Department of Chemistry and Chemical Biology, Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani School of Medicine, Tampa, FL 33620, USA.
Angew Chem Int Ed Engl. 2023 Jun 5;62(23):e202212636. doi: 10.1002/anie.202212636. Epub 2023 Apr 28.
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.
载脂蛋白 E（ApoE）的 ϵ4 等位基因是晚发性阿尔茨海默病（AD）最重要的遗传风险因素。细胞表面硫酸乙酰肝素（HS）是 ApoE/LRP1 相互作用和 tau 病理学在细胞间类朊病毒传播的辅助因子。HS 的 3-O-磺酸（3-O-S）修饰通过与 tau 的相互作用与 AD 相关联，并且 AD 大脑中 3-O-磺化 HS 和 3-O-磺基转移酶的水平升高。在这项研究中，我们在野生型 ApoE3、与 AD 相关的 ApoE4 以及 AD 保护型 ApoE2 和 ApoE3-Christchurch 中表征了 ApoE/HS 相互作用。糖基微阵列和 SPR 测定表明，所有 ApoE 同工型均识别 3-O-S。NMR 滴定将 ApoE/3-O-S 结合定位在经典 HS 结合基序附近。在细胞中，HS3ST1 的敲除（一种主要的 3-O 磺基转移酶）减少了 ApoE 的细胞表面结合和摄取。因此，3-O-S 被 tau 和 ApoE 识别，这表明 3-O-磺化 HS、tau 和 ApoE 同工型之间的相互作用可能调节 AD 风险。
