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Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates alzheimer's disease-related neuropathies: Involvement of non-amyloidogenic processing

Academic Article
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Overview

authors

  • Hwang, S. H.
  • Shin, E. J.
  • Shin, T. J.
  • Lee, B. H.
  • Choi, S. H.
  • Kang, J.
  • Kim, H. J.
  • Kwon, S. H.
  • Jang, Choon-Gon
  • Lee, Jiing-Dwan
  • Kim, H. C.
  • Nah, S. Y.

publication date

  • 2012

journal

  • Journal of Alzheimers Disease  Journal

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-? protein (A?) accumulation. A? is derived from amyloid-? protein precursors (A?PPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble A?PP? (sA?PP?). Here, we describe our investigations of the effect of gintonin on sA?PP? release, A? formation, Swedish-A?PP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and A?-induced neuropathy in mice. Gintonin promoted sA?PP? release in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, ?-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased A?1-42 release and attenuated A?1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued A?1-40-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 sA?PP? release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy.
  • 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.

subject areas

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Analysis of Variance
  • Animals
  • Brain
  • Calcium
  • Calcium-Binding Proteins
  • Cell Survival
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Egtazic Acid
  • Enzyme Inhibitors
  • Glycoproteins
  • Humans
  • Indans
  • Isoxazoles
  • Ligands
  • Maze Learning
  • Memory Disorders
  • Metalloproteases
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins
  • Mutation
  • Neuroblastoma
  • Nootropic Agents
  • Panax
  • Peptide Fragments
  • Phytotherapy
  • Piperidines
  • Plant Proteins
  • Presenilin-1
  • Propionates
  • Protein Binding
  • Receptors, Lysophosphatidic Acid
  • Signal Transduction
  • Time Factors
  • Transfection
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Research

keywords

  • Alzheimer's disease
  • amyloid-beta protein precursor
  • memory
  • transgenic mice
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Identity

International Standard Serial Number (ISSN)

  • 1387-2877

Digital Object Identifier (DOI)

  • 10.3233/jad-2012-120439

PubMed ID

  • 22543851
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Additional Document Info

start page

  • 207

end page

  • 223

volume

  • 31

issue

  • 1

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