Andreia Ferreira, Ines Royaux, Jian Liu, Zhangjie Wang, Guowei Su, Diederik Moechars, Nico Callewaert, Louis De Muynck
{"title":"硫酸乙酰肝素蛋白聚糖的3-O硫酸化有助于tau聚集体的细胞内化。","authors":"Andreia Ferreira, Ines Royaux, Jian Liu, Zhangjie Wang, Guowei Su, Diederik Moechars, Nico Callewaert, Louis De Muynck","doi":"10.1186/s12860-022-00462-1","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Results: </strong>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<sup>-/-</sup> cells was further corroborated with an LC-MS/MS using <sup>13</sup>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":2,"journal":{"name":"ACS Applied Bio Materials","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2022-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9789671/pdf/","citationCount":"4","resultStr":"{\"title\":\"The 3-O sulfation of heparan sulfate proteoglycans contributes to the cellular internalization of tau aggregates.\",\"authors\":\"Andreia Ferreira, Ines Royaux, Jian Liu, Zhangjie Wang, Guowei Su, Diederik Moechars, Nico Callewaert, Louis De Muynck\",\"doi\":\"10.1186/s12860-022-00462-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Results: </strong>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<sup>-/-</sup> cells was further corroborated with an LC-MS/MS using <sup>13</sup>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":2,\"journal\":{\"name\":\"ACS Applied Bio Materials\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2022-12-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9789671/pdf/\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Applied Bio Materials\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12860-022-00462-1\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MATERIALS SCIENCE, BIOMATERIALS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Bio Materials","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12860-022-00462-1","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MATERIALS SCIENCE, BIOMATERIALS","Score":null,"Total":0}
The 3-O sulfation of heparan sulfate proteoglycans contributes to the cellular internalization of tau aggregates.
Background: 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.
Results: 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 13C-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.
Conclusions: 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.