Ginsenoside Rh1 Attenuates Alzheimer's Disease-Like Deficits by Modulating Oxidative Stress and Mitochondrial Dysfunction via SIRT1-Related Signaling.

Abstract

Alzheimer's disease (AD) remains a progressive neurodegenerative disorder with limited therapeutic options. Ginsenoside Rh1 has been reported to possess neuroprotective properties, yet its specific role and underlying mechanisms in AD are not fully understood. This study aimed to investigate the protective effects of Rh1 against AD-related deficits and elucidate its molecular mechanisms. Using a D-galactose and AlCl3-induced AD-like mouse model and an okadaic acid (OA)-injured HT22 hippocampal neuronal cell model, we demonstrated that Rh1 administration significantly ameliorated spatial learning and memory impairments, reduced hippocampal neuronal damage, and suppressed abnormal Tau hyperphosphorylation. Serum metabolomics analysis revealed that Rh1 markedly modulated amino acid metabolism pathways in AD-like mice, notably increasing aspartate (Asp) levels and decreasing glutamate (Glu) levels. Mechanistically, Rh1 activated the Nrf2 antioxidant pathway, thereby alleviating cellular oxidative stress. Concurrently, Rh1 ameliorated mitochondrial dysfunction by enhancing mitochondrial biogenesis, improving the mitochondrial fusion-fission balance, and modulating mitophagy. Importantly, the SIRT1 inhibitor EX-527 and SIRT1 knockdown both significantly reversed these protective effects. Cellular thermal shift assay and molecular docking suggested a potential interaction between Rh1 and SIRT1. In conclusion, our findings indicate that ginsenoside Rh1 exerts neuroprotective effects against AD in vivo and in vitro, at least partly through SIRT1-related signaling, which subsequently attenuates oxidative stress and ameliorates mitochondrial dysfunction. These results suggest that Rh1 may represent a promising candidate for further investigation for AD intervention.