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

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 βAP_25-35 opens irreversibly a Ca²⁺-carrying channel, as does aggregated βAP_1-42. 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 βAP_25-35. 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 βAP_25-35 and βAP_1-42.