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

Angew Chem Int Ed Engl. 2023 Jun 5;62(23):e202212636. doi: 10.1002/anie.202212636. Epub 2023 Apr 28.


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.

Keywords: 3-O-Sulfation; Alzheimer's Disease; Apolipoprotein E; Glycobiology; Heparan Sulfate.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / metabolism
  • Apolipoprotein E3 / genetics
  • Apolipoproteins E / chemistry
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Heparitin Sulfate / chemistry
  • Humans
  • Protein Isoforms / metabolism


  • Apolipoprotein E3
  • Apolipoproteins E
  • Heparitin Sulfate
  • Protein Isoforms