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A γ‐secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish
Open accessAbstract
Inhibition of amyloid beta-peptide (Abeta) production by blocking gamma-secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer's disease pathology. gamma-secretase inhibitors apparently block Abeta generation via interference with presenilin (PS) function. Besides being an essential component of the gamma-secretase complex, PS itself may be an aspartyl protease with gamma-secretase activity, which is not only required for Abeta production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate that treatment of zebrafish embryos with a known gamma-secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels. This indicates severe side-effects of gamma-secretase inhibitors in any Notch-dependent cell fate decision and demonstrates that the zebrafish is an ideal vertebrate system to validate compounds that selectively affect Abeta production, but not Notch signaling, under in vivo conditions.
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“DAPT, which prevents Notch cleavage and subsequent signaling by its intracellular domain, NICD”
From HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration (2012) · cites this paper as Geling et al., 2002
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Metadata
- Authors
- Geling, A., Steiner, H., Willem, M., Bally‐Cuif, L., & Haass, C.
- Affiliations
- Technical University of Munich (DE)
- Adolf-Butenandt-Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie (DE)
- Venue
- The EMBO Reports
- Published
- 2002-07-01
- Volume
- 3
- Issue
- 7
- Pages
- 688-694
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- OpenAlex
- W2082694975
- Cited by
- 497
- References
- 56
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 12 · 2023: 7 · 2022: 13 · 2021: 15 · 2020: 14 · 2019: 27 · 2018: 13 · 2017: 17 · 2016: 25 · 2015: 16 · 2014: 19 · 2013: 28 · 2012: 34
- FWCI
- 11.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- EMBO Reports (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- gamma-secretase inhibitors, Notch signaling, presenilin, amyloid-beta, Alzheimer's disease, neurogenesis, zebrafish embryos, embryonic development, off-target effects, cell fate determination, adverse drug reactions
- MeSH terms
- Alzheimer Disease, Animals, Cell Line, Enzyme Inhibitors, gamma-Aminobutyric Acid, Humans, Membrane Proteins, Microinjections, Endopeptidases, Phenotype, RNA, Messenger, Triglycerides, Zebrafish, Signal Transduction, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, In Situ Hybridization, Body Patterning, Receptors, Notch, Presenilin-1, Amyloid Precursor Protein Secretases
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