20()-protopanaxadiol and oleanolic acid ameliorate cognitive deficits in APP/PS1 transgenic mice by enhancing hippocampal neurogenesis.

Background: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. Enhancing hippocampal neurogenesis by promoting proliferation and differentiation of neural stem cells (NSCs) is a promising therapeutic strategy for AD. 20()-protopanaxadiol (PPD) and oleanolic acid (OA) are small, bioactive compounds found in ginseng that can promote NSC proliferation and neural differentiation . However, it is currently unknown whether PPD or OA can attenuate cognitive deficits by enhancing hippocampal neurogenesis in a transgenic APP/PS1 AD mouse model. Here, we administered PPD or OA to APP/PS1 mice and monitored the effects on cognition and hippocampal neurogenesis.

Methods: We used the Morris water maze, Y maze, and open field tests to compare the cognitive capacities of treated and untreated APP/PS1 mice. We investigated hippocampal neurogenesis using Nissl staining and BrdU/NeuN double labeling. NSC proliferation was quantified by Sox2 labeling of the hippocampal dentate gyrus. We used western blotting to determine the effects of PPD and OA on Wnt/GSK3β/β-catenin pathway activation in the hippocampus.

Results: Both PPD and OA significantly ameliorated the cognitive impairments observed in untreated APP/PS1 mice. Furthermore, PPD and OA significantly promoted hippocampal neurogenesis and NSC proliferation. At the mechanistic level, PPD and OA treatments resulted in Wnt/GSK-3β/β-catenin pathway activation in the hippocampus.

Conclusion: PPD and OA ameliorate cognitive deficits in APP/PS1 mice by enhancing hippocampal neurogenesis, achieved by stimulating the Wnt/GSK-3β/β-catenin pathway. As such, PPD and OA are promising novel therapeutic agents for the treatment of AD and other neurodegenerative diseases.