Kang, Min Suk Baek, Seung-Hoon Chun, Yoon Sun Moore, A. Zenobia Landman, Natalie Berman, Diego Yang, Hyun Ok Morishima-Kawashima, Maho Osawa, Satoko Funamoto, Satoru Ihara, Yasuo Di Paolo, Gilbert Park, Jeong Hill Chung, Sungkwon Kim, Tae-Wan 2024-01-20T12:01:47Z 2024-01-20T12:01:47Z 2021-09-05 2013-07-19 0021-9258 https://pubs.kist.re.kr/handle/201004/127862 Amyloid beta-peptide (A beta) 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 beta levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced A beta 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 gamma-secretase complex are enriched. The A beta-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase II alpha (PI4KII alpha), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KII alpha overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KII alpha abolished the A beta-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KII alpha and phosphoinositide modulation in gamma-secretase activity and A beta biogenesis. English AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC AMYLOID-PRECURSOR-PROTEIN ALZHEIMERS-DISEASE PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE INTRAMEMBRANE PROTEOLYSIS BETA-PEPTIDE COGNITIVE PERFORMANCE NATURAL-PRODUCTS CHOLESTEROL HYPOTHESIS REVEALS Modulation of Lipid Kinase PI4KII alpha Activity and Lipid Raft Association of Presenilin 1 Underlies gamma-Secretase Inhibition by Ginsenoside (20S)-Rg3 Article 10.1074/jbc.M112.445734 1 JOURNAL OF BIOLOGICAL CHEMISTRY, v.288, no.29, pp.20868 - 20882 JOURNAL OF BIOLOGICAL CHEMISTRY 288 29 20868 20882 scie scopus 000322014400011 2-s2.0-84880548804 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article AMYLOID-PRECURSOR-PROTEIN ALZHEIMERS-DISEASE PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE INTRAMEMBRANE PROTEOLYSIS BETA-PEPTIDE COGNITIVE PERFORMANCE NATURAL-PRODUCTS CHOLESTEROL HYPOTHESIS REVEALS Alzheimer&apos s disease amyloid β-peptide (Aβ) ginseng ginsenoside lipid kinase lipid rafts natural compound phosphatidylinositol-4,5-bisphosphate secretase