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

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease associated with amyloid-β (Aβ) 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 Aβ aggregate-induced neurotoxicity and mitigating gut microbiota disorder in aluminum chloride (AlCl 3 ) 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 Aβ and decreasing Aβ aggregation, effectively inhibiting Aβ deposition in the hippocampus; (2) decreasing Aβ-induced reactive oxygen species (ROS) and increasing activity of antioxidation enzymes in PC12 cells and in vivo; (3) down-regulating Aβ-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.

Multifunctional Selenium Nanoparticles with Different Surface Modifications Ameliorate Neuroinflammation through the Gut Microbiota-NLRP3 Inflammasome-Brain Axis in APP/PS1 Mice

“…The Morris Water Maze (MWM) experiment was performed as described previously. 18 The experiment lasted for 7 days that consisted of five training days. During training day, mice were swim freely to find the escape platform in 90 s. At the last day, the escape platform was removed, and the number of each time that the mice passed through the platform area in memory and the escape latency was recorded to evaluate their spatial memory.…”

“…Aβ deposition and microglia were analyzed by immunofluorescence staining as described previously. 18 2.6. Analysis of Gut Microbiota Composition.…”

“…The concentrations of LPS and Dlac were measured by a previous method. 18 To investigate gut microbiota composition, the microbial DNA was extracted from colonic contents, and variable three-variable four region of 16S rRNA was measured followed the method as described previously. 18 2.7.…”

“…We have previously found that resveratrol-selenium-peptide nanocomposites alleviate AD-like pathogenesis by regulating inflammatory-related gut microbiota such as Faecalibaculum, Rikenella, and Alistipes. 18 However, the bioactivity of DMY-modified SeNPs with different surface modifications and their impact on Aβ aggregation or microbiotagut-inflammasome-brain axis is still unclear in vivo. In this study, we investigated whether these nanoparticles could regulate Aβ deposition, gut microbiota dysfunction, and NLRP3 related neuroinflammation both in vitro and in vivo.…”

Dietary Supplements and Natural Products: An Update on Their Clinical Effectiveness and Molecular Mechanisms of Action During Accelerated Biological Aging

“…Several studies suggest that despite the low bioavailability, resveratrol treatment is effective, safe, and well-tolerated in elderly individuals with age-related diseases and may promote healthy aging ( Movahed et al, 2020 ; Harper et al, 2021 ). Moreover, resveratrol and its metabolites can permeate the blood-brain barrier ( Turner et al, 2015 ), offering some supportive grounds for animal studies that have suggested resveratrol and its enhanced nano-formulations as potential anti-Alzheimer’s disease drugs ( Li et al, 2021b ). Aside from neurodegenerative diseases, resveratrol is beneficial for various diabetes-related organ injuries, including diabetic neuropathy, diabetic retinopathy, diabetes-induced liver damage, and cardiovascular diseases.…”