<scp>T</scp>he Improvement Effects of Sika Deer Antler Protein in an Alzheimer's Disease Mouse Model via the Microbe–Gut–Brain Axis

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The interplay between the intestinal microbiota and metabolites is believed to influence brain function and the pathogenesis of neurodegenerative conditions through the microbe-gut-brain axis. Sika deer antler protein possesses neuroprotective properties; however, the precise mechanism by which it improves AD remains unclear. Sika deer antler protein ameliorated AD in vivo by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The metabolome of brain and intestinal tissues and the microbiota of intestinal contents were tested and analyzed according to the microbe-gut-brain theory. Sika deer antler protein increased beneficial bacterial levels and decreased harmful bacterial levels. Correlation analyses using the gut flora-metabolomics pathway ultimately revealed that sika deer antler protein modulated the brain and intestinal tract bi-directionally via the tyrosine metabolism pathway, thereby establishing a connection within the microbe-gut-brain axis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the differential metabolite targets of the DAP4 group showed that the enriched pathways mainly included PI3K/AKT, which was consistent with the findings of the pharmacodynamic mechanisms observed in in vivo experiments. This suggests that antler protein may be involved in microbe-gut-brain interactions through tyrosine metabolism and may improve AD by activating the PI3K/AKT/Nrf2 signaling pathway. These findings add to our understanding of the microbe-gut-brain axis facilitated by sika deer antler protein and offer novel insights for further research on sika deer antler protein in alleviating AD.