2. Academic Validation
  3. Modulation of lipid kinase PI4KIIα activity and lipid raft association of presenilin 1 underlies γ-secretase inhibition by ginsenoside (20S)-Rg3

Modulation of lipid kinase PI4KIIα activity and lipid raft association of presenilin 1 underlies γ-secretase inhibition by ginsenoside (20S)-Rg3

  • J Biol Chem. 2013 Jul 19;288(29):20868-20882. doi: 10.1074/jbc.M112.445734.
Min Suk Kang 1,  Seung-Hoon Baek 2,  Yoon Sun Chun 3,  A Zenobia Moore 1,  Natalie Landman 1,  Diego Berman 1,  Hyun Ok Yang 4,  Maho Morishima-Kawashima 5,  Satoko Osawa 6,  Satoru Funamoto 7,  Yasuo Ihara 7,  Gilbert Di Paolo 1,  Jeong Hill Park 8,  Sungkwon Chung 9,  Tae-Wan Kim 10
Affiliations

Affiliations

  • 1 From the Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York 10032.
  • 2 College of Pharmacy, Ajou University, Suwon 443-749, Korea.
  • 3 Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
  • 4 Natural Products Research Center, Korea Institute of Science and Technology-Gangneung Institute, Gangneung, Gangwon-do 210-340, Korea.
  • 5 Department of Molecular Neuropathology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0808, Japan.
  • 6 Department of Neuropathology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
  • 7 Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan, and.
  • 8 Research Institute of Pharmaceutical Sciences, Seoul National University, College of Pharmacy, Seoul 151-742, Korea.
  • 9 Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea,. Electronic address: [email protected].
  • 10 From the Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York 10032,. Electronic address: [email protected].
PMID: 23723072 DOI: 10.1074/jbc.M112.445734
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.

Keywords

Alzheimer Disease; Lipid Raft; Lipids; Natural Products; Phosphatidylinositol; Presenilin.

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