Substoichiometric inhibition of Aβ 1–40 aggregation by a tandem Aβ 40–1-Gly8-1-40 peptide

Abstract

Aβ peptides aggregate to form insoluble and neurotoxic fibrils associated with Alzheimer’s disease. Inhibition of the aggregation has been the subject of numerous studies. Here we describe a novel, substoichiometric inhibitor of Aβ 1–40 fibrillization as a tandem dimeric construct consisting of Aβ 40–1 (reverse sequence) linked to Aβ 1–40 via an eight residue glycine linker. At molar ratios of the tandem peptide to Aβ 1–40 of 1:10 to 1:25 inhibition of fibrillization, as measured by ThioflavinT, was observed. We postulate that the tandem construct binds to a fibrillar intermediate but the reverse sequence delays or prevents further monomer association.