Gamma secretase modulators and BACE inhibitors reduce Aβ production without altering gene expression in Alzheimer's disease iPSC-derived neurons and mice

Publication date: Available online 2 August 2019Source: Molecular and Cellular NeuroscienceAuthor(s): Carlo Cusulin, Isabelle Wells, Solveig Badillo, Gonzalo Christian Duran Pacheco, Karlheinz Baumann, Christoph PatschAbstractIn 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.
Source: Molecular and Cellular Neuroscience - Category: Neuroscience Source Type: research