Oral Administration of Resveratrol-Selenium-Peptide Nanocomposites Alleviates Alzheimer's Disease-like Pathogenesis by Inhibiting Aβ Aggregation and Regulating Gut Microbiota

Alzheimer's disease (AD) is a neurodegenerative disease associated with amyloid-beta (A beta ) deposition, leading to neurotoxicity (oxidative stress and neuroinflammation) and gut microbiota imbalance. Resveratrol (Res) has neuroprotective properties, but its bioavailability in vivo is very low. Herein, we developed a small Resselenium-peptide nanocomposite to enable the application of Res for eliminating A beta aggregate-induced neurotoxicity and mitigating gut microbiota disorder in aluminum chloride (AlCl3) and D-galactose(D-gal)-induced AD model mice. Res functional selenium nanoparticles (Res@SeNPs) (8 +/- 0.34 nm) were prepared first, after which the surface of Res@SeNPs was decorated with a blood-brain barrier transport peptide (TGN peptide) to generate Res-selenium-peptide nanocomposites (TGN-Res@SeNPs) (14 +/- 0.12 nm). Oral administration of TGN-Res@SeNPs improves cognitive disorder through (1) interacting with AP and decreasing A beta aggregation, effectively inhibiting A beta deposition in the hippocampus; (2) decreasing A beta-induced reactive oxygen species (ROS) and increasing activity of antioxidation enzymes in PC12 cells and in vivo; (3) down-regulating A beta-induced neuroinflammation via the nuclear factor kappa B/mitogen-activated protein kinase/Akt signal pathway in BV-2 cells and in vivo; and (4) alleviating gut microbiota disorder, particularly with respect to oxidative stress and inflammatory-related bacteria such as Alistipes, Helicobacter, Rikenella, Desulfovibrio, and Faecalibaculum. Thus, we anticipate that Res-selenium-peptide nanocomposites will offer a new potential strategy for the treatment of AD.

Automated summary

A Res-selenium-peptide nanocomposite was developed to improve cognitive dysfunction in AD model mice by reducing Aβ aggregation, inhibiting Aβ deposition, decreasing oxidative stress and inflammation, and alleviating gut microbiota disorder.