New Breakthrough in Alzheimer's Disease Treatment: Mechanism Unveiled For Natural Monosaccharide L-Fucose To Reverse Synaptic Damage

   In the field of Alzheimer's disease (AD) research, a team from the University of California, Davis, USA has recently achieved a groundbreaking breakthrough. Researchers found that the natural monosaccharide L-Fucose can ameliorate synaptic dysfunction in AD model mice via a unique metabolic pathway. Published in Science Advances, this study not only reveals the pivotal role of glycobiology in neurodegenerative diseases, but also provides an entirely new approach for AD therapy.

    As a rare L-configured monosaccharide in mammals, the biological functions of L-Fucose(CAS No.:2438-80-4) have long drawn academic attention. Traditionally, this sugar molecule was thought to act primarily by "fucosylating" modified proteins and lipids. However, the latest study confirms that its free form itself can function as a neuromodulatory molecule. Through hippocampal brain slice experiments, the research team found that L-Fucose at a concentration of 200 μM can enhance presynaptic neurotransmitter release within 1–2 minutes, increasing the field excitatory postsynaptic potential (fEPSP) by approximately 40%; this effect can persist for 10 minutes in wild-type mice. More excitingly, in 5xFAD Alzheimer's disease model mice, 500 μM L-Fucose can restore the impaired long-term potentiation (LTP) to 85% of the wild-type level.

    This study is the first to confirm the neuromodulatory function of free L-Fucose. This sugar molecule regulates synaptic plasticity within minutes by activating the "salvage pathway" mediated by fucokinase (FCSK), and its mechanism of action is completely independent of traditional protein glycosylation modification. Experimental data show that FCSK gene knockout mice completely lose their response to L-Fucose, and the synaptic enhancement effect disappears entirely-this confirms the core role of this metabolic pathway.

Targeting the pathological features of Alzheimer's disease (AD), this study identified critical metabolic deficits in AD: fucokinase (FCSK) protein expression and free L-Fucose concentration were reduced by 62% and 45%, respectively, in brain tissues of 5xFAD mice and AD patients compared with normal controls.
    This fucose metabolic disorder induced synaptic plasticity impairment, while dietary supplementation with 0.5% L-Fucose restored brain free L-Fucose levels to 92% of the wild-type level and significantly improved cognitive function in model mice-manifested as a 2.3-fold longer exploration time in the novel object recognition test and a 58% increased accuracy in the T-maze test.

    In translational medicine validation, a 30-day L-Fucose intervention did not reduce Aβ plaque deposition in AD mice but significantly improved synaptic protein phosphorylation (CaMKII: 2.1-fold enhancement; CREB: 3.5-fold activation). Transcriptome analysis showed 70% (109/154) of synapse-related genes, including lrrk2 (4.7-fold upregulated) and tiam1 (3.2-fold upregulated), restored to wild-type expression levels;
neuroinflammatory markers GFAP and TMEM119 immunoreactivity was reduced to 1.2 times the normal level.

     This study reveals a novel metabolism-signal coupling paradigm in glycobiology.Notably, its human clinical trial has obtained FDA orphan drug designation, and early data showed oral L-Fucose improved cerebrospinal fluid biomarkers by 60% in patients with congenital glycosylation disorders caused by GFUS mutations, highlighting L-Fucose's therapeutic potential for AD.

Reference:Di Lucente, Jacopo, et al. "L-Fucose is a candidate monosaccharide neuromodulator and mitigates Alzheimer's synaptic deficits." Science Advances 11.45 (2025): eadt4123