title: Modulation of lipid kinase PI4KIIα activity and lipid raft association of presenilin 1 underlies γ-secretase inhibition by ginsenoside (20S)-Rg3.
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.
authors.affiliation: 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.
authors.forename: Min Suk
authors.initials: MS
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Ajou University, Suwon 443-749, Korea.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Baek
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Chun
authors.affiliation: 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.
authors.forename: A Zenobia
authors.initials: AZ
authors.lastname: Moore
authors.affiliation: 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.
authors.forename: Natalie
authors.initials: N
authors.lastname: Landman
authors.affiliation: 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.
authors.forename: Diego
authors.initials: D
authors.lastname: Berman
authors.affiliation: Natural Products Research Center, Korea Institute of Science and Technology-Gangneung Institute, Gangneung, Gangwon-do 210-340, Korea.
authors.forename: Hyun Ok
authors.initials: HO
authors.lastname: Yang
authors.affiliation: Department of Molecular Neuropathology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0808, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Morishima-Kawashima
authors.affiliation: Department of Neuropathology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Osawa
authors.affiliation: Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan, and.
authors.forename: Satoru
authors.initials: S
authors.lastname: Funamoto
authors.affiliation: Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan, and.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ihara
authors.affiliation: 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.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.affiliation: Research Institute of Pharmaceutical Sciences, Seoul National University, College of Pharmacy, Seoul 151-742, Korea.
authors.forename: Jeong Hill
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea,. Electronic address: schung@skku.edu.
authors.forename: Sungkwon
authors.initials: S
authors.lastname: Chung
authors.affiliation: 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: twk16@columbia.edu.
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D036145:Ginsenosides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D053764:Presenilin-1 / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism; D051880:Receptors, Notch / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D036145:Ginsenosides; D015778:Minor Histocompatibility Antigens; D019269:Phosphatidylinositol 4,5-Diphosphate; D053764:Presenilin-1; D017475:Receptors, Nerve Growth Factor; D051880:Receptors, Notch; C517634:Ngfr protein, mouse; C097367:ginsenoside Rg3; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer Disease; Lipid Raft; Lipids; Natural Products; Phosphatidylinositol; Presenilin