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

Fucosylation, a major glycan modification, has been shown to influence neuronal and microglial mechanisms, but whether unconjugated free L-fucose can impact 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 pre-synaptic release. Such effects required L-fucose metabolism through the FCSK-driven salvage pathway and were not likely dependent on fucosylation, 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. Dietary L-fucose supplement, which increased cerebral free L-fucose levels and upregulated FCSK to drive the salvage pathway, mitigated synaptic and behavioral deficits of 5xFAD mice. Our data suggests an unrecognized neuromodulatory function of free L-fucose and reveals its therapeutic potential for AD.