Abstract 抽象的

Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer’s disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer’s disease. However, there is currently no effective CypD inhibitor for Alzheimer’s disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood–brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer’s disease mitochondrial and glycolytic bioenergetics in Alzheimer’s disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer’s disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer’s disease mouse models.
线粒体功能障碍是阿尔茨海默病的早期病理特征,在阿尔茨海默病的发生和发展中发挥着至关重要的作用。拯救线粒体功能和认知的策略仍有待探索。亲环蛋白 D (CypD),肽基脯氨酰异构酶 F (PPIase),是打开线粒体膜通透性转换孔的关键成分,导致线粒体功能障碍和细胞死亡。通过抑制 CypD 活性来阻断膜通透性转换孔的开放是治疗阿尔茨海默病的一种有前景的方法。然而,目前尚无有效治疗阿尔茨海默病的 CypD 抑制剂,之前的候选药物毒性高、穿过血脑屏障的能力差、生物相容性差且选择性低。在此,我们报告了一类新型无毒且生物相容性 CypD 抑制剂依布硒啉 (ebselen),它使用传统的 PPIase 测定法筛选约 2000 种 FDA 批准的药物库,并对 CypD-依布硒啉 (ebselen) 晶体结构进行晶体学分析(PDB 代码:8EJX) 。更重要的是,我们评估了 CypD 的遗传和药理学阻断对阿尔茨海默病衍生的线粒体 cybrid 细胞(一种离体人散发性阿尔茨海默病线粒体模型)中阿尔茨海默病线粒体和糖酵解生物能的影响,以及对突触功能、炎症反应和学习的影响。阿尔茨海默病小鼠模型的记忆。

Inhibition of CypD by ebselen protects against sporadic Alzheimer’s disease- and amyloid-β-induced mitochondria