Korean black ginseng extract alleviates Alzheimer's disease-related cognitive impairment by activating the Nrf2/HO-1 pathway and suppressing the p38 MAPK/NF-κB/STAT3 pathways and NLRP3 inflammasome via TLR2 and TLR4 modulation

Background: Korean black ginseng, a specially processed ginseng through repeat steaming and drying, has various pharmacological effects. However, its role in cognitive impairment remains unclear. Purpose and methods: This study examined whether Korean black ginseng extract (BGE; 50 and 100 mg/kg, orally, 18 weeks) may mitigate cognitive impairment in a 5xFAD mouse model of Alzheimer's disease (AD). Results: BGE significantly improved cognitive performance in 5xFAD mice, associated with reduced Aβ accumulation in the frontal cortex and hippocampus. BGE suppressed microglial and astrocytic activation, alongside the downregulation of pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α) and enzymes (cyclooxygenase-2 and inducible nitric oxide synthase). These changes coincided with the inhibition of key inflammatory signaling pathways, such as p38 mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB)/p65, signal transducer and activator of transcription (STAT) 3, and NOD-like receptor protein 3 (NLRP3) inflammasome. Furthermore, BGE reduced the generation of reactive oxygen species and enhanced the nuclear-E2-related factor 2 (Nrf2)-heme oxygenase 1 (HO-1) signaling pathway in the brains linked to the downregulation of toll-like receptors (TLR)-2 and TLR-4 in the brain. Conclusion: Taken together, BGE could improve AD-related cognitive decline and neurodegeneration by simultaneously regulating anti-inflammatory pathways (p38 MAPK/NF-κB/STAT3 and NLRP3 inflammasome) and an antioxidant pathway (Nrf2/HO-1) via modulation of TLR2/4.