Designing novel therapeutics for Alzheimer’s disease using structural studies of tau

项目摘要/摘要 阿尔茨海默病(AD)是一种衰老的疾病，主要困扰65岁及以上的成年人，是最常见的 世界范围内痴呆症的共同原因。AD的组织病理学特征是淀粉样斑块和 神经原纤维缠结(NFT)，分别由淀粉样蛋白-β和tau蛋白聚集形成。研究表明， 研究表明，NFT的形成与大脑萎缩和认知能力下降有关。因此，停止tau聚合 早期预防疾病进展是治疗阿尔茨海默病的潜在途径。在我们之前的研究中 小组测定了305SVQIVY310的微电子衍射结构，它是一种容易聚集的片段 陶先生。我们设计了一种基于多肽的抑制剂来靶向它的聚集界面，称为WiW，它已经 已被证明在体外和细胞模型中可以阻止tau聚集。将WW运送到血脑 屏障(BBB)，我已经将WW与一个肽标签联系在一起，它通过受体介导的内吞作用进入大脑，通过 结合低密度脂蛋白受体相关蛋白1。在目的1中，我将探讨其作用机制 通过解决WW与其目标肽SVQIVY的共晶结构。在目标2中，我将把WW修改为 优化其中枢神经系统的递送和血浆稳定性。在目标3中，我将确定Wiw或优化的模拟 能抑制tau在PS19小鼠体内的聚集，这是一种牛磺酸病的小鼠模型。尽管WW已经被证明 为了阻止tau在体外和细胞模型中聚集，这些拟议的研究将是第一个结构性的研究。 肌萎缩侧索硬化症作用机制的表征及其抑制tau能力的首次表征 体内聚集。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a condition of aging, primarily afflicting adults 65 and older, and is the most common cause of dementia worldwide. The histopathological hallmarks of AD are amyloid plaques and neurofibrillary tangles (NFTs), formed by aggregation of proteins amyloid-β and tau, respectively. Studies have shown NFT formation is correlated with brain atrophy and cognitive decline. Therefore, halting tau aggregation at early stages to prevent disease progression is a potential therapeutic avenue for AD. Previous studies in our group determined the micro-electron diffraction structure of 305SVQIVY310, an aggregation-prone segment of tau. We designed a peptide-based inhibitor to target its aggregating interfaces, referred to as WIW, which has been demonstrated to halt tau aggregation in vitro and in cell models. To transport WIW across the blood-brain barrier (BBB), I have linked WIW to a peptide tag that enters the brain via receptor-mediated endocytosis by binding to low-density lipoprotein receptor-related protein 1. In Aim 1, I will probe the mechanism of action of WIW by solving a co-crystal structure of WIW with its target peptide, SVQIVY. In Aim 2, I will modify WIW to optimize its CNS delivery and plasma stability. In Aim 3, I will determine whether WIW or an optimized analog can inhibit tau aggregation in PS19 mice, a mouse model of tauopathy. Although WIW has been demonstrated to halt tau aggregation in vitro and in cell models, these proposed investigations will be the first structural characterization of the mechanism of action of WIW and the first characterization of its ability to halt tau aggregation in vivo.