Background/Objectives: Alzheimer’s disease (AD) is characterized by amyloid-beta accumulation and neuroinflammation, yet the molecular target of Ginsenoside Rg1 remains elusive. This study aimed to elucidate the neuroprotective mechanism of Ginsenoside Rg1, specifically investigating its interaction with C-C motif chemokine receptor 3 (CCR3). Methods: We utilized 5xFAD transgenic mice and CCR3-overexpressing BV2 microglial cells. Behavioral assessments, enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, molecular docking, and surface plasmon resonance were employed to evaluate cognitive function and molecular pathways. Results: Ginsenoside Rg1 treatment significantly ameliorated spatial learning and memory deficits. Quantitatively, Rg1 reduced cortical amyloid-beta 1–40 levels (p < 0.05) and bound directly to CCR3 with a dissociation constant of 3.599 × 10⁻⁵ mol/L. This inhibition suppressed neuroinflammation and restored neurotrophic factors, including Brain-derived neurotrophic factor. Conclusions: CCR3 is a novel pharmacological target for Ginsenoside Rg1, providing a precise molecular basis for its neuroprotective effects. Future research should focus on clarifying the pharmacokinetic profile and brain bioavailability of Ginsenoside Rg1 to facilitate clinical translation.

With the rapid aging of the global population, the incidence of cognitive dysfunction is on the rise. The efficacy of existing clinical medications has been less than satisfactory, leading researchers to explore traditional medicinal practices. Tibetan medicine, a vital segment of traditional medicine, has been extensively utilized for the treatment of mental, psychological, and neurological conditions. Modern clinical and experimental pharmacological studies have shown that Rhodiola L., Terminalia chebula Retz., Sibiraea laevigata (L.) Maxim., Centella asiatica (L.) Urban, Gymnadeniaconopsea (L.) R. Br., Crocus sativus L., Ganoderma lucidum (Curtis) P. Karst., Seventy Flavor Pearl Pills, Twenty-Five Flavor Coral Pills, Ruyi Treasure Pills, and Twenty-Five Flavor Pearl Pills have effects on improving cognitive dysfunction. This review meticulously examines the research progress on these Tibetan medicinal substances for their role in mitigating cognitive dysfunction, with the goal of providing valuable insights for the development of novel therapeutic approaches to cognitive deterioration.

Cognitive impairment is a major public health concern, and the liver–brain axis has attracted growing interest. Gamma-glutamyl transferase (GGT) is a serum marker of liver function, but its association with cognitive outcomes remains uncertain. We conducted a cross-species analysis. In 5xFAD mice (n = 52), we examined serum liver markers and spatial cognition using the Morris water maze. In NHANES 2011–2014 (n = 3181, aged ≥60 years), we evaluated liver markers and low cognitive performance (LCP) using multivariable logistic regression. We also performed virtual hepatic GGT1 knockout in a human liver single-cell atlas and integrated GTEx liver co-expression, transcription factor enrichment, and WGCNA analyses. In mice, GGT–cognition associations largely attenuated after strain adjustment, but a positive association with platform crossings emerged (r = 0.321, p = 0.02). In NHANES, serum GGT was inversely associated with LCP (Q4 vs. Q1 OR = 0.54, p < 0.001), with a nonlinear association and an inflection point near 19 U/L. Virtual hepatic GGT1 knockout identified eight immunoglobulin-related genes associated with SPI1 and oxidative stress-related pathways. These parallel findings are hypothesis-generating. A testable hypothesis is that lower hepatic GGT1 activity or serum GGT is associated with upregulated cholangiocyte immunoglobulin-related programs and poorer cognition.