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Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra\u2010cerebroventricular injection (ICV)\u00a0or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases \u03b2\u2010amyloid (A\u03b2) burdens and exacerbates cognitive impairments, which are reversed by a mannose\u2010free diet or mannose transporter antagonists. Mechanistically, single\u2010cell RNA sequencing and metabolomics suggested that mannose\u2010mediated N\u2010glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting A\u03b2 production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering A\u03b2 production and mitigating AD pathology. this results highlight that high\u2010dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits.<\/jats:p>","DOI":"10.1002\/advs.202409105","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T03:12:12Z","timestamp":1736824332000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Mannose Promotes \u03b2\u2010Amyloid Pathology by Regulating BACE1 Glycosylation in Alzheimer's Disease"],"prefix":"10.1002","volume":"12","author":[{"given":"Chensi","family":"Liang","sequence":"first","affiliation":[{"name":"Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research Institute of Neuroscience School of Medicine Xiamen University  Xiangan South Road Xiamen Fujian 361102 P. R. 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