Opposing actions of thrombin and protease nexin-1 on amyloid β-peptide toxicity and on accumulation of peroxides and calcium in hippocampal neurons

V. L. Smith-Swintosky, S. Zimmer, J. W. Fenton, M. P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

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 homeoetasis, 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.

Original languageEnglish (US)
Pages (from-to)1415-1418
Number of pages4
JournalJournal of Neurochemistry
Volume65
Issue number3
StatePublished - 1995
Externally publishedYes

Keywords

  • 2,7-Dichlorofluorescein
  • Alzheimer's disease
  • Amyloid β-peptide
  • Apoptosis
  • Calcium and cell death
  • Fura 2
  • Hippocampus
  • Protease nexin
  • Thrombin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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