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 Citations (Scopus)

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

Fingerprint

Amyloid
Alzheimer Disease
Peptides
Calcium
6-Cyano-7-nitroquinoxaline-2,3-dione
Aptitude
Fura-2
Cell Death
Ions
Neurons
Amino Acids
AP25 peptide

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mechanism and prevention of neurotoxicity caused by β-amyloid peptides : Relation to Alzheimer's disease. / Blanchard, Barbara J.; Konopka, Genevieve; Russell, Margaret; Ingram, Vernon M.

In: Brain Research, Vol. 776, No. 1-2, 21.11.1997, p. 40-50.

Research output: Contribution to journalArticle

Blanchard, Barbara J. ; Konopka, Genevieve ; Russell, Margaret ; Ingram, Vernon M. / Mechanism and prevention of neurotoxicity caused by β-amyloid peptides : Relation to Alzheimer's disease. In: Brain Research. 1997 ; Vol. 776, No. 1-2. pp. 40-50.
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