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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publication date

  • 2012

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.

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