Modulation of Lipid Kinase PI4KIIα Activity and Lipid Raft Association of Presenilin 1 Underlies γ-Secretase Inhibition by Ginsenoside (20S)-Rg3

Amyloid beta-peptide (A beta) pathology is an invariant feature of Alzheimer disease, preceding any detectable clinical symptoms by more than a decade. To this end, we seek to identify agents that can reduce A beta levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced A beta levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20S)-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the gamma-secretase complex are enriched. The A beta-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase II alpha (PI4KII alpha), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KII alpha overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KII alpha abolished the A beta-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KII alpha and phosphoinositide modulation in gamma-secretase activity and A beta biogenesis.