Effect of introducing a short amyloidogenic sequence from the Aß peptide at the N-terminus of 18-residue amphipathic helical peptides

Fibril formation is the hallmark of pathogenesis in Alzheimer's disease and other amyloid disorders caused by conformational alterations leading to the aggregation of soluble monomers. A beta 40 self-associates to form amyloid fibrils. Its central seven-residue segment KLVFFAE (A beta 16-22), which is thought to be crucial for fibril formation of the full-length peptide, forms fibrils even in isolation. Context-dependent induction of amyloid formation by such sequences in peptides, which otherwise do not have that propensity, is of considerable interest. We have examined the effect of introducing the A beta 16-22 sequence at the N-terminus of two amphipathic helical 18-residue peptides Ac-WYSEMKRNVQRLERAIEE-am and Ac-KQLIRFLKRLDRNLWGLA-am, which have high average hydrophobic moment <mu H > values but have net charges of 0 and +4, respectively, at neutral pH. Upon incubation in aqueous buffer, fibril-like aggregates were discernible by transmission electron microscopy for the peptide with only 0 net charge, which also displayed ThT binding and beta-structure. Although both the sequences have been derived from amphipathic helical segments in globular proteins and possess high average hydrophobic moments, the +4 charge peptide lacks the ability to form fibrils, while the peptide with 0 charge has the tendency to form fibrillar structures. Variation in the net charge and the presence of several glutamic acids in the sequence of the peptide with net charge 0 appear to favor the formation of fibrils when the A beta 16-22 sequence is attached at the N-terminus. Copyright (C) 2011 European Peptide Society and John Wiley & Sons, Ltd.