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

Amyloid β-peptide (Aβ) 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 Aβ levels in the brain via novel mechanisms. We found that (20 S )-Rg3, a triterpene natural compound known as ginsenoside, reduced Aβ levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20 S )-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the γ-secretase complex are enriched. The Aβ-lowering activity of (20 S )-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase IIα (PI4KIIα), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KIIα overexpression recapitulated the effects of (20 S )-Rg3, whereas reduced expression of PI4KIIα abolished the Aβ-reducing activity of (20 S )-Rg3 in neurons. Our results substantiate an important role for PI4KIIα and phosphoinositide modulation in γ-secretase activity and Aβ biogenesis. Background: Cerebral elevation and accumulation of amyloid β-peptide is an invariant feature of Alzheimer disease. Results: Natural compound (20 S )-Rg3, a PI4KIIα activator, modulates γ-secretase activity in lipid rafts by increasing levels of phosphoinositides. Conclusion: Activation of a key phospholipid synthetic pathway by a natural product regulates γ-secretase activity. Significance: We identify a novel molecular mechanism for the regulation of γ-secretase activity by (20 S )-Rg3.