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Fucosylated Chondroitin Sulfate Modulates Microglia-Associated Responses and Reduces Aβ Burden with ERK1/2-Related
Xiaodan Xiao1, Feng Gao2, Jiaxing Xie2
1School of Basic Medical Sciences, Guangdong Medical University, Zhanjiang 524023, China; The Second School of Clinical Medicine, Guangdong Medical University, Zhanjiang, Guangdong, 524023, China.
Introduction:
Fucosylated chondroitin sulfate (FCS) is a sulfated polysaccharide derived from the marine organism Apostichopus japonicus. This study aimed to investigate its neuroprotective potential, specifically focusing on microglial modulation and ERK1/2 signaling, in Alzheimer's disease (AD) models.
Methods:
An integrated in vitro and in vivo approach was employed. In vitro, Aβ42-stimulated BV2 microglia were treated with FCS, and the broad protein kinase C activator TPA was used as a pharmacological perturbation to examine whether the FCS-associated ERK1/2 signaling changes were reversible. Cytokine levels, microglial phenotype markers (CD86, CD206, iNOS, Arg-1), Aβ handling, and MAPK pathway proteins (p-ERK1/2, p38, JNK) were analyzed. In vivo, 5xFAD transgenic mice received intraperitoneal FCS for 28 days. Aβ plaque burden, soluble/insoluble Aβ levels, cognitive performance (Morris water maze, Y-maze), cortical Iba1-positive cell counts, activation state (Iba1+CD86+, Iba1+CD206+), and expression of p-ERK1/2, iNOS, and Arg-1 were assessed.
Results:
In vitro, FCS attenuated Aβ42-induced pro-inflammatory responses (reduced IL-6, TNF-α; increased IL-10), modulated phenotype (decreased CD86/iNOS; increased CD206/Arg-1), and increased the cell-associated Aβ fraction while reducing supernatant Aβ. FCS reduced Aβ42-associated ERK1/2 phosphorylation and the nuclear-to-cytoplasmic p-ERK1/2 fluorescence signal ratio, and these changes were partially attenuated by TPA. In vivo, FCS treatment reduced cerebral Aβ burden, improved spatial and working memory, decreased the number and proportion of cortical Iba1+CD86+ microglia, and increased the Iba1+CD206+ subset. Cortical p-ERK1/2/total ERK1/2 and iNOS expression were downregulated, while Arg-1 was upregulated.
Conclusion:
FCS reduced Aβ-related pathological burden, improved selected behavioral outcomes, and modulated microglia-associated inflammatory and phenotype-related readouts in AD models. These effects were accompanied by ERK1/2-related signaling changes, supporting a pathway-associated interpretation rather than definitive proof of ERK1/2 causality in vivo.