Amyloid β-peptide alters thrombin-induced calcium responses in cultured human neural cells

Mark P. Mattson, James G. Begley

Research output: Contribution to journalArticlepeer-review

Abstract

The presence of prothrombin, thrombin receptors and thrombin inhibitors in the brain, together with recent evidence that thrombin can affect neuronal outgrowth and survival, suggests that thrombin signaling may be involved in neuronal plasticity and injury. In Alzheimer's disease, thrombin is associated with plaques comprised largely of amyloid β-peptide (Aβ). Because recent studies have shown that Aβ can destabilize neuronal calcium homeostasis, and because thrombin receptors are linked to inositol phospholipid hydrolysis and elevation of [Ca2+]i,we tested the hypothesis that Aβ modifies [Ca2+]i responses to thrombin. Studies using thrombin receptor antibodies and antisense oligodeoxynucleotide technology to suppress expression of thrombin receptors demonstrated that human SH-SY5Y neuroblastoma cells expressed thrombin receptors linked to Ca2+ release from intracellular stores. Relatively short term pretreatment (1 to 3 h) of the SH-SY5Y cells with Aβ25-35 or Aβ1-40 resulted in a significant two- to three-fold enhancement of thrombin-induced elevation of [Ca2+]i. In contrast, chronic pretreatment with Aβs (8 to 16 h) resulted in an attenuation or complete abrogation of [Ca2+]i responses to thrombin. Imaging of thiobarbituric acid fluorescence demonstrated that Aβ induced lipid peroxidation, and the effects of both short and long term exposure to Aβ on [Ca2+]i responses, were largely abrogated in cultures pretreated with antioxidants. Collectively, these data suggest that Aβ induces lipid peroxidation which impairs thrombin receptor-mediated Ca2+ signaling. Taken together with an increasing amount of data suggesting that thrombin plays roles in neuronal plasticity and neurodegenerative processes, our data suggest that Aβ may induce aberrant thrombin signal transduction which could contribute to the pathogenesis of AD.

Original languageEnglish (US)
Pages (from-to)28-40
Number of pages13
JournalAmyloid
Volume3
Issue number1
StatePublished - 1996
Externally publishedYes

Keywords

  • β-Amyloid precursor
  • Alzheimer's disease
  • Antioxidants
  • Antisense
  • Free radicals
  • Fura-2
  • Human neuroblastoma SH-SY5Y
  • Lipid peroxidation
  • Oligodeoxynucleotide
  • Protease nexin-1
  • Thiobarbituric acid

ASJC Scopus subject areas

  • Medicine(all)
  • Pathology and Forensic Medicine

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