In drug discovery, as well as in the study of disease biology, it is fundamental to develop models that recapitulate aspects of a disorder, in order to understand the pathology and test therapeutic approaches. Patient-derived induced pluripotent stem cells (iPSCs) offer the potential of obtaining tissue-specific cells with a given human genotype. Here we derived neural cultures from Alzheimer's disease patient iPSCs and characterized their response to three classes of compounds that reduce the production of Aβ42, a major driving force of this pathology. We characterized their effect on the cells, looking at Tau proteostasis and gene expression changes by RNAseq. β-secretase inhibitor and γ-secretase modulators left the transcriptional balance of the cells virtually unaffected, while γ-secretase inhibitors caused drastic gene expression changes due to Notch inhibition. We observed similar effects in vivo, treating mice with the same compound classes. Our results show that β-secretase inhibitors and γ-secretase modulators are attractive candidates for modulating Aβ production in Alzheimer's disease. Moreover, we demonstrate that the response to compounds obtained with iPSC-derived neurons is similar to the one observable in vivo.

中文翻译：

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γ分泌酶调节剂和BACE抑制剂可减少Aβ的产生，而不会改变阿尔茨海默氏病iPSC衍生的神经元和小鼠的基因表达。

在药物开发以及疾病生物学研究中，开发模型以概括疾病的各个方面，以了解病理学和测试治疗方法，是至关重要的。患者来源的诱导性多能干细胞（iPSC）提供了获得具有给定人类基因型的组织特异性细胞的潜力。在这里，我们从阿尔茨海默氏病患者iPSC衍生了神经培养物，并表征了它们对三类化合物的反应，这些化合物减少了Aβ42的产生，而Aβ42是这种病理学的主要驱动力。我们通过RNAseq观察了Tau蛋白变性和基因表达的变化，从而表征了它们对细胞的作用。β-分泌酶抑制剂和γ-分泌酶调节剂几乎不影响细胞的转录平衡，而γ-分泌酶抑制剂由于Notch抑制而导致基因表达急剧变化。我们在体内观察到相似的效果，用相同的化合物类别治疗小鼠。我们的结果表明，β-分泌酶抑制剂和γ-分泌酶调节剂是调节阿尔茨海默氏病中Aβ产生的诱人候选物。此外，我们证明，对使用iPSC衍生的神经元获得的化合物的反应与体内可观察到的相似。