The 3-O sulfation of heparan sulfate proteoglycans contributes to the cellular internalization of tau aggregates

• Published in: BMC molecular and cell biology Vol. 23; no. 1; p. 61
• Main Authors: Ferreira, Andreia, Royaux, Ines, Liu, Jian, Wang, Zhangjie, Su, Guowei, Moechars, Diederik, Callewaert, Nico, De Muynck, Louis
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24.12.2022; BioMed Central; BMC
• Subjects: 3-O sulfation; Alzheimer's disease; Analysis; Chromatography, Liquid; Composition; Health aspects; Heparan Sulfate Proteoglycans - metabolism; Heparan sulfates proteoglycans; Heparitin Sulfate - metabolism; Heparitin Sulfate - pharmacology; HS 3-O sulfotransferase 1; Prevention; Proteoglycans; Risk factors; Sulfates; Tandem Mass Spectrometry; Tau proteins; tau Proteins - metabolism; Tau uptake; Tau-heparan sulfates interaction; United States; Heparan sulfates proteoglycans; Tau-heparan sulfates interaction; Tau uptake; HS 3-O sulfotransferase 1; 3-O sulfation
• ISSN: 2661-8850; 2661-8850
• DOI: 10.1186/s12860-022-00462-1

Considering the high correlation between the functional decline in Alzheimer's disease (AD) and the propagation of aggregated tau protein, many research efforts are focused on determining the underlying molecular mechanisms of tau spreading. Heparan sulfate proteoglycans (HSPGs) were reported to mediate cellular uptake of tau aggregates. Specifically, the heparan sulfates (HS) sulfation plays a critical role in the interaction of HSPGs with aggregated tau. HS can be N-/2-O/6-O- or 3-O-sulfated, some of which have been reported to take part in the interaction with tau aggregates. However, the role of the 3-O sulfation remains enigmatic. Here, we studied the contribution of HS 3-O sulfation in the binding and cellular uptake of tau aggregates. We observed reduced tau aggregates uptake in absence of 3-O sulfation or when outcompeting available cellular 3-O sulfated HS (3S-HS) with antithrombin III. The lack of HS3ST1-generated HS products in the HS3ST1 cells was further corroborated with an LC-MS/MS using C-labeled HS calibrants. Here, we showed that these functional changes can be explained by a higher affinity of aggregated tau to 3S-HS. When targeting tau aggregates with 3-O sulfation-containing HS, we observed an increase in inhibition of tau aggregates uptake. These data indicate that HS 3-O sulfation plays a role in the binding of tau aggregates and, thus, contributes to their cellular uptake, highlighting a potential target value to modulate tau pathogenesis.