Xanthohumol Protects Against Neuronal Excitotoxicity and Mitochondrial Dysfunction in APP/PS1 Mice: An Omics-Based Study

<b>Background</b>: Neuronal excitotoxicity and metabolic decline, which begin in the early stages of Alzheimer's disease (AD), pose challenges for effective amelioration. Our previous work suggested that the natural compound xanthohumol, the most abundant prenylated flavonoid in hops, prevents memory deficits in APP/PS1 mice; however, the underlying mechanisms remain unclear. <b>Methods</b>: This study utilized APP/PS1 mice and cutting-edge omics techniques to investigate the effects of xanthohumol on hippocampal proteome, serum metabolome, and microbiome. <b>Results</b>: Our findings revealed that xanthohumol reduces the postsynaptic overexpression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, <i>N</i>-methyl-D-aspartate, and metabotropic glutamate receptors, but enhances ATP synthesis and mitophagy in the young AD hippocampus. Further mechanistic analyses suggested systemic regulatory effects, particularly on the decreasing glutamate synthesis in the blood and intestines of AD mice following xanthohumol administration. <b>Conclusions</b>: These results underscore the potential of xanthohumol in mitigating AD pathology through multifaceted mechanisms, sparking interest and curiosity in its preventive and therapeutic potential in AD.