Thrombin attenuates neuronal cell death and modulates astrocyte reactivity induced by beta-amyloid in vitro
| Autor: | Dennis D. Cunningham, Patrick J. Vaughan, Christian J. Pike, Carl W. Cotman |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Basic fibroblast growth factor
Blotting Western Neurotoxins Hirudin Biology Thrombomodulin Biochemistry Rats Sprague-Dawley Cellular and Molecular Neuroscience chemistry.chemical_compound Thrombin Thrombin receptor medicine Animals Cells Cultured Neurons Amyloid beta-Peptides Cell Death Dose-Response Relationship Drug Immunohistochemistry Cell biology Rats medicine.anatomical_structure Neuroprotective Agents chemistry Astrocytes Receptors Thrombin Signal transduction Astrocyte medicine.drug Discovery and development of direct thrombin inhibitors Signal Transduction |
| Zdroj: | Journal of neurochemistry. 66(4) |
| ISSN: | 0022-3042 |
| Popis: | beta-Amyloid protein has been implicated as a potential causative agent in the neuropathology associated with Alzheimer's disease. This possibility is supported by observations that beta-amyloid induces neuronal degeneration and astrocyte reactivity in vitro by as yet undefined mechanism(s). In this report, we present data demonstrating that the pathological effects of beta-amyloid on cultured cells are modulated by activation of the thrombin receptor. At concentrations between 50 and 500 nM, thrombin pretreatment significantly attenuates neurotoxicity mediated by fibrillar aggregates of beta 1-42 and beta 25-35 peptides. In cultured astrocytes, the stellate morphology induced by beta 1-42 and beta 25-35 aggregates can be prevented and reversed by thrombin exposures between 10 pM and 1 microM. In contrast, thrombin potentiates rather than attenuates the beta-amyloid-induced increased expression of basic fibroblast growth factor, suggesting that thrombin differentially modulates the effects of beta-amyloid on astrocytes. Thrombin's effects on both neurons and astrocytes are mimicked by thrombin receptor-activating peptide and inhibited by two potent thrombin inhibitors, hirudin and protease nexin-1. These data provide both new insight into the signaling pathways underlying the cellular effects of beta-amyloid and additional support for the role of thrombin as an important mediator of neuropathological events. |
| Databáze: | OpenAIRE |
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