animal model of Alzheimer's disease. This study was aimed to investigate whether GS-Rd could improve non-amyloidogenic pathway by activating estrogen receptor (ER). Main methods 10 mg/kg GS-Rd in ovariectomy (OVX) + GS-Rd group and equivalent volume of saline in sham operated group and OVX group were administrated intraperitoneally for two months, respectively. The Morris Water Maze was used to examine cognitive function of rats, with sAPPα and Aβ levels in the hippocampi measured. The culture medium of HT22 hippocampal neuronal cells were incubated with GS-Rd, ER antagonist ICI182.780, MAPK inhibitor PD98059, or PI3Kinhibitor LY294002, respectively. sAPPα levels was measured, and expression of α-secretase, sAPPα, β-secretase, Aβ, phosphorylation form of AKT (p-AKT), total AKT, p-ERK, total ERK, p-ERα, total ERα, p-ERβ and total ERβ were examined by Western blot to explore the estrogenic-like activity of GS-Rd. Key findings GS-Rd attenuate cognitive and memory impairment, increased levels of sAPPα and reduced extracellular Aβ of OVX rats. In HT22, GS-Rd could upregulate sAPPα level, which can be inhibited by inhibitor of MAPK and PI3K pathway. In addition, inhibitor of estrogen receptor prevented GS-Rd triggered release of sAPPα and activation of MAPK and PI3K pathways. GS-Rd could increase expression of α-secretase and sAPPα, while decrease expression of β-secretase and Aβ. Besides, GS-Rd promoted phosphorylation of estrogen receptor alpha at Ser118 residue. Significance Our findings show that GS-Rd enhances learning and memory function of OVX rats by activating estrogen-like activity.