Interactions With Imidazole Side Groups As A Mechanism To Block The Alzheimer'S Aβ Peptide-induced Intracellular Calcium Increase

Abstract

We have proposed the formation of Aβ ion channels as a mechanism to explain the intracellular calcium increase which occurs after cells are exposed to the cytotoxic Alzheimer's Aβ peptide. We developed highly effective and specific histidine-related Aβ channel blockers which prevent the Aβ-induced intracellular calcium response. Substitution experiments showed that histidine is essential for the blocking process. We hypothesized that the blocking efficiency of these compounds was related to imidazole side chains in the histidine residues. We rationalized that the resonance structure of the imidazole ring would be attracted to a full or partial positively charged form of the Histidine in the Aβ subunits of the Aβ channels. This investigation studied the intracellular calcium increase which occurs after cells are exposed to the Aβ peptide. The role of the imidazole side chains in mechanism of action was determined using histidine-related Aβ channel blockers in which the imidazole side chains were methylated. Additionally, we studied these compounds when modified by amidation and acetylation of the carboxyl and amine end groups, respectively. Our results showed that the efficacy to prevent the Aβ-induced intracellular calcium increase, and the capacity to protect cells from the toxic action of Aβ, is completely abolished when the imidazole side chains of the histidine-related Aβ channel blockers are methylated. On the other hand, the efficacy of the Aβ channel blockers is significantly improved when the ends of the molecules are capped leaving the imidazole side chain as the sole group available for interaction. We conclude that aromatic interactions between the imidazole side chains in the histidine-related blockers, and the charged form of the His residues in the Aβ channels, constitutes a blocking mechanism for the Aβ peptide-induced intracellular calcium increase.