Objective: To evaluate the mechanisms underlying the protective effect of Chinese herbal medicine Fructus broussonetiae (FB) in both mouse and cell models of Alzheimer's disease (AD).
Methods: APP/PS1 mice treated with FB for 2 months and vehicle-treated controls were run through the Morris water maze and object recognition test to evaluate learning and memory capacity. RNA-Seq, Western blotting, and immunofluorescence staining were also conducted to evaluate the effects of FB treatment on various signaling pathways altered in APP/PS1 mice. To further explore the mechanisms underlying FB's protective effect, PC-12 cells were treated with Aβ25-35 in order to establish an in vitro model of AD.
Results: FB-treated mice showed improved learning and memory capacity on both the Morris water maze and object recognition tests. RNA-seq of hippocampal tissue from APP/PS1 mice showed that FB had effects on multiple signaling pathways, specifically decreasing cell apoptotic signaling and increasing AKT and β-catenin signaling. Similarly, FB up-regulated both AKT and β-catenin signaling in PC-12 cells pre-treated with Aβ25-35, in which AKT positively regulated β-catenin signaling. Further study showed that AKT promoted β-catenin signaling via enhancing β-catenin (Ser552) phosphorylation. Moreover, AKT and β-catenin signaling inhibition both resulted in the attenuated survival of FB-treated cells, indicating the AKT/β-catenin signaling is a crucial mediator in FB promoted cell survival.
Conclusions: FB exerted neuroprotective effects on hippocampal cells of APP/PS1 mice, as well as improved cell viability in an in vitro model of AD. The protective actions of FB occurred via the upregulation of AKT/β-catenin signaling.
Keywords: Alzheimer disease; Chinese medicine; Fructus broussonetiae; apoptosis regulatory proteins; neuroprotective agent.