Gintonin, a Ginseng-Derived Lysophosphatidic Acid Receptor Ligand, Attenuates Alzheimer's Disease-Related Neuropathies: Involvement of Non-Amyloidogenic Processing

초록

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

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