title: An Aβ42 uptake and degradation via Rg3 requires an activation of caveolin, clathrin and Aβ-degrading enzymes in microglia.
abstract: We demonstrated previously that ginsenoside Rg3 enhances the expression of macrophage scavenger receptor class A (SRA) and amyloid β peptide 1-42 (Aβ42) uptake in BV2 cells. In this study, we investigated the biochemical and mechanistic roles of Rg3 in human microglia and animal models to identify the determinants that participate in restoring memory and learning in brains disrupted by the Aβ42 peptide. SRA was expressed highly in Rg3-treated rats, and learning and memory functions were maintained at a normal level after the infusion of Aβ42. SRA-transfected HMO6 human microglial cells (HMO6.hSRA) overexpressed SRA and took up a remarkable amount of Aβ42. Rg3-treated HMO6 cells showed highly enhanced SRA expression and dramatically promoted Aβ42 uptake. Moreover, high levels of clathrin and caveolin1 supported the roles of Rg3 in endocytic biogenesis by activating p38 and extracellular signal-regulated protein kinase signaling. Notably, both neprilysin (NEP) and insulin-degrading enzyme (IDE) were significantly expressed by Rg3, suggesting independent and compensatory hydrolytic activity for the Aβ peptide. In conclusion, Rg3 successfully triggered Aβ42 uptake via SRA and clathrin-/caveolae-mediated endocytic mechanisms and further contributed to accelerate the degradation of Aβ peptide via the increase of intracellular NEP and IDE, which may be a promising Alzheimer׳s disease therapy.
authors.affiliation: College of Life Science, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung, Gangwon 210-702, Republic of Korea.
authors.forename: Su Kil
authors.initials: SK
authors.lastname: Jang
authors.affiliation: College of Life Science, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung, Gangwon 210-702, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Yu
authors.affiliation: College of Life Science, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung, Gangwon 210-702, Republic of Korea.
authors.forename: Seung Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: College of Life Science, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung, Gangwon 210-702, Republic of Korea.
authors.forename: Gwang Hoon
authors.initials: GH
authors.lastname: Kim
authors.affiliation: College of Life Science, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung, Gangwon 210-702, Republic of Korea.
authors.forename: Da Woon
authors.initials: DW
authors.lastname: Park
authors.affiliation: College of Pharmacy, Chung-Ang University, 221 Heuksuk-dong, Dongjak-gu, Seoul 156-756, Republic of Korea.
authors.forename: Do Ik
authors.initials: DI
authors.lastname: Lee
authors.affiliation: College of Life Science, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung, Gangwon 210-702, Republic of Korea. Electronic address: ssj66@gwnu.ac.kr.
authors.forename: Seong Soo
authors.initials: SS
authors.lastname: Joo
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D051242:Caveolin 1 / Q000138:chemical synthesis / Q000378:metabolism*; D002478:Cells, Cultured; D002966:Clathrin / Q000187:drug effects / Q000378:metabolism*; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D007339:Insulysin / Q000378:metabolism*; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D015260:Neprilysin / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D051117:Scavenger Receptors, Class A / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051242:Caveolin 1; D002966:Clathrin; D036145:Ginsenosides; D010446:Peptide Fragments; D051117:Scavenger Receptors, Class A; C075222:amyloid beta-protein (1-42); C097367:ginsenoside Rg3; D015260:Neprilysin; D007339:Insulysin
keywords: Aβ42; Endocytosis; Insulin degrading enzyme; Macrophage scavenger receptor class A; Neprilysin; Rg3