ArticleJournal of cellular and molecular medicine2022
γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.
Article in Journal of cellular and molecular medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 7 citations in OpenAlex.
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.The EMBO journal · 2024Review
- Gamma-secretase modulators: a promising route for the treatment of Alzheimer's disease.Frontiers in molecular neuroscience · 2023Review
- γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.Journal of cellular and molecular medicine · 2022Article
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Authors and funding
16 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The aggregation of β-amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 that are produced as a result of γ-secretase-mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ-Secretase modulators (GSMs) represent a promising class of Aβ42-lowering anti-amyloidogenic compounds for the treatment of AD. Gamma-secretase modulators change the relative proportion of secreted Aβ peptides, while sparing the γ-secretase-mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ-secretase cleavage of three γ-secretase substrates, E-cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ-secretase-dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ-secretase processing of EphA4 and EphB2 results in the release of several Aβ-like peptides, but that only the production of Aβ-like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ-secretase-mediated Aβ production.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.