A New Amyloid-Like β-Aggregate with Amyloid Characteristics, Except Fibril Morphology

Amyloid plaques, formed from amyloid beta (A beta) peptides (mainly A beta 40 or A beta 42), are one of the most important pathological characteristics of Alzheimer's disease. Here, a single D-form proline substitution in the 40-amino-acid A beta 40 peptide can totally change the aggregation behavior of this peptide. The residue immediately preceding each glycine in A beta 40 (S8, V24, I32, and V36) was individually replaced by D-form proline ((D)Pro). The resulting P-D-G sequence (the (D)Pro residue and the following Gly residue) was designed as a structural clip to force the formation of a bend in the peptide, as this sequence has been reported to be a strong promoter of beta-hairpin formation. The mutant peptide with Val24-to-(D)Pro substitution, named V24P, formed a new amyloid-like beta-aggregate at high peptide concentration. The aggregate has most of the characteristics of amyloid fibrils, except fibril morphology. Moreover, the mutant peptide V24P, when mixed with A beta 40, can attenuate the cytotoxicity of A beta 40. (C) 2008 Elsevier Ltd. All rights reserved.