Apolipoprotein E Recognizes Alzheimer's Disease Associated 3‐O Sulfation of Heparan Sulfate

Abstract Apolipoprotein E (ApoE)’s ϵ4 alle is the most important genetic risk factor for late onset Alzheimer's Disease (AD). Cell‐surface heparan sulfate (HS) is a cofactor for ApoE/LRP1 interaction and the prion‐like spread of tau pathology between cells. 3‐ O ‐sulfo (3‐ O ‐S) modification of HS has been linked to AD through its interaction with tau, and enhanced levels of 3‐ O ‐sulfated HS and 3‐ O ‐sulfotransferases in the AD brain. In this study, we characterized ApoE/HS interactions in wildtype ApoE3, AD‐linked ApoE4, and AD‐protective ApoE2 and ApoE3‐Christchurch. Glycan microarray and SPR assays revealed that all ApoE isoforms recognized 3‐ O ‐S. NMR titration localized ApoE/3‐ O ‐S binding to the vicinity of the canonical HS binding motif. In cells, the knockout of HS3ST1‐a major 3‐ O sulfotransferase‐reduced cell surface binding and uptake of ApoE. 3‐ O ‐S is thus recognized by both tau and ApoE, suggesting that the interplay between 3‐ O ‐sulfated HS, tau and ApoE isoforms may modulate AD risk.