A Flower-like Brain Targeted Selenium Nanocluster Lowers the Chlorogenic Acid Dose for Ameliorating Cognitive Impairment in APP/PS1 Mice.

Aß aggregation-related neuroinflammation and imbalance of brain glucose homeostasis play important roles in the pathological process of Alzheimer's disease (AD). Chlorogenic acid (CGA) is one of the most common dietary polyphenols with neuroprotective effects. However, due to the low bioavailability of CGA, its application dose is usually high in vivo. In our previous study, the spherical selenium nanoparticles act as drug carriers to improve the bioactivity of resveratrol. Here, the brain-targeting peptide (TGN peptide) and CGA were used to prepare a new flowerlike selenium nanocluster (TGN-CGA@SeNCs) for enhancing the bioavailability of CGA. After decoration on selenium nanoclusters, the solubility and stability of CGA was obviously increased. Oral administration of a low dose of CGA (80 mg/kg/body weight) only slightly inhibited Aß aggregate-related neuroinflammation and glucose homeostasis disorder in the brain. Moreover, CGA showed less effect on increasing the diversity and richness of gut microbiota. At the same concentration, the CGA-modified selenium nanocluster (CGA@SeNCs) and TGN-CGA@SeNCs showed better function in ameliorating the gut microbiota disorder. Especially, TGN-CGA@SeNCs significantly increased the relative abundance of Turicibacter, Colidextribacter, Ruminococcus, Alloprevotella, and Alistipes against oxidative stress, inflammation, and glucose homeostasis imbalance. Notably, only TGN-CGA@SeNCs can transport through the blood-brain barrier (BBB), and TGN-CGA@SeNCs showed better effects than CGA@SeNCs in regulating Aß aggregation and improving brain glucose homeostasis. These results broadened the application of TGN-CGA@SeNCs, effectively improving the bioactivity of CGA, which also lowers the CGA dose for preventing AD progression.

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

Neuroinflammation plays a critical role in Alzheimer's disease (AD). However, it is still unknown if neuroinflammation can be effectively treated using selenium nanoparticles (SeNPs) with different surface modifications. In this study, SeNPs were coated with dihydromyricetin (DMY), a natural polyphenol, to obtain DMY@SeNPs. Given that DMY@SeNPs are unstable under physiological conditions, they were decorated step-by-step with chitosan (CS/DMY@SeNPs) and with the blood brain barrier (BBB) targeting peptide Tg (TGNYKALHPHNG) to yield Tg-CS/DMY@SeNPs, which significantly reduced the aggregation of Aß and improved the anti-inflammatory effects of SeNPs in vitro. The mechanisms of CS/DMY@SeNPs and Tg-CS/DMY@SeNPs on regulating neuroinflammation are different. Only Tg-CS/DMY@SeNPs can cross the BBB; therefore, Tg-CS/DMY@SeNPs more successfully inhibited Aß aggregation and reduced inflammatory cytokine secretion via the NF-κB pathway in the brain of APP/PS1 mice compared to CS/DMY@SeNPs. Furthermore, both types of nanoparticles, however, were able to repair the gut barrier and regulate the population of inflammatory-related gut microbiota such as Bifidobacterium, Dubosiella, and Desulfovibrio. Of note, the relative abundance of Gordonibacter was only enhanced by Tg-CS/DMY@SeNPs, thereby downregulating the protein expression of the NLRP3 inflammasome and the concentrations of serum inflammatory factors. This demonstrates that Tg-CS/DMY@SeNPs ameliorate neuroinflammation through the gut microbiota-NLRP3 inflammasome-brain axis. Overall, our data suggest that Tg-CS/DMY@SeNPs are an ideal drug candidate for AD treatment.