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Cell\u2010surface heparan sulfate (HS) is a cofactor for ApoE\/LRP1 interaction and the prion\u2010like spread of tau pathology between cells. 3\u2010<jats:italic>O<\/jats:italic>\u2010sulfo (3\u2010<jats:italic>O<\/jats:italic>\u2010S) modification of HS has been linked to AD through its interaction with tau, and enhanced levels of 3\u2010<jats:italic>O<\/jats:italic>\u2010sulfated HS and 3\u2010<jats:italic>O<\/jats:italic>\u2010sulfotransferases in the AD brain. In this study, we characterized ApoE\/HS interactions in wildtype ApoE3, AD\u2010linked ApoE4, and AD\u2010protective ApoE2 and ApoE3\u2010Christchurch. Glycan microarray and SPR assays revealed that all ApoE isoforms recognized 3\u2010<jats:italic>O<\/jats:italic>\u2010S. NMR titration localized ApoE\/3\u2010<jats:italic>O<\/jats:italic>\u2010S binding to the vicinity of the canonical HS binding motif. In cells, the knockout of HS3ST1\u2010a major 3\u2010<jats:italic>O<\/jats:italic> sulfotransferase\u2010reduced cell surface binding and uptake of ApoE. 3\u2010<jats:italic>O<\/jats:italic>\u2010S is thus recognized by both tau and ApoE, suggesting that the interplay between 3\u2010<jats:italic>O<\/jats:italic>\u2010sulfated HS, tau and ApoE isoforms may modulate AD risk.<\/jats:p>","DOI":"10.1002\/anie.202212636","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T17:36:52Z","timestamp":1680629812000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Apolipoprotein\u2005E Recognizes Alzheimer's Disease Associated 3\u2010<i>O<\/i> Sulfation of Heparan Sulfate"],"prefix":"10.1002","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7734-6101","authenticated-orcid":false,"given":"Dylan","family":"Mah","sequence":"first","affiliation":[{"name":"Department of Chemistry and 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