Modulation of Lipid Kinase PI4KIIa Activity and Lipid Raft Association of Presenilin 1 Underlies g-Secretase Inhibition by Ginsenoside (20S)Rg3

Title
Modulation of Lipid Kinase PI4KIIa Activity and Lipid Raft Association of Presenilin 1 Underlies g-Secretase Inhibition by Ginsenoside (20S)Rg3
Authors
강민석백승훈천윤선A. Zenobia MooreNatalie LandmanDiego Berman양현옥Maho Morishima-KawashimaSatoko OsawaSatoru FunamotoYasuo IharaGilbert Di Paolo박정일정성권김태완
Keywords
Alzheimer's disease; amyloid β-peptide (Aβ); ginseng; ginsenoside; lipid kinase; lipid rafts; natural compound; phosphatidylinositol-4,5-bisphosphate; secretase
Issue Date
2013-07
Publisher
The Journal of biological chemistry
Citation
VOL 288, NO 29, 20868-20882
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.
URI
http://pubs.kist.re.kr/handle/201004/46705
ISSN
00219258
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KIST Publication > Article
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