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 Aβ 25-35 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.