Brain-Targeting Dihydromyricetin-Decorated Selenium Nanoparticles Attenuate Oxidative Stress for Treatment of Alzheimer’s Disease

The onset of Alzheimer's disease (AD) is significantly influenced by oxidative stress. Trace element selenium (Se) can be incorporated into selenoproteins to participate in redox regulation. In our previous study, it was found that brain-targeting chlorogenic acid-modified selenium nanoparticles (SeNPs) could effectively relieve oxidative stress in AD. However, the main mechanism of polyphenol-decorated SeNPs on antioxidant enzymes such as glutathione peroxidase is still unknown. Dihydromyricetin (DMY) is one polyphenol that has neuroprotective effects through antioxidant activities. In this study, chitosan (CS) was introduced as a stabilizer for the synthesis of a brain-targeted peptide (Tg: TGNYKALHPHNG) and DMY-modified SeNPs (Tg-CS/DMY@SeNPs). Tg-CS/DMY@SeNPs could improve the solubility of DMY and exhibited better free radical scavenging ability than DMY. Meanwhile, Tg-CS/DMY@SeNPs significantly enhanced the activity of antioxidant enzymes, which effectively inhibited ROS accumulation in Aβ aggregate-induced PC12 cells. More importantly, Tg-CS/DMY@SeNPs could activate the Nrf2/Keap-1 signaling pathway to regulate the activity of antioxidant enzymes, especially selenophenase glutathione peroxidase in the brain and liver of APP/PS1 mice. In that case, Tg-CS/DMY@SeNPs also prevented oxidative damage-induced apoptosis by inhibiting the Caspase-3 signaling pathway in the brain and liver of APP/PS1 mice. Finally, Tg-CS/DMY@SeNPs remarkably improved cognitive disorders in the APP/PS1 mice. These results indicated that Tg-CS/DMY@SeNPs exhibited promising therapeutic effects in the antioxidant therapy of AD.