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Opposing Actions of Thrombin and Protease Nexin‐1 on Amyloid β‐Peptide Toxicity and on Accumulation of Peroxides and Calcium in Hippocampal Neurons
Author(s) -
SmithSwintosky Virginia L.,
Zimmer Stephen,
Fenton John W.,
Mattson Mark P.
Publication year - 1995
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.1471-4159.1995.65031415.x
Subject(s) - thrombin , senile plaques , hippocampal formation , amyloid beta , amyloid (mycology) , chemistry , pharmacology , microbiology and biotechnology , biology , biochemistry , alzheimer's disease , endocrinology , medicine , peptide , immunology , inorganic chemistry , platelet , disease
Amyloid β‐peptide (Aβ) is the principal component of neuritic plaques in the brain in Alzheimer's disease (AD). Recent studies revealed that Aβ can be neurotoxic by a mechanism involving free radical production and loss of cellular ion homeostasis, thus implicating Aβ as a key factor in the pathogenesis of AD. However, other proteins are present in plaques in AD, including the protease thrombin and protease nexin‐1 (PN1), a thrombin inhibitor. We therefore tested the hypothesis that thrombin and PN1 modify neuronal vulnerability to Aβ toxicity. In dissociated rat hippocampal cell cultures the toxicity of Aβ was significantly enhanced by coincubation with thrombin, whereas PN1 protected neurons against Aβ toxicity. Aβ induced an increase in levels of intracellular peroxides and calcium. Thrombin enhanced, and PN1 attenuated, the accumulation of peroxides and calcium induced by Aβ. Taken together, these data demonstrate that thrombin and PN1 have opposing effects on neuronal vulnerability to Aβ and suggest that thrombin and PN1 play roles in the pathogenesis of neuronal injury in AD.