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.

Plant Lysophosphatidic Acids: A Rich Source for Bioactive Lysophosphatidic Acids and Their Pharmacological Applications

“…Gintoninmediated LPA receptor activation is coupled to the increase of soluble amyloid precursor protein α (sAPPα) release instead of β-amyloid in neuroblastoma SH-SY5Y cells. 22) In addition, long-term oral administration of gintonin attenuated neuropathies of β-amyloid plaques in the cortex and hippocampus and restored β-amyloid-induced memory dysfunctions. Third, long-term administration of gintonin to wild-type mice increased the immunoreactivity of hippocampal choline acetyltransferase, which is responsible for increase of acetylcholine synthesis.…”

“…23) Thus, LPAs in gintonin contributed to the restoration of adult brain cholinergic dysfunctions following neurodegeneration. 22) Fourth, Kim et al observed that hippocampal long-term potentiation (LTP) increased in mice that were previously treated with gintonin for 7 d orally compared to saline-treated mice. 24) In addition, the hippocampi of mice that were previously treated for 7 d with gintonin showed increased expressions of learning and memory-related proteins such as phosphorylated cAMP-response element binding (pCREB) protein and brain-derived neurotrophic factor (BDNF).…”

Preparation of a Monoclonal Antibody against Gintonin and Its Use in an Enzyme Immunoassay

“…sient is coupled to important pharmacological effects, such as the attenuation of amyloid plaque formation in the brain. 7,13) In addition, gintonin inhibits autotaxin activity to suppress metastasis. 8) However, a method for quantifying the amount of gintonin in ginseng has not been developed.…”

“…2,3,5,6) The gintonin-mediated [Ca 2+ ] i transient is coupled to the regulation of Ca 2,7) Oral administration of gintonin elicits anti-Alzheimer's disease effects in vivo by activating the non-amyloidogenic pathway through LPA receptors and induces anti-metastatic effects by inhibiting autotaxin activity. 7,8) Biochemical analysis has shown that gintonin consists of carbohydrates, lipids, and proteins.…”

“…Gintonin, but not ginsenosides, induces an intracellular free calcium concentration ([Ca 2,7) Oral administration of gintonin elicits anti-Alzheimer's disease effects in vivo by activating the non-amyloidogenic pathway through LPA receptors and induces anti-metastatic effects by inhibiting autotaxin activity. 7,8) Biochemical analysis has shown that gintonin consists of carbohydrates, lipids, and proteins.2) The protein component of gintonin consists of ginseng major latex-like protein 151 (GLP) and ginseng ribonuclease-like storage protein (GSP). …”