Abstract
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 (20S)-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 (20S)-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 (20S)-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 (20S)-Rg3, whereas reduced expression of PI4KIIα abolished the Aβ-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KIIα and phosphoinositide modulation in γ-secretase activity and Aβ biogenesis.
Highlights
Cerebral elevation and accumulation of amyloid -peptide is an invariant feature of Alzheimer disease
Identification of (20S)-Rg3 as an A-lowering Natural Compound—We initially tested a number of natural products for their ability to reduce Amyloid -peptide (A)42 production
We found that several ginsenosides, including 20R and 20S epimers of Rg3, Rk1, and Rg5, inhibited the secretion of A42 (Fig. 1B)
Summary
Cerebral elevation and accumulation of amyloid -peptide is an invariant feature of Alzheimer disease. Results: Natural compound (20S)-Rg3, a PI4KII␣ activator, modulates ␥-secretase activity in lipid rafts by increasing levels of phosphoinositides. Amyloid -peptide (A) 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 levels in the brain via novel mechanisms. Our results substantiate an important role for PI4KII␣ and phosphoinositide modulation in ␥-secretase activity and A biogenesis. Elevation and accumulation of amyloid -peptide (A) in the brain are invariable events associated with Alzheimer disease (AD) [1, 2]. We have previously reported that phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2), a phospholipid that regulates key aspects of neuronal function [9], is involved with cellular mechanisms underlying AD, such as the biogenesis of
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