Ginsenoside Rh4 Alleviates Amyloid β Plaque and Tau Hyperphosphorylation by Regulating Neuroinflammation and the Glycogen Synthase Kinase 3β Signaling Pathway

Alzheimer's disease (AD) is a primary neurodegenerative disease. It can be caused by aging and brain trauma and severely affects the abilities of cognition and memory of patients. Therefore, it seriously threatens the mental and physical health of humans worldwide. As a traditional Chinese medicine, ginsenosides have been proven to have a variety of pharmacological activities. Ginsenoside Rh4 (Rh4) is one of the rare ginsenosides with higher pharmacological activity than ordinary ginsenosides, but its effect on alleviating AD and its molecular mechanism have not been studied. Here, we investigated the anti-AD effects of Rh4 and its potential mechanisms using an AD mouse model induced by a combination of AlCl₃·6H₂O and d-galactose. The results showed that Rh4 could significantly improve the ability of cognizance and reduce neuronal damage in mice. Concurrently, Rh4 attenuates amyloid β accumulation, increases the density of dendritic spines, and logically inhibits synaptic structural damage as a result of neuronal excessive apoptosis and autophagy. Rh4 can not only inhibit the inflammatory response caused by the overactivation of microglia and astrocytes, reduce the levels of pro-inflammatory factors, increase the level of antioxidant enzymes in serum, and significantly improve the activity of antioxidant enzyme SOD1 in the hippocampus but also inhibit the hyperphosphorylation of tau protein in the hippocampus of mice by regulating the Wnt2b/GSK-3β/SMAD4 signaling pathway. Together, this study provides a theoretical basis for Rh4 in the treatment of AD and reveals that Rh4 is a potential drug for the treatment of AD.