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Thrombin Attenuates Neuronal Cell Death and Modulates Astrocyte Reactivity Induced by β‐Amyloid In Vitro
Author(s) -
Pike Christian J.,
Vaughan Patrick J.,
Cunningham Dennis D.,
Cotman Carl W.
Publication year - 1996
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1996.66041374.x
Subject(s) - thrombin , astrocyte , hirudin , amyloid beta , chemistry , microbiology and biotechnology , amyloid (mycology) , senile plaques , alzheimer's disease , pharmacology , biology , neuroscience , biochemistry , medicine , central nervous system , peptide , immunology , inorganic chemistry , platelet , disease
β‐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 β‐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 β‐amyloid on cultured cells are modulated by activation of the thrombin receptor. At concentrations between 50 and 500 n M , thrombin pretreatment significantly attenuates neurotoxicity mediated by fibrillar aggregates of β1–42 and β25–35 peptides. In cultured astrocytes, the stellate morphology induced by β1–42 and β25–35 aggregates can be prevented and reversed by thrombin exposures between 10 p M and 1 µ M . In contrast, thrombin potentiates rather than attenuates the β‐amyloid‐induced increased expression of basic fibroblast growth factor, suggesting that thrombin differentially modulates the effects of β‐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 β‐amyloid and additional support for the role of thrombin as an important mediator of neuropathological events.