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

Author:

Mah Dylan1ORCID,Zhu Yanan2,Su Guowei3,Zhao Jing14,Canning Ashely1,Gibson James1,Song Xuehong2,Stancanelli Eduardo5ORCID,Xu Yongmei5ORCID,Zhang Fuming1,Linhardt Robert J.1ORCID,Liu Jian35,Wang Lianchun2,Wang Chunyu1ORCID

Affiliation:

1. Department of Chemistry and Chemical Biology, Department of Biological Sciences Rensselaer Polytechnic Institute Troy NY 12180 USA

2. Department of Molecular Pharmacology and Physiology University of South Florida, Morsani School of Medicine Tampa FL 33620 USA

3. Glycan Therapeutics Raleigh NC 27606 USA

4. China Agricultural University Beijing 100083 China

5. Division of Chemical Biology and Medicinal Chemistry University of North Carolina at Chapel Hill, Eshelman School of Pharmacy Chapel Hill NC 27599 USA

Abstract

AbstractApolipoprotein 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.

Funder

National Institute on Aging

National Institute of General Medical Sciences

Publisher

Wiley

Subject

General Chemistry,Catalysis

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