Mechanism of ellagic acid improving cognitive dysfunction in APP/PS double transgenic mice based on PI3K/AKT/GSK-3β signaling pathway

Aim To investigate the effect of ellagic acid (EA) on cognitive function in APP/PS1 double-transgenic mice, and to explore the regulatory mechanism of ellagic acid on the level of oxidative stress in the hippocampus of double-transgenic mice based on the phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3 (PI3K/AKT/GSK-3β) signaling pathway. Methods Thirty-two SPF-grade 6-month-old APP/PS1 double transgenic mice were randomly divided into four groups, namely, APP/PS1 group, APP/PS1+EA group, APP/PS1+LY294002 group, APP/PS1+EA+LY294002 group, with eight mice in each group, and eight SPF-grade C57BL/6J wild type mice (Wild type) were selected as the blank control group. The APP/PS1+EA group was given 50 mg/kg/day of EA by gavage; the APP/PS1+LY294002 group was given 1.5 mg/kg/d of PI3K inhibitor LY294002 by intraperitoneal injection; the APP/PS1+EA+LY294002 group was given 50 mg/kg/day of EA by gavage, and the APP/PS1+EA+LY294002 group was given 50 mg/kg/day of EA by gavage. The WT group and APP/PS1 group were given equal volume of 10% dimethyl sulfoxide (DMSO) by gavage at the same time. Morris water maze was administered once a day for 60 days, and the learning and memory abilities of mice were measured by immunohistochemistry and protein immunoblotting (WB), and the expressions of PI3K, AKT and GSK-3β-related proteins were detected by transmission electron microscopy. Results Compared with the WT group, the other four groups all showed an increase in escape latency (P<0.05) and a significant decrease in the number of plateaus crossed (P<0.01); PI3K and AKT protein expression was significantly lower in the APP/PS1 group, APP/PS1+LY294002 group and APP/PS1+EA+LY294002 group (P<0.01), GSK-3β expression was significantly higher (P<0.01); PI3K expression was lower (P<0.05), AKT expression was significantly lower (P<0.01) and GSK-3β expression was higher (P<0.05) in the APP/PS1+EA group; compared with the WT group, the APP/PS1 group had a lower number of hippocampal neuronal cells, disrupted mitochondrial structure, and most mitochondria appeared swollen. The number of neuronal cells in the APP/PS1+EA group was higher than that in the APP/PS1 group, and the mitochondrial structure was clearer, with clear mitochondrial cristae and mild mitochondrial edema. Microtubules and microfilaments were arranged more neatly and orderly. Conclusions Ellagic acid improves learning and memory abilities, reduces hippocampal neuronal cell damage and apoptosis in AD model mice, and its mechanism of action may involve reducing hippocampal oxidative stress levels in AD model mice by regulating PI3K, AKT, GSK-3β and other related proteins.