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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / metabolism
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Enzyme Activation / drug effects
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Ginsenosides / chemistry
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Ginsenosides / pharmacology*
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Humans
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Membrane Microdomains / drug effects
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Membrane Microdomains / metabolism*
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Mice
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Mice, Transgenic
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Minor Histocompatibility Antigens
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Phosphatidylinositol 4,5-Diphosphate / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Presenilin-1 / metabolism*
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Protein Binding / drug effects
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Protein Structure, Tertiary
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Receptors, Nerve Growth Factor / chemistry
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Receptors, Nerve Growth Factor / metabolism
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Receptors, Notch / chemistry
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Receptors, Notch / metabolism
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Structure-Activity Relationship
Substances
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Amyloid beta-Peptides
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Ginsenosides
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Minor Histocompatibility Antigens
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Phosphatidylinositol 4,5-Diphosphate
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Presenilin-1
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Receptors, Nerve Growth Factor
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Receptors, Notch
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Ngfr protein, mouse
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ginsenoside Rg3
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Phosphotransferases (Alcohol Group Acceptor)
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phosphatidylinositol phosphate 4-kinase
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Amyloid Precursor Protein Secretases