Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by memory loss, speech and motor defects, personality changes, and psychological disorders. The exact cause of AD remains unclear. Current treatments focus on maintaining neurotransmitter levels or targeting β-amyloid (Aβ) protein, but these only alleviate symptoms and do not reverse the disease. Developing new drugs is time-consuming, costly, and has a high failure rate. Utilizing multi-omics for drug repositioning has emerged as a new strategy. Based on transcriptomic perturbation data of over 40,000 drugs in human cells from the LINCS-L1000 database, our study employed the Jaccard index and hypergeometric distribution test for reverse transcriptional feature matching analysis, identifying Givinostat as a potential treatment for AD. Our research found that Givinostat improved cognitive behavior and brain pathology in models and enhanced hippocampal synaptic plasticity. Transcriptome sequencing revealed increased expression of mitochondrial respiratory chain complex proteins in the brains of APP/PS1 mice after Givinostat treatment. Functionally, Givinostat restored mitochondrial membrane potential, reduced reactive oxygen species, and increased ATP content in Aβ-induced HT22 cells. Additionally, it improved mitochondrial morphology and quantity in the hippocampus of APP/PS1 mice and enhanced brain glucose metabolic activity. These effects are linked to Givinostat promoting mitochondrial biogenesis and improving mitochondrial function. In summary, Givinostat offers a promising new strategy for AD treatment by targeting mitochondrial dysfunction.

中文翻译：

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一种有前途的阿尔茨海默病治疗药物再利用方法：Givinostat 改善 APP/PS1 小鼠的认知行为和病理特征


阿尔茨海默病 （AD） 是最常见的神经退行性疾病，其特征是记忆力减退、言语和运动缺陷、性格改变和心理障碍。AD 的确切原因尚不清楚。目前的治疗侧重于维持神经递质水平或靶向 β-淀粉样蛋白 （Aβ） 蛋白，但这些只能缓解症状，不能逆转疾病。开发新药耗时、成本高、失败率高。利用多组学进行药物重新定位已成为一种新策略。基于 LINCS-L1000 数据库中人类细胞中 40,000 多种药物的转录组扰动数据，我们的研究采用 Jaccard 指数和超几何分布检验进行逆转录特征匹配分析，确定 Givinostat 是 AD 的潜在治疗方法。我们的研究发现，Givinostat 改善了模型中的认知行为和脑病理学，并增强了海马突触可塑性。转录组测序显示 Givinostat 处理后 APP/PS1 小鼠大脑中线粒体呼吸链复合物蛋白的表达增加。在功能上，Givinostat 恢复了 Aβ 诱导的 HT22 细胞中的线粒体膜电位，减少了活性氧，并增加了 ATP 含量。此外，它改善了 APP/PS1 小鼠海马体的线粒体形态和数量，并增强了脑葡萄糖代谢活性。这些作用与 Givinostat 促进线粒体生物发生和改善线粒体功能有关。总之，Givinostat 通过靶向线粒体功能障碍为 AD 治疗提供了一种有前途的新策略。