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

项目总结/摘要 阿尔茨海默病（AD）是一种衰老的病症，主要折磨65岁及以上的成年人，并且是最常见的疾病。 全球痴呆症的常见原因AD的组织病理学标志是淀粉样斑块， 神经纤维缠结（NFT），分别由蛋白质淀粉样蛋白-β和tau聚集形成。研究 NFT的形成与脑萎缩和认知能力下降有关。因此，停止tau聚集 在早期阶段预防疾病进展是AD的潜在治疗途径。我们以前的研究 小组确定了305 SVQIVY 310的微电子衍射结构，305 SVQIVY 310是一种易于聚集的片段， τ的我们设计了一种基于肽的抑制剂来靶向其聚集界面，称为WIW，其具有 已经证明在体外和细胞模型中停止tau聚集。将WIW传送到血脑 在血脑屏障（BBB）中，我将WIW连接到一个肽标签上，该肽标签通过受体介导的内吞作用进入大脑， 与低密度脂蛋白受体相关蛋白1结合。在目标1中，我将探讨 通过求解WIW与其靶肽SVQIVY的共晶体结构来确定WIW。在目标2中，我将修改WIW， 优化其CNS递送和血浆稳定性。在目标3中，我将确定WIW或优化的模拟 可以抑制tau蛋白病的小鼠模型PS19小鼠中的tau蛋白聚集。尽管WIW已经被证明 为了阻止tau蛋白在体外和细胞模型中的聚集，这些拟议的研究将是第一个结构性的研究。 WIW作用机制的表征及其阻止tau蛋白的能力的首次表征 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.