Mechanism and prevention of neurotoxicity caused by β-amyloid peptides: Relation to Alzheimer's disease

Barbara J. Blanchard, Genevieve Konopka, Margaret Russell, Vernon M. Ingram

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

In Alzheimer's disease, neurotoxic β-amyloid peptides cause a deleterious influx of calcium ions into neurons. This increase in [Ca2+](int) is expected to trigger intracellular events that eventually cause cell dysfunction and cell death. We find that the aggregated β- amyloid peptide βAP25-35 opens irreversibly a Ca2+-carrying channel, as does aggregated βAP1-42. The opening of this channel is unaffected by DL-AP5, but it is blocked by Mg2+, CNQX and DNQX, suggesting a non-NMDA channel. External calcium enters and cytosolic calcium levels rise several- fold, as measured by fura-2 ratiometric analysis. Our findings illustrate a very early molecular event in the neurotoxicity of Alzheimer's disease. To combat the neurotoxic effect of aggregated β-amyloid peptides, we have devised a series of very short antagonistic peptides. Using a combinatorial library of hexapeptides made from D-amino acids, we have selected peptides by their ability to complex with the tagged β-amyloid peptide βAP25-35. Certain of these so-called 'decoy peptides', as well as some modified decoy peptides, are able to abolish the calcium influx caused by aggregated, probably fibrillar, β-amyloid peptides βAP25-35 and βAP1-42.

Original languageEnglish (US)
Pages (from-to)40-50
Number of pages11
JournalBrain Research
Volume776
Issue number1-2
DOIs
StatePublished - Nov 21 1997

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Keywords

  • Calcium homeostasis
  • Calcium ion channel
  • Calcium ion concentration
  • Decoy peptide
  • HNT neuron
  • Non-NMDA channel
  • β-Amyloid fibril
  • β-Amyloid peptide

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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