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

Abstract

In Alzheimer's disease, neurotoxic beta-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 beta-amyloid peptide beta AP25-35 opens irreversibly a Ca(2+)-carrying channel, as does aggregated beta AP1-42. 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 beta-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 beta-amyloid peptide beta AP25-35. 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, beta-amyloid peptides beta AP25-35 and beta AP1-42.