Astaxanthin attenuates cognitive deficits in Alzheimer’s disease models by reducing oxidative stress via the SIRT1/PGC-1α signaling pathway

Abstract Objective Oxidative stress plays a pivotal role in neurodegenerative diseases. Astaxanthin (AST) can play a neuroprotective role owing to its long-chain conjugated unsaturated double bond, which imparts potent antioxidant, anti-neuroinflammatory, and anti-apoptotic properties. However, the biological mechanisms underlying these effects remain unknown. Therefore, this study aimed to investigate and validate the protective effect of AST on neuronal senescence and apoptosis caused by oxidative stress induced by Aβ25–35 peptide, with the goal of preventing the onset of cognitive dysfunction. Methods Alzheimer's disease models comprising ICR mice and PC12 cells were established using Aβ25–35. The Morris water maze test was used to assess mouse behavior. Nissl staining revealed morphological changes in the mouse hippocampal neurons. To elucidate the mechanism of action of AST, ICR mice and PC12 cells were treated with the silent information regulator 1 (SIRT1) inhibitor nicotinamide (NAM). Additionally, immunofluorescence, western blotting, and reverse transcription polymerase chain reaction were used to evaluate changes in the expression of Bcl-2 and Bax in the mouse hippocampus, and SIRT1/PGC-1α signaling pathway proteins were detected. Moreover, the oxidative stress markers in ICR mice and PC12 cells were evaluated. Further, CCK-8 assays, Annexin V/PI double staining, and β-galactosidase activity assays were performed in PC12 cells to evaluate the anti-senescence and apoptotic effects of AST. Results In vivo experiments showed that Aβ25–35 impaired cognitive function, promoted morphological changes in hippocampal neurons, decreased Bcl-2 expression, increased Bax expression, decreased superoxide dismutase and GSH-px levels, and increased reactive oxygen species and malondialdehyde levels. Conversely, AST alleviated the impact of Aβ25–35 in mice, with reversed outcomes. NAM administration reduced SIRT1 and PGC-1α expression in the hippocampus. This decrease was accompanied by cognitive dysfunction and hippocampal neuron atrophy, which were also evident in the mice. Additionally, in vitro experiments showed that Aβ25–35 could promote oxidative stress and induce the senescence and apoptosis of PC12 cells. Nonetheless, AST treatment counteracted this effect by inhibiting oxidative stress and altering the state of PC12 cells. Notably, the Aβ + NAM group exhibited the most significant rates of senescence and apoptosis in PC12 cells following NAM treatment. Conclusion AST can improve cellular senescence and apoptosis mediated by oxidative stress via the SIRT1/PGC-1α signaling pathway and plays a vital role in inhibiting neuronal senescence and apoptosis and enhancing cognitive ability.