title: Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates Alzheimer's disease-related neuropathies: involvement of non-amyloidogenic processing.
abstract: Ginseng extracts show cognition-enhancing effects in Alzheimer's disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-β protein (Aβ) accumulation. Aβ is derived from amyloid-β protein precursors (AβPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AβPPα (sAβPPα). Here, we describe our investigations of the effect of gintonin on sAβPPα release, Aβ formation, Swedish-AβPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Aβ-induced neuropathy in mice. Gintonin promoted sAβPPα release in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, α-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Aβ1-42 release and attenuated Aβ1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Aβ1-40-induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAβPPα release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy.
authors.affiliation: Ginsentology Research Laboratory, Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Shin
authors.forename: Byung-Hwan
authors.initials: BH
authors.lastname: Lee
authors.forename: Sun-Hye
authors.initials: SH
authors.lastname: Choi
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kang
authors.forename: Hyeon-Joong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Kwon
authors.forename: Choon-Gon
authors.initials: CG
authors.lastname: Jang
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.forename: Seung-Yeol
authors.initials: SY
authors.lastname: Nah
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007189:Indans / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D018697:Nootropic Agents / Q000494:pharmacology; D005894:Panax / Q000737:chemistry*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D008517:Phytotherapy / Q000379:methods*; D010880:Piperidines / Q000494:pharmacology; D010940:Plant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D053764:Presenilin-1 / Q000235:genetics; D011422:Propionates / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D007189:Indans; D007555:Isoxazoles; D008024:Ligands; D008840:Microfilament Proteins; D018697:Nootropic Agents; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D010880:Piperidines; D010940:Plant Proteins; D053764:Presenilin-1; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D004533:Egtazic Acid; D000077265:Donepezil; D045726:Metalloproteases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium