Resveratrol-loaded selenium/chitosan nano-flowers alleviate glucolipid metabolism disorder-associated cognitive impairment in Alzheimer's disease

Resveratrol (Res) is a common natural polyphenol that inhibits inflammation and oxidative stress in Alzheimer's disease (AD). However, the absorption efficiency and in vivo bioactivity of Res are poor. High fat diet-induced metabolic disorders, including obesity and insulin resistance, can promote AD-related β-amyloid (Aβ) aggregation, Tau protein phosphorylation and neurotoxicity. Gut microbiota play a role in modulating metabolic syndrome and cognitive impairment. Herein, flower-like Res-loaded selenium nanoparticles/chitosan nanoparticles (Res@SeNPs@Res-CS-NPs) with higher loading capacity (64 %) were prepared to regulate gut microbiota in cases of AD with metabolic disorder. The nano-flowers could restore gut microbiota homeostasis to reduce lipopolysaccharide (LPS) formation and LPS-induced neuroinflammation. Additionally, Res@SeNPs@Res-CS-NPs can prevent lipid deposition and insulin resistance by decreasing Firmicutes levels and increasing Bacteroidetes levels in the gut, further inhibiting Aβ aggregation and Tau protein phosphorylation through the JNK/AKT/GSK3β signaling pathway. Moreover, Res@SeNPs@Res-CS-NPs treatment was able to regulate the relative levels of gut microbiota associated with oxidative stress, inflammation and lipid deposition, including Entercoccus, Colidextribacter, Rikenella, Ruminococcus, Candidatus_Saccharimonas, Alloprevotella and Lachnospiraceae_UCG-006. Overall, Res@SeNPs@Res-CS-NPs significantly enhances cognitive ability in AD mice with metabolic disorder, highlighting their potential for preventing cognitive impairments in AD. The mechanism of Res@SeNPs@Res-CS-NPs alleviates cognitive impairment in Alzheimer’s disease with metabolic disorder: 1) Res@SeNPs@Res-CS-NPs can restore the gut microbiota homeostasis to reduce lipopolysaccharide (LPS) formation and LPS induced neuroinflammation. 2) Res@SeNPs@Res-CS-NPs treatment prevented lipid deposition and insulin resistance by decreasing Firmicutes level and increasing Bacteroidetes level in gut microbiota, which further decreased the phosphorylated Tau and Aβ aggregation via JNK/AKT/GSK3β pathway in the brain. 3) Res@SeNPs@Res-CS-NPs treatment also regulated the relative abundance of oxidative stress, inflammatory and lipid deposition related gut microbiota including Entercoccus, Colidextribacter, Rikenella, Ruminococcus, Candidatus_Saccharimonas, Alloprevotella and Lachnospiraceae_UCG-006. Thus, the alleviation of glucolipid metabolism, oxidative stress, neuroinflammation a