The Aβ1-42M35C mutated amyloid peptide Aβ1-42 and the 25-35 fragment fail to mimic the subtype-specificity of actions on recombinant human nicotinic acetylcholine receptors (α7, α4β2, α3β4)

Alzheimer's disease (AD) is a neurodegenerative condition involving accumulation of the β-amyloid peptide, Aβ1-42. Previously we have shown that amyloid peptides (Aβ1-42, Aβ1-40) have different actions on the three major brain nicotinic acetylcholine receptor (nAChR) subtypes (α7, α4β2 and α3β4). The methionine in position 35 of Aβ (M35) has been shown to be important in the toxicity of Aβ and the 25-35 fragment can mimic some of the actions of the Aβ1-42 peptide. However, the extent to which this mutant and the fragment mimic subtype selectivity is unknown. Two-electrode voltage-clamp electrophysiology has been used to study the actions on α7, α4β2 and α3β4 recombinant nAChRs expressed in Xenopus laevis oocytes of full length Aβ1-42, and Aβ peptide fragments, scrambled peptides, and the Aβ1-42 peptide containing mutations of the methionine in position 35. The Aβ25-35 fragment did not display subunit specificity. Aβ1-42 with an M35C mutation showed similar subtype-specificity to wild-type Aβ1-42. However, Aβ1-42 with an M35V substitution reduced the peak amplitude of ACh-induced currents recorded from α4β2 nAChRs, but did not affect those recorded from α7 or α3β4. These results indicate that the amino acid in position 35 of Aβ1-42 is an important determinant of the subtype-specificity of this peptide on human recombinant α7, α4β2 and α3β4 nAChRs and that the 25-35 fragment fails to mimic all of the actions of the full-length peptide. © 2007 Elsevier Ireland Ltd. All rights reserved.