Tau spreading in Alzheimer's disease is mediated by cell surface heparan sulfate (HS). As a class of sulfated polysaccharides, fucoidans might compete with HS to bind tau, resulting in the cessation of tau spreading. The structural determinants of fucoidans for competition with HS binding to tau are not well understood. Sixty previously prepared fucoidans/glycans with different structural determinants were used to determine their binding abilities to tau using SPR and AlphaLISA. Finally, it was found that fucoidans had two fractions (sulfated galactofucan (SJ-I) and sulfated heteropolysaccharide (SJ-GX-3)), which exhibited strong binding abilities than heparin. Tau cellular uptake assays using wild type mouse lung endothelial cell lines were performed. It was shown SJ-I and SJ-GX-3 inhibited tau-cell interaction and tau cellular uptake, suggesting that fucoidans might be good candidates for inhibiting tau spreading. NMR titration mapped fucoidans binding sites, which could provide the theoretical basis for the design of tau spreading inhibitors.
Keywords: Alzheimer's disease; Fucoidans; Heparin; Sulfated glycan; Tau protein.
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