Wolfson Centre for Age-Related Diseases, King's College London, London Bridge, London, SE1 1UL, UK.
College of Medicine and Health, University of Exeter, Exeter, EX1 2LU, UK.
Transl Psychiatry. 2019 Sep 6;9(1):220. doi: 10.1038/s41398-019-0555-x.
Alzheimer's disease is a complex disorder encompassing multiple pathological features with associated genetic and molecular culprits. However, target-based therapeutic strategies have so far proved ineffective. The aim of this study is to develop a methodology harnessing the transcriptional changes associated with Alzheimer's disease to develop a high content quantitative disease phenotype that can be used to repurpose existing drugs. Firstly, the Alzheimer's disease gene expression landscape covering severe disease stage, early pathology progression, cognitive decline and animal models of the disease has been defined and used to select a set of 153 drugs tending to oppose disease-associated changes in the context of immortalised human cancer cell lines. The selected compounds have then been assayed in the more biologically relevant setting of iPSC-derived cortical neuron cultures. It is shown that 51 of the drugs drive expression changes consistently opposite to those seen in Alzheimer's disease. It is hoped that the iPSC profiles will serve as a useful resource for drug repositioning within the context of neurodegenerative disease and potentially aid in generating novel multi-targeted therapeutic strategies.
阿尔茨海默病是一种复杂的紊乱，包含多种病理特征，以及相关的遗传和分子罪魁祸首。然而，基于靶点的治疗策略迄今为止已被证明无效。本研究的目的是开发一种利用与阿尔茨海默病相关的转录变化的方法，以开发一种高内涵定量疾病表型，可用于重新定位现有的药物。首先，定义了涵盖严重疾病阶段、早期病理进展、认知能力下降和疾病动物模型的阿尔茨海默病基因表达图谱，并用于从永生化的人类癌细胞系中选择一组 153 种倾向于对抗与疾病相关变化的药物。然后在更具生物学相关性的 iPSC 衍生皮质神经元培养物中检测所选化合物。结果表明，51 种药物的作用可使表达变化与阿尔茨海默病患者的变化一致。希望 iPSC 图谱能够成为神经退行性疾病背景下药物重新定位的有用资源，并可能有助于生成新的多靶点治疗策略。
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