Frontotemporal dementia (FTD) is the second most common type of dementia in individuals aged below 65 years with no current cure. Current treatment plan is the administration of multiple medications. This has the issue of causing adverse effects due to unintentional drug–drug interactions. Therefore, there exists an urgent need to propose a novel targeted therapy that can maximize the benefits of FTD-specific drugs while minimizing its associated adverse side effects. In this study, we implemented the concept of network pharmacology to understand the mechanism underlying FTD and highlight specific drug–gene and drug–drug interactions that can provide an interesting perspective in proposing a targeted therapy against FTD. We constructed protein–protein, drug–gene and drug–drug interaction networks to identify highly connected nodes and analysed their importance in associated enriched pathways. We also performed a historeceptomics analysis to determine tissue-specific drug interactions. Through this study, we were able to shed light on the APP gene involved in FTD. The APP gene which was previously known to cause FTD cases in a small percentage is now being extensively studied owing to new reports claiming its participation in neurodegeneration. Our findings strengthen this hypothesis as the APP gene was found to have the highest node degree and betweenness centrality in our protein–protein interaction network and formed an essential hub node between disease susceptibility genes and neuroactive ligand–receptors. Our findings also support the study of FTD being presented as a case of substance abuse. Our protein–protein interaction network highlights the target genes common to substance abuse (nicotine, morphine and cocaine addiction) and neuroactive ligand–receptor interaction pathways, therefore validating the cognitive impairment caused by substance abuse as a symptom of FTD. Our study abandons the one-target one-drug approach and uses networks to define the disease mechanism underlying FTD. We were able to highlight important genes and pathways involved in FTD and analyse their relation with existing drugs that can provide an insight into effective medication management.

中文翻译：

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使用网络药理学方法研究额颞叶痴呆的药物-靶标相互作用

额颞叶痴呆 (FTD) 是 65 岁以下人群中第二常见的痴呆类型，目前尚无法治愈。目前的治疗计划是服用多种药物。这存在由于无意的药物-药物相互作用而引起不良反应的问题。因此，迫切需要提出一种新的靶向疗法，它可以最大限度地发挥 FTD 特异性药物的益处，同时最大限度地减少其相关的不良副作用。在这项研究中，我们实施了网络药理学的概念来了解 FTD 的潜在机制，并强调特定的药物-基因和药物-药物相互作用，这些相互作用可以为提出针对 FTD 的靶向治疗提供有趣的视角。我们构建了蛋白质-蛋白质，药物-基因和药物-药物相互作用网络以识别高度连接的节点并分析它们在相关丰富途径中的重要性。我们还进行了组织受体组学分析以确定组织特异性药物相互作用。通过这项研究，我们能够阐明参与 FTD 的 APP 基因。由于新的报告声称其参与神经变性，以前已知会导致 FTD 病例的 APP 基因占一小部分，现在正在广泛研究。我们的发现加强了这一假设，因为发现 APP 基因在我们的蛋白质 - 蛋白质相互作用网络中具有最高的节点度和介数中心性，并在疾病易感基因和神经活性配体 - 受体之间形成了一个重要的枢纽节点。我们的研究结果还支持将 FTD 作为药物滥用案例提出的研究。我们的蛋白质-蛋白质相互作用网络突出了药物滥用（尼古丁、吗啡和可卡因成瘾）和神经活性配体-受体相互作用途径中常见的靶基因，因此证实了药物滥用引起的认知障碍是 FTD 的一种症状。我们的研究放弃了单靶点一药的方法，并使用网络来定义 FTD 的疾病机制。我们能够突出 FTD 中涉及的重要基因和通路，并分析它们与现有药物的关系，从而深入了解有效的药物管理。吗啡和可卡因成瘾）和神经活性配体 - 受体相互作用途径，因此证实了由药物滥用引起的认知障碍是 FTD 的症状。我们的研究放弃了单靶点一药的方法，并使用网络来定义 FTD 的疾病机制。我们能够突出 FTD 中涉及的重要基因和通路，并分析它们与现有药物的关系，从而深入了解有效的药物管理。吗啡和可卡因成瘾）和神经活性配体 - 受体相互作用途径，因此证实了由药物滥用引起的认知障碍是 FTD 的症状。我们的研究放弃了单靶点一药的方法，并使用网络来定义 FTD 的疾病机制。我们能够突出 FTD 中涉及的重要基因和通路，并分析它们与现有药物的关系，从而深入了解有效的药物管理。