Histidines 13 and 14 in the Abeta sequence are targets for inhibition of Alzheimer's disease Abeta ion channel and cytotoxicity
Díaz, J.Carlos.; Linnehan, J.; Pollard, H.; Arispe, N.
Biological Research 39(3): 447-460
2006
ISSN/ISBN: 0716-9760 PMID: 17106577 Document Number: 600354
The fact that Alzheimer's beta amyloid (A beta) 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 A beta ion channel could be blocked selectively with small peptides that copy the amino acid sequence of the predicted mouth region of the A beta 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 A beta 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 A beta cytotoxicity. These data thus contribute to the definition of the region of the A beta sequence that participates in the formation of the channel pore. Additionally, these data support the hypothesis that the ion channel activity of A beta contributes significantly to the cytotoxic properties of A beta. These data also emphasize the potential value in using inhibition of A beta ion channel activity as an end point for Alzheimer's disease drug discovery.