Abstract
Limitations of current Alzheimer's disease (AD) therapies necessitate novel neuroprotective strategies. This study elucidated the multi-target mechanisms of ginseng aqueous extract (GAE) using complementary in vitro and in vivo AD models. Structural characterization indicated that the active ingredients of GAE included total saponins (19.64 ± 0.89%), total flavonoids (0.04±0.03%) and total polyphenols (6.41±0.15%). The primary active components in GAE are total saponins, which account for its highest compositional proportion. In vitro, GAE (0.8 mg/ml) exhibited potent antioxidant activity, evidenced by DPPH scavenging (27.14%), ABTS[+] reduction (59.49%), and ·OH quenching (28.08%). It restored neuronal homeostasis by normalizing intracellular Ca[2+] levels, reinstating mitochondrial membrane potential, and reducing ROS production. In transgenic Drosophila, GAE conferred multi-mechanistic neuroprotection via upregulation of antioxidant genes, autophagy activation, and enhanced insulin signaling. These actions translated to functional improvements, including reduced Aβ deposition, decreased neuronal apoptosis, preserved gut barrier integrity, extended lifespan, and improved locomotion-stress tolerance. Collectively, GAE represents a promising multi-target therapeutic candidate for AD by synergistically modulating oxidative stress, protein homeostasis and metabolic pathways.
