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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. Methods: This study utilized APP\/PS1 mice and cutting-edge omics techniques to investigate the effects of xanthohumol on hippocampal proteome, serum metabolome, and microbiome. Results: Our findings revealed that xanthohumol reduces the postsynaptic overexpression of \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, N-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. Conclusions: 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.<\/jats:p>","DOI":"10.3390\/nu16213754","type":"journal-article","created":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T04:59:54Z","timestamp":1730437194000},"page":"3754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Xanthohumol Protects Against Neuronal Excitotoxicity and Mitochondrial Dysfunction in APP\/PS1 Mice: An Omics-Based Study"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8884-3568","authenticated-orcid":false,"given":"Fei-Fei","family":"Hu","sequence":"first","affiliation":[{"name":"Hubei Provincial Clinical Research Center for Alzheimer\u2019s Disease, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Brain Science and Advanced Technology Institute, Medical School, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Yao","family":"Pan","sequence":"additional","affiliation":[{"name":"Hubei Provincial Clinical Research Center for Alzheimer\u2019s Disease, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Brain Science and Advanced Technology Institute, Medical School, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Yu","family":"Chu","sequence":"additional","affiliation":[{"name":"Hubei Provincial Clinical Research Center for Alzheimer\u2019s Disease, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Brain Science and Advanced Technology Institute, Medical School, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9662-8294","authenticated-orcid":false,"given":"Jian-Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Ting","family":"Duan","sequence":"additional","affiliation":[{"name":"Hubei Provincial Clinical Research Center for Alzheimer\u2019s Disease, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Brain Science and Advanced Technology Institute, Medical School, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Luo","sequence":"additional","affiliation":[{"name":"Hubei Provincial Clinical Research Center for Alzheimer\u2019s Disease, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Brain Science and Advanced Technology Institute, Medical School, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Hubei Provincial Clinical Research Center for Alzheimer\u2019s Disease, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Brain Science and Advanced Technology Institute, Medical School, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Ming","family":"Wang","sequence":"additional","affiliation":[{"name":"Hubei Provincial Clinical Research Center for Alzheimer\u2019s Disease, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Brain Science and Advanced Technology Institute, Medical School, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Hubei Provincial Clinical Research Center for Alzheimer\u2019s Disease, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Brain Science and Advanced Technology Institute, Medical School, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2023). 2023 Alzheimer\u2019s Disease Facts and Figures. 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