Oxyberberine-nanoparticle attenuates the cognitive deficits in a transgenic mouse model of Alzheimer's disease via modulating gut microbiota through suppressing CXCL10/CXCR3 pathway.

Oxyberberine (OBB) has good potential neuroprotective effects. However, the poor water solubility of OBB poses a challenge to its therapeutic effects. In this study, OBB-hydroxypropyl-β-cyclodextrin (OBB-β-CD) was prepared to increase the water solubility and improve bioavailability of OBB. The neuroprotective effects of OBB-β-CD against AD were investigated using 3×Tg transgenic AD mouse model. OBB-β-CD exhibited dual regulatory capabilities in improving both behavioral deficits and pathological features of AD. OBB-β-CD was more effective than OBB in modulating the amyloid precursor protein (APP) processing and inhibiting the hyperphosphorylation of Tau protein. OBB-β-CD was effective in reducing both the concentration of beta-amyloid 42 (Aβ42) and the deposition of Aβ plaques in 3×Tg mouse models. OBB-β-CD also suppressed neuroinflammation by promoting microglial polarization from an M1-like to an M2-like phenotype. Furthermore, OBB-β-CD restored the gut dysbiosis and inhibited the activation of the C-X-C motif chemokine receptor 3 (CXCR3) and the level of C-X-C motif chemokine ligand 10 (CXCL10) in the brain and colon tissues of 3×Tg mice. Simultaneously, the effect of OBB that suppressed microglial M1 and promoted M2 polarization to improve the neuronal micro-environment was verified in vitro using BV-2 cells. Importantly, OBB-β-CD showed similar anti-AD effects of knockdown of CXCR3 in 3×Tg mice, but no synergistic effects were observed in the shCXCR3 + OBB-β-CD group compared to the shCXCR3 group. Furthermore, the results of molecular docking and surface plasmon resonance (SPR) assay indicated that CXCR3 could bind with OBB. Additionally, the fecal microbiota transplantation (FMT) of fecal microbiota from the OBB-β-CD-treated 3×Tg mice (OBB-β-CD-FMT) significantly alleviated the cognitive deficits in the pseudo-germ-free 3×Tg mice via markedly suppressing the hyperphosphorylation of Tau protein, Aβ level and the activation of CXCR3 in the brain of 3×Tg mice. OBB-β-CD has good potential for further development into a therapeutic agent for AD treatment.