Efficiency of Histidine-Associating Compounds for Blocking the Alzheimer's Aβ Channel Activity and Cytotoxicity

The opening of the Alzheimer's A beta channel permits the flux of calcium into the cell, thus critically disturbing intracellular ion homeostasis. Peptide segments that include the characteristic histidine ( His) diad, His(13) and His(14), efficiently block the A beta channel activity, blocking A beta cytotoxicity. Wehypothesize that the vicinal His-His peptides coordinate with the rings of His in the mouth of the pore, thus blocking the flow of calcium ions through the channel, with consequent blocking of A beta cytotoxicity. To test this hypothesis, we studied A beta ion channel activity and cytotoxicity after the addition of compounds that are known to have His association capacity, such as Ni2+, imidazole, His, and a series of His-related compounds. All compounds were effective at blocking both A beta channel and preventing A beta cytotoxicity. The efficiency of protection of His-related compounds was correlated with the number of imidazole side chains in the blocker compounds. These data reinforce the premise that His residues within the A beta channel sequence are in the pathway of ion flow. Additionally, the data confirm the contribution of the A beta channel to the cytotoxicity of exogenous A beta.