Thrombin attenuates neuronal cell death and modulates astrocyte reactivity induced by beta-amyloid in vitro.
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.
Pike
C J
CJ
Institute for Brain Aging and Dementia, University of California, Irvine, USA.
Vaughan
P J
PJ
Cunningham
D D
DD
Cotman
C W
CW
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000648:ultrastructure; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018179:Receptors, Thrombin / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018179:Receptors, Thrombin; D013917:Thrombin