Fu Mengjie, Wang Qiuchen, Gao Lihui, Ma Qianhui, Wang Ju
School of Biomedical Engineering, Tianjin Medical University, Tianjin, 300070, China.
Mol Neurobiol. 2025 Feb;62(2):2493-2514. doi: 10.1007/s12035-024-04416-w. Epub 2024 Aug 12.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease that is characterized by memory loss and cognitive impairment. Evidence shows that depression is a common co-occurrence in AD patients, and major depressive disorder (MDD) is considered a risk factor for AD. The crosstalk between the biological procedures related to the two disorders makes it very difficult to treat the comorbid conditions caused by them. Considering the common pathophysiological mechanisms underlying AD and MDD, antidepressant drugs may have beneficial therapeutic effects against their concurrence. In this study, we aimed to explore the potential drug candidates for the prevention and treatment of the comorbidity of AD and MDD. First, we screened the potential drugs for treating MDD by evaluating the distances of drug targets to MDD-related genes on the human protein-protein interaction network (PPIN) via a network-based algorithm. Then, the drugs were further screened to identify those that may be effective for AD treatment by analyzing their affinities with tau protein and Aβ42 peptide via molecular docking. Furthermore, the most stable binding modes were identified via molecular dynamics simulations, and the regulatory effects of drug candidates on genes involved in the pathogenesis of AD and MDD were analyzed. A total of 506 MDD-related genes were retrieved, and 831 drug candidates for MDD treatment were screened via the network-based approach. The results from molecular docking and molecular dynamics simulations indicated dihydroergotamine had the lowest binding affinity with tau protein and bromocriptine could form the most stable binding mode with Aβ42 peptide. Further analyses found that both dihydroergotamine and bromocriptine could regulate the expression of genes involved in the pathogenesis of AD and/or MDD in the brain. The exact mechanisms of the two drugs in treating AD and MDD, as well as their comorbidity, are still unclear, and further exploration is needed to evaluate their roles and mechanisms, both in vitro and in vivo. This study revealed that dihydroergotamine and bromocriptine may be the potential drug candidates for the treatment of the comorbidity of AD and MDD, and the therapeutic effects may be achieved by inhibiting the accumulation and aggregation of Aβ42 and tau protein and regulating the expression of disease-related genes in the brain.
阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征为记忆丧失和认知障碍。有证据表明，抑郁症在AD患者中很常见，且重度抑郁症（MDD）被认为是AD的一个风险因素。这两种疾病相关生物学过程之间的相互作用使得治疗由它们引起的共病非常困难。考虑到AD和MDD潜在的共同病理生理机制，抗抑郁药物可能对它们的共病具有有益的治疗效果。在本研究中，我们旨在探索预防和治疗AD与MDD共病的潜在候选药物。首先，我们通过基于网络的算法评估药物靶点与人类蛋白质-蛋白质相互作用网络（PPIN）上MDD相关基因之间的距离，筛选出治疗MDD的潜在药物。然后，通过分子对接分析药物与tau蛋白和Aβ42肽的亲和力，进一步筛选出可能对AD治疗有效的药物。此外，通过分子动力学模拟确定最稳定的结合模式，并分析候选药物对AD和MDD发病机制中涉及基因的调控作用。共检索到506个与MDD相关的基因，并通过基于网络的方法筛选出831个治疗MDD的候选药物。分子对接和分子动力学模拟结果表明，双氢麦角胺与tau蛋白的结合亲和力最低，而溴隐亭与Aβ42肽可形成最稳定的结合模式。进一步分析发现，双氢麦角胺和溴隐亭均可调节大脑中AD和/或MDD发病机制中涉及基因的表达。这两种药物治疗AD和MDD及其共病的确切机制仍不清楚，需要进一步探索以评估它们在体外和体内的作用及机制。本研究表明，双氢麦角胺和溴隐亭可能是治疗AD与MDD共病的潜在候选药物，其治疗效果可能是通过抑制Aβ42和tau蛋白的积累与聚集以及调节大脑中疾病相关基因的表达来实现的。
