Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse, 4070 Basel, Switzerland.
Roche Pharma Development, Grenzacherstrasse, 4070 Basel, Switzerland.
Mol Cell Neurosci. 2019 Oct;100:103392. doi: 10.1016/j.mcn.2019.103392. Epub 2019 Aug 2.
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.
在药物发现以及疾病生物学研究中，开发能够再现疾病某些方面的模型对于理解病理学和测试治疗方法至关重要。患者来源的诱导多能干细胞（iPSC）提供了获得具有特定人类基因型的组织特异性细胞的潜力。在这里，我们从阿尔茨海默病患者的 iPSC 中获得了神经培养物，并对它们对三类可降低 Aβ42 产生的化合物的反应进行了表征，Aβ42 是该病理学的主要驱动力。我们通过 RNAseq 研究了它们对细胞的影响，观察 Tau 蛋白稳态和基因表达变化。β-分泌酶抑制剂和 γ-分泌酶调节剂几乎没有改变细胞的转录平衡，而 γ-分泌酶抑制剂由于 Notch 抑制导致了明显的基因表达变化。我们在体内用相同的化合物进行了类似的处理，观察到了类似的效果。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病中 Aβ产生的有吸引力的候选药物。此外，我们证明了使用 iPSC 衍生神经元获得的化合物的反应与体内观察到的反应相似。
