Gamma secretase modulators and BACE inhibitors reduce Aβ production without altering gene expression in Alzheimer’s disease iPSC-derived neurons and mice
Abstract
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.
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The reduction in amyloid beta production by NB-360 in oligodendrocytes is similar to what has previously been shown in human iPSC-derived neurons upon administration of NB-360 or similar BACE inhibitors.
“Notably, this reduction in Aβ production is similar to what has previously been shown in human iPSC-derived neurons upon administration of NB-360 or similar BACE inhibitors [21–24]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [22]
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- Authors
- Cusulin, C., Wells, I., Badillo, S., Duran-Pacheco, G. C., Baumann, K., & Patsch, C.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Patsch, Christoph
- Venue
- Molecular and Cellular Neuroscience
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 100
- Pages
- 103392
- ISSN
- 1044-7431 (ISSN-L)
- OpenAlex
- W2966642577
- Cited by
- 13
- References
- 36
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2022: 3 · 2021: 3 · 2020: 2
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Roche
- Seventh Framework Programme
- Innovative Medicines Initiative (115439)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta production, γ-secretase modulators, beta-secretase inhibitors, gamma-secretase inhibitors, iPSC-derived neurons, gene expression changes, Notch signaling, amyloid-beta 42, drug screening model, in vivo drug effects
- MeSH terms
- Proteostasis, Alzheimer Disease, Animals, Cell Line, Cells, Cultured, Enzyme Inhibitors, Humans, Male, Mice, Inbred C57BL, Neurons, Amyloid beta-Peptides, tau Proteins, Mice, Amyloid Precursor Protein Secretases, Induced Pluripotent Stem Cells
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