Basic Science and Pathogenesis.

Background: Heparan sulfate (HS) interacts with many important proteins. These interactions are primarily driven by electrostatics, with specificity determined by sulfation patterns. Although 3-O-sulfation is a rare modification in HS, several genome-wide association studies (GWAS) revealed that the Hs3st1 gene, encoding HS-3-O-sulfotransferase-1, is significantly linked to late onset AD risk.

Method: NMR, SPR, glycan array were used to study HS-protein interactions. A novel LC-MS/MS method was developed to quantify the low abundance 3-O-sulfated HS from human brain, with C labeled calibrants. Alexa-488 labeled Tau and ApoE was used to assess tau cell surface binding and uptake in HS3ST-1 knockout cellular lines.

Result: We have demonstrated that tau, the major component of neurofibrillary tangles, specifically recognizes the 3-O-sulfation (3-OS). In addition, ApoE, whose isoform ApoE4 is the most significant genetic risk factor for late onset AD, also interacts with 3-OS. In addition, the affinity between ApoE isoform and heparin correlates with AD risk, with ApoE4 having the highest affinity to heparin, while the protective ApoE2 and Christchurch having significantly lower affinity. With a novel LC-MS/MS method for quantifying 3-O-sulfation, our recent studies have further demonstrated a marked increase in 3-O-sulfated HS in AD brains.

Conclusion: Taken together, our findings underscore the importance of 3-OS in AD pathogenesis, suggesting its potential as a novel drug target and biomarker in Alzheimer's disease.