l -Fucose is a candidate monosaccharide neuromodulator and mitigates Alzheimer’s synaptic deficits
- 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
2025-11-07
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.