Efficiency of histidine-associating compounds for blocking the alzheimer's Abeta channel activity and cytotoxicity.
The opening of the Alzheimer's Abeta 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 Abeta channel activity, blocking Abeta cytotoxicity. We hypothesize 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 Abeta cytotoxicity. To test this hypothesis, we studied Abeta ion channel activity and cytotoxicity after the addition of compounds that are known to have His association capacity, such as Ni(2+), imidazole, His, and a series of His-related compounds. All compounds were effective at blocking both Abeta channel and preventing Abeta 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 Abeta channel sequence are in the pathway of ion flow. Additionally, the data confirm the contribution of the Abeta channel to the cytotoxicity of exogenous Abeta.
Arispe
Nelson
N
Department of Anatomy, Physiology and Genetics, and Institute for Molecular Medicine, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. narispe@usuhs.mil
Diaz
Juan Carlos
JC
Flora
Michael
M
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D006639:Histidine / Q000008:administration & dosage*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats
D016229:Amyloid beta-Peptides; D006639:Histidine