Functional Selection of Tau Oligomerization-Inhibiting Aptamers.
Functional Selection of Tau Oligomerization-Inhibiting Aptamers.
复制标题
Tau 寡聚化抑制适体的功能选择。
DOI：
10.1002/anie.202402007
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Tan
中科院分区：
文献类型：
--
作者：
Wang,Bang;Pan,Xiaoshu;Teng,I-Ting;Li,Xiaowei;Kobeissy,Firas;Wu,Zo-Yu;Zhu,Jiepei;Cai,Guangzheng;Yan,He;Yan,Xin;Liang,Mingwei;Yu,Fahong;Lu,Jianrong;Yang,Zunyi;Biondi,Elisa;Haskins,William;Cao,YCharles;Benner,StevenA;Tan
微管相关Tau蛋白的病理性过度磷酸化和聚集导致阿尔茨海默病（AD）和其他相关Tau蛋白病。目前，阿尔茨海默病还没有治愈方法。适体在生物技术和神经系统疾病的治疗中作为下一代疗法提供了巨大的潜力。Tau蛋白的传统适体选择方法集中于结合亲和力而不是对病理性Tau的干扰。在这项研究中，我们开发了一种新的选择策略，以富集在通常促进Tau聚集的条件下与存活的单体Tau蛋白结合的DNA适体。采用这种方法，我们鉴定了一组适体候选物。值得注意的是，BW1c表现出对Tau蛋白的高结合亲和力（Kd=6.6 nM），并有效抑制花生四烯酸（AA）诱导的Tau蛋白寡聚化和聚集。 此外，它还能抑制无细胞系统中GSK 3 β介导的Tau过度磷酸化和细胞环境中冈田酸介导的Tau过度磷酸化。最后，BW1c tau适体的眶后注射显示了穿过血脑屏障并进入神经元细胞体的能力。通过进一步的改进和开发，这些Tau适体可能为一流的神经治疗铺平道路，以减轻Tau蛋白病相关的神经退行性疾病。
Pathological hyperphosphorylation and aggregation of microtubule‐associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next‐generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd=6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)‐induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β‐mediated Tau hyperphosphorylation in cell‐free systems and okadaic acid‐mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro‐orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first‐in‐class neurotherapeutic to mitigate tauopathy‐associated neurodegenerative disorders.