The fact that Alzheimer's beta amyloid (Aβ) peptides forms cation channels in lipid bilayers was discovered during the course of our experiments in the laboratory of "Guayo" Rojas at NIH in Bethesda, Maryland (USA). Recently, we found that the Aβ ion channel could be blocked selectively with small peptides that copy the amino acid sequence of the predicted mouth region of the Aβ channel pore. We now have searched for the essential amino acid residues required for this blocking effect by mutations. We found that the ability of peptides to block Aβ channel activity could be lost by replacement of histidines 13 and 14 by alanine or lysine. The amino acid substitution also resulted in the loss of the capacity of the peptides to protect cells from Aβ cytotoxicity. These data thus contribute to the definition of the region of the Aβ sequence that participates in the formation of the channel pore. Additionally, these data support the hypothesis that the ion channel activity of Ab contributes significantly to the cytotoxic properties of Aβ. These data also emphasize the potential value in using inhibition of Aβ ion channel activity as an end point for Alzheimer's disease drug discovery.