Poria cocos Polysaccharide Reshapes Gut Microbiota to Regulate Short-Chain Fatty Acids and Alleviate Neuroinflammation-Related Cognitive Impairment in Alzheimer’s Disease

polysaccharide (PCP) improves cognitive impairment in Alzheimer's disease (AD); however, its underlying mechanism, particularly its relationship with the gut microbiota, remains unclear. In the current study, we aimed to investigate the mechanism of PCP in improving cognitive impairment in AD. The results demonstrated that PCP markedly enhanced cognitive function and mitigated AD-related pathological alterations in 3 × Tg-AD mice. PCP treatment reversed the age-dependent gut microbiota dysbiosis in 3 × Tg-AD mice by 16S rDNA sequencing. The contents of propanoic acid, butanoic acid and isohexanoic acid were increased by short-chain fatty acid determination. In addition, PCP could restore both the intestinal barrier and the blood-brain barrier, as demonstrated by immunofluorescence staining of tight junction proteins. Furthermore, PCP alleviated systemic inflammation and neuroinflammation, as evidenced by reduced LPS levels in circulation and decreased IL-6 levels in the brain, likely by inhibiting the TLR4/NF-κB signaling pathway. In conclusion, PCP can reshape gut microbiota to regulate short-chain fatty acids and alleviate neuroinflammation-related cognitive impairment in AD mice.