First and Second Generation γ-Secretase Modulators (GSMs) Modulate Amyloid-β (Aβ) Peptide Production through Different Mechanisms
| Autor: | Santiago Parpal, Fredrik Olsson, Alan Sabirsh, Didier Rotticci, Ann-Cathrin Radesäter, Håkan Eriksson, Anders Juréus, Tingsheng Li, Rebecka Klintenberg, Magnus Waldman, Tomas Borgegard, Johan Nord, Rajeshwar Singh, Susanne Rosqvist, Kim Paulsen, Hongmei Yan, Johan Lundkvist, Jonas S. Johansson, Anna Regner, David Malinowsky, Kia Strömberg |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Pyridines
Peptide Plasma protein binding Pharmacology Biochemistry Amyloid beta-Protein Precursor Mice Sulindac Neurobiology Piperidines Dibenzazepines Amyloid precursor protein Drug Interactions Receptor chemistry.chemical_classification Sulfonamides Alanine biology Receptors Notch Imidazoles Receptor EphA4 Brain Azepines Dipeptides Cell biology Female Alzheimer's disease medicine.symptom Protein Binding Receptor EphB2 Guinea Pigs Binding Competitive medicine Animals Humans Molecular Biology Pyrans Amyloid beta-Peptides Cell-Free System HEK 293 cells Cell Biology medicine.disease Rats Mice Inbred C57BL HEK293 Cells Pyrimidines chemistry Mechanism of action Flurbiprofen biology.protein Carbamates Amyloid Precursor Protein Secretases Amyloid precursor protein secretase Protein Processing Post-Translational |
| Popis: | γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-β (Aβ) peptides. The Aβ42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aβ production by targeting the APP. Here, we describe novel GSMs that are selective for Aβ modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aβ both in cell and cell-free systems as well as lower amyloidogenic Aβ42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a (3)H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aβ modulation and have a different mechanism of action compared with the original class of GSMs described. |
| Databáze: | OpenAIRE |
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