Increased 3-O-sulfated heparan sulfate in Alzheimer's disease brain is associated with genetic risk gene HS3ST1

• Type of Material: Article
• Authors: Zhangjie Wang, UNC Eshelman School of Pharmacy; Vaishail N Patel, National Institute of Dental and Craniofacial Research (NIDCR); Xuehong Song, Byrd Alzheimer’s Center and Research Institute; Yongmei Xu, UNC Eshelman School of Pharmacy; Andrea M Kaminski, National Institute of Environmental Health Sciences (NIEHS); Vivien Uyen Doan, UNC Eshelman School of Pharmacy; Guowei Su, GLYCAN THERAPEUTICS, LLC; Yien Liao, UNC Eshelman School of Pharmacy; Dylan Mah, Center for Biotechnology & Interdisciplinary Studies; Fuming Zhang, Center for Biotechnology & Interdisciplinary Studies; Vijayakanth Pagadala, GLYCAN THERAPEUTICS, LLC; Chunyu Wang, Center for Biotechnology & Interdisciplinary Studies; Lars C Pedersen, National Institute of Environmental Health Sciences (NIEHS); Lianchun Wang, Byrd Alzheimer’s Center and Research Institute; Matthew P Hoffman, National Institute of Dental and Craniofacial Research (NIDCR); Marla Gearing, Emory University; Jian Liu, UNC Eshelman School of Pharmacy
• Language: English
• Date: 2023-05-26
• Publisher: American Association for the Advancement of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.adf6232
• Title of Journal or Parent Work: Science Advances
• Volume: 9
• Issue: 21
• Start Page: eadf6232
• End Page: eadf6232
• Grant/Funding Information: J.L. lab at UNC has received a gift from Glycan Therapeutics to support research in glycosciences.
• Keywords: Mice; Brain; Chromatography, Liquid; Animals; Tandem Mass Spectrometry; Sulfates; Mice, Knockout; Heparitin Sulfate; Sulfotransferases; Alzheimer Disease
• Research Categories: Health Sciences, Pharmacology

Abstract

HS3ST1 is a genetic risk gene associated with Alzheimer's disease (AD) and overexpressed in patients, but how it contributes to the disease progression is unknown.We report the analysis of brain heparan sulfate (HS) from AD and other tauopathies using a LC-MS/MS method. A specific 3-O-sulfated HS displayed sevenfold increase in the AD group (n = 14, P < 0.0005). Analysis of the HS modified by recombinant sulfotransferases and HS from genetic knockout mice revealed that the specific 3-O-sulfated HS is made by 3-O-sulfotransferase isoform 1 (3-OST-1), which is encoded by the HS3ST1 gene. A synthetic tetradecasaccharide (14-mer) carrying the specific 3-O-sulfated domain displayed stronger inhibition for tau internalization than a 14-mer without the domain, suggesting that the 3-O-sulfated HS is used in tau cellular uptake. Our findings suggest that the overexpression of HS3ST1 gene may enhance the spread of tau pathology, uncovering a previously unidentified therapeutic target for AD.