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

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 d...

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Detalles Bibliográficos
Autores principales: Wang, Zhangjie, Patel, Vaishali N., Song, Xuehong, Xu, Yongmei, Kaminski, Andrea M., Doan, Vivien Uyen, Su, Guowei, Liao, Yien, Mah, Dylan, Zhang, Fuming, Pagadala, Vijayakanth, Wang, Chunyu, Pedersen, Lars C., Wang, Lianchun, Hoffman, Matthew P., Gearing, Marla, Liu, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10219595/
https://www.ncbi.nlm.nih.gov/pubmed/37235665
http://dx.doi.org/10.1126/sciadv.adf6232
Descripción
Sumario: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.