Neuroprotective Effects of Food-Derived Cyanidin Glycosides in an Alzheimer's Disease-Like Zebrafish Model Through Modulation of PI3K/Akt/GSK3β Signaling

Alzheimer's disease (AD) is a progressive neurodegenerative disorder lacking effective and safe interventions. Food-derived anthocyanins have gained increasing attention due to their neuroprotective potential; however, the specific mechanisms of individual cyanidin glycosides remain insufficiently understood. Notably, the comparative efficacy and mechanistic differences among structurally distinct cyanidin glycosides have not been systematically evaluated in vivo. In the present study, three cyanidin glycosides, cyanidin-3-O-rutinoside (C3R), cyanidin-3-O-sophoroside (C3S), and cyanidin-3-O-xyloside (C3X), were evaluated using an aluminum chloride (AlCl3)-induced zebrafish model of AD-like pathology. The results showed that these compounds improved cognitive performance and anxiety-like behavior, while attenuating oxidative stress and neuroinflammation and restoring cholinergic function, as evidenced by biochemical and immunofluorescence analyses. In addition, neuronal damage and Tau phosphorylation at Ser396 were markedly alleviated. Among the tested compounds, C3R consistently exhibited the most pronounced effects across multiple indicators. Mechanistically, the three cyanidin glycosides modulated PI3K/Akt/GSK3β signaling, as reflected by overall increases in p-PI3K (Tyr458)/PI3K and p-Akt (Ser473)/Akt and decreases in p-GSK3β (Tyr216)/GSK3β and p-Tau (Ser396)/Tau. LY294002 attenuated the pathway-associated protective effects, supporting the involvement of PI3K/Akt signaling. Collectively, these findings demonstrate neuroprotective effects associated with modulation of PI3K/Akt/GSK3β signaling, with C3R showing the strongest overall efficacy.