title: The Abeta1-42M35C mutated amyloid peptide Abeta1-42 and the 25-35 fragment fail to mimic the subtype-specificity of actions on recombinant human nicotinic acetylcholine receptors (alpha7, alpha4beta2, alpha3beta4).
abstract: Alzheimer's disease (AD) is a neurodegenerative condition involving accumulation of the beta-amyloid peptide, Abeta1-42. Previously we have shown that amyloid peptides (Abeta1-42, Abeta1-40) have different actions on the three major brain nicotinic acetylcholine receptor (nAChR) subtypes (alpha7, alpha4beta2 and alpha3beta4). The methionine in position 35 of Abeta (M35) has been shown to be important in the toxicity of Abeta and the 25-35 fragment can mimic some of the actions of the Abeta1-42 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 alpha7, alpha4beta2 and alpha3beta4 recombinant nAChRs expressed in Xenopus laevis oocytes of full length Abeta1-42, and Abeta peptide fragments, scrambled peptides, and the Abeta1-42 peptide containing mutations of the methionine in position 35. The Abeta25-35 fragment did not display subunit specificity. Abeta1-42 with an M35C mutation showed similar subtype-specificity to wild-type Abeta1-42. However, Abeta1-42 with an M35V substitution reduced the peak amplitude of ACh-induced currents recorded from alpha4beta2 nAChRs, but did not affect those recorded from alpha7 or alpha3beta4. These results indicate that the amino acid in position 35 of Abeta1-42 is an important determinant of the subtype-specificity of this peptide on human recombinant alpha7, alpha4beta2 and alpha3beta4 nAChRs and that the 25-35 fragment fails to mimic all of the actions of the full-length peptide.
authors.affiliation: MRC Functional Genetics Unit, Department of Physiology, Anatomy and Genetics, Oxford University, South Parks Road, Oxford OX1 3QX, United Kingdom.
authors.forename: Luanda J
authors.initials: LJ
authors.lastname: Pym
authors.forename: Steven D
authors.initials: SD
authors.lastname: Buckingham
authors.forename: Victor
authors.initials: V
authors.lastname: Tsetlin
authors.forename: C A R
authors.initials: CA
authors.lastname: Boyd
authors.forename: David B
authors.initials: DB
authors.lastname: Sattelle
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D009154:Mutation / Q000235:genetics; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000109:Acetylcholine; D016229:Amyloid beta-Peptides; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D011993:Recombinant Fusion Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579167:Chrna7 protein, human; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C403531:nicotinic receptor alpha4beta2