Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Neurology, RWTH University Aachen, 52074 Aachen, Germany.
Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
J Biol Chem. 2020 Mar 6;295(10):2974-2983. doi: 10.1074/jbc.RA119.010353. Epub 2020 Jan 23.
Tau aggregation underlies neurodegeneration in Alzheimer's disease and related tauopathies. We and others have proposed that transcellular propagation of pathology is mediated by Tau prions, which are ordered protein assemblies that faithfully replicate and cause specific biological effects. The prion model predicts the release of aggregates from a first-order cell and subsequent uptake into a second-order cell. The assemblies then serve as templates for their own replication, a process termed "seeding." We have previously observed that heparan sulfate proteoglycans on the cell surface mediate the cellular uptake of Tau aggregates. This interaction is blocked by heparin, a sulfated glycosaminoglycan. Indeed, heparin-like molecules, or heparinoids, have previously been proposed as a treatment for PrP prion disorders. However, heparin is not ideal for managing chronic neurodegeneration, because it is difficult to synthesize in defined sizes, may have poor brain penetration because of its negative charge, and is a powerful anticoagulant. Therefore, we sought to generate an oligosaccharide that would bind Tau and block its cellular uptake and seeding, without exhibiting anticoagulation activity. We created a compound, SN7-13, from pentasaccharide units and tested it in a range of assays that measured direct binding of Tau to glycosaminoglycans and inhibition of Tau uptake and seeding in cells. SN7-13 does not inhibit coagulation, binds Tau with low nanomolar affinity, and inhibits cellular Tau aggregate propagation similarly to standard porcine heparin. This synthetic heparinoid could facilitate the development of agents to treat tauopathy.
tau 聚集是阿尔茨海默病和相关 tau 病神经退行性变的基础。我们和其他人已经提出，病理学的细胞间传播是由 Tau 朊病毒介导的，Tau 朊病毒是有序的蛋白质组装体，能够忠实复制并引起特定的生物学效应。朊病毒模型预测，聚集物从一级细胞中释放，并随后被二级细胞摄取。然后，这些组装物作为自身复制的模板，这个过程被称为“接种”。我们之前观察到，细胞表面的硫酸乙酰肝素蛋白聚糖介导 Tau 聚集物的细胞摄取。这种相互作用被肝素阻断，肝素是一种硫酸化糖胺聚糖。事实上，以前曾有人提议肝素样分子或肝素类药物作为 PrP 朊病毒疾病的治疗方法。然而，肝素并不适合治疗慢性神经退行性变，因为它难以按规定大小合成，由于其带负电荷，可能难以穿透大脑，而且是一种强大的抗凝剂。因此，我们试图生成一种寡糖，它可以结合 Tau 并阻止其细胞摄取和接种，而不表现出抗凝活性。我们从五糖单元中创建了一种化合物 SN7-13，并在一系列测定中对其进行了测试，这些测定测量了 Tau 与糖胺聚糖的直接结合以及 Tau 在细胞内摄取和接种的抑制作用。SN7-13 不抑制凝血，与 Tau 的结合亲和力为纳摩尔级，并且以类似于标准猪肝素的方式抑制细胞 Tau 聚集物的传播。这种合成的肝素类药物可以促进治疗 tau 病的药物的开发。
