Increased 3-O-sulfated heparan sulfate in Alzheimer’s disease brain is associated with genetic risk gene HS3ST1
Authors:
Zhangjie Wang, Vaishali N. Patel, Xuehong Song, Yongmei Xu, Andrea M. Kaminski, Vivien Uyen Doan, Guowei Su, Yien Liao, Dylan Mah, Fuming Zhang, Vijayakanth Pagadala, Chunyu Wang, Lars C. Pedersen, Lianchun Wang, Matthew P. Hoffman, Marla Gearing, Jian Liu*
Affiliation:
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA.
Department of Molecular Pharmacology and Physiology, Byrd Alzheimer’s Center and Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612 USA.
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Glycan Therapeutics Corp., 617 Hutton Street, Raleigh, NC 27606, USA.
Department of Biological Sciences, Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Department of Molecular Pharmacology and Physiology, Byrd Alzheimer’s Center and Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612 USA.
Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
Description:
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.