Korean Red Ginseng Marc-Derived Gintonin Improves Alzheimer's Cognitive Dysfunction by Upregulating LPAR1

Ginseng is a well-established functional food for brain health. However, its active ingredients have not yet been identified. Gintonin is a promising compound isolated from white/red ginseng. Its lysophosphatidic acid (LPA) is an exogenous G protein-coupled LPA receptor (LPAR) agonist. Korean red ginseng marc (KRGM) is a by-product after KRG extractions. In a previous study, we demonstrated that KRGM-derived gintonin (KRGM-G) contains LPA C18:2, a major functional component of both white and red ginseng. 5×FAD transgenic mice and SH-SY5Y cells were used to determine molecular mechanisms involved in KRGM-G-mediated anti-Alzheimer's disease (AD) effects. KRGM-G improved cognition impairment associated with alleviation of amyloid-β accumulation in the brain (hippocampus and cortex) in 5×FAD mice. KRGM-G inhibited activation of inflammatory cells (Iba-1-positive microglia and GFAP-positive astrocyte) and expression of pro-inflammatory mediators (IL-1β, IL-6, iNOS, or NO) in the brains of 5×FAD mice, increased the viability of H₂O₂-induced SH-SY5Y cells, and down-regulated the p38 MAPK, NF-κB p65, and STAT3 signaling pathways. KRGM-G also prevented the formation of reactive oxygen species and stimulated the Nrf2-HO-1/4-HNE signaling pathway in the brains of 5×FAD mice and SH-SY5Y cells. Interestingly, these positive effects of KRGM-G on AD-related symptoms and immunopathology were associated with up-regulation of LPAR1 in the brains of 5×FAD mice. These results suggest that KRGM-G might improve AD-related cognitive dysfunction by stimulating the anti-oxidant pathway (Nrf2) and inhibiting inflammatory pathways (p38/NF-κB/STAT3) through LPAR1.