Liang Chensi, Yuan Ziqi, Yang Shangchen, Zhu Yufei, Chen Zhenlei, Can Dan, Lei Aiyu, Li Huifang, Leng Lige, Zhang Jie
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. China.
Department of Pediatrics, Xiamen Maternity and Child Health Hospital affiliated to Xiamen University, Zhenhai Road, Xiamen, Fujian, 361003, P. R. China.
Adv Sci (Weinh). 2025 Mar;12(9):e2409105. doi: 10.1002/advs.202409105. Epub 2025 Jan 14.
Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. 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-cerebroventricular injection (ICV) or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits.
高血糖会加速阿尔茨海默病（AD）的进展，但单糖的作用仍不清楚。在此，研究表明，一种己糖——甘露糖，与AD的病理特征密切相关，这一点通过测量AD小鼠大脑和血清以及AD患者血清中的甘露糖水平得到了证实。通过脑室内注射（ICV）或饮用水给予AD小鼠甘露糖，以研究甘露糖对认知和AD病理进展的影响。长期的甘露糖过载会增加β淀粉样蛋白（Aβ）负担并加剧认知障碍，而无糖饮食或甘露糖转运体拮抗剂可逆转这种情况。从机制上讲，单细胞RNA测序和代谢组学表明，甘露糖介导的β-分泌酶1（BACE1）和尼卡斯特林的N-糖基化增强了它们的蛋白质稳定性，促进了Aβ的产生。此外，减少甘露糖摄入会降低BACE1和尼卡斯特林的稳定性，最终降低Aβ的产生并减轻AD病理。这些结果表明，高剂量摄入甘露糖可能会加剧AD的发病机制。限制饮食中的甘露糖可能具有治疗益处。
