载脂蛋白E
硫酸乙酰肝素
化学
硫酸化
生物化学
基因亚型
阿尔茨海默病
分子生物学
生物
细胞
疾病
基因
内科学
医学
作者
Dylan James Mah,Yanan Zhu,Guowei Su,Jing Zhao,Ashely Canning,James Gibson,Xuehong Song,Eduardo Stancanelli,Yongmei Xu,Fuming Zhang,Robert J Linhardt,Jian Liu,Lianchun Wang,Chunyu Wang
标识
DOI:10.1002/anie.202212636
摘要
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.
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