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

J. Lucente,Jennyfer Tena,U. R. Mendiola,Xi Chen,Carlito B. Lebrilla,Izumi Maezawa,Lee-Way Jin

Published 2022 in bioRxiv

ABSTRACT

We identified a novel signaling function of L-fucose, a structurally unique monosaccharide. We showed that L-fucose enhanced excitatory neurotransmission and long-term potentiation (LTP) in Schaffer-collateral-CA1 synapses. L-fucose was released by neurons in an activity- and store-dependent manner, and induced rapid signaling changes to enhance presynaptic release. Such effects required L-fucose metabolism through the salvage pathway driven by fucokinase (FUK). Thus, L-fucose could be the first described monosaccharide neuromodulator affecting 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 could be corrected by exogenous L-fucose, exemplified by rectification of LTPdeficits in 5xFAD hippocampus. Dietary L-fucose supplement, which increased cerebral free L-fucose levels and upregulated FUK to drive the salvage pathway, mitigated synaptic and behavioral deficits of 5xFAD mice. Our data reveals a therapeutic potential of oral L-fucose for AD, which is safe and easy to comply with.

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