l -Fucose is a candidate monosaccharide neuromodulator and mitigates Alzheimer’s synaptic deficits

作者：Jacopo Di Lucente, Jennyfer Tena, Yuanyuan Bai, Catelynn C. Shafer, Ulises Ruiz Mendiola, Elizabeth K. Neumann, Xi Chen, Carlito B. Lebrilla, Izumi Maezawa, Lee‐Way Jin · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adt4123 · 被引用次数：3 · 研究领域：Glycosylation and Glycoproteins Research、Seaweed-derived Bioactive Compounds、Lysosomal Storage Disorders Research

Fucosylation, a major glycan modification, has been shown to influence neuronal and microglial mechanisms, but whether unconjugated free l-fucose can affect brain function is unknown. l-Fucose can be transported into cells and metabolized by fucokinase (FCSK) via the poorly understood salvage pathway. Using mouse hippocampal slices, we showed that l-fucose enhanced excitatory neurotransmission and long-term potentiation (LTP) through regulation of presynaptic release. Such effects required l-fucose be metabolized through the FCSK-driven salvage pathway, suggesting a metabolic-signaling mechanism. Human Alzheimer's disease (AD) and 5xFAD mouse brains showed signs of fucose hypometabolism with impaired l-fucose signaling. Such abnormalities were corrected by exogenous l-fucose, exemplified by rectification of LTP deficits in 5xFAD hippocampus. A dietary l-fucose supplement, which increased cerebral free l-fucose levels and up-regulated FCSK to drive the salvage pathway, mitigated synaptic and behavioral deficits of 5xFAD mice. Our data suggest an unrecognized neuromodulatory function of free l-fucose and reveals its therapeutic potential for AD.