Arrest of -Amyloid Fibril Formation by a Pentapeptide Ligand

Abstract

Polymerization of amyloid β-peptide (Aβ) into amyloid fibrils is a critical step in the pathogenesis of Alzheimer's disease. Here, we show that peptides incorporating a short Aβ fragment (KLVFF; Aβ) can bind full-length Aβ and prevent its assembly into amyloid fibrils. Through alanine substitution, it was demonstrated that amino acids Lys, Leu, and Phe are critical for binding to Aβ and inhibition of Aβ fibril formation. A mutant Aβ molecule, in which these residues had been substituted, had a markedly reduced capability of forming amyloid fibrils. The present data suggest that residues Aβ serve as a binding sequence during Aβ polymerization and fibril formation. Moreover, the present KLVFF peptide may serve as a lead compound for the development of peptide and non-peptide agents aimed at inhibiting Aβ amyloidogenesis in vivo. Polymerization of amyloid β-peptide (Aβ) into amyloid fibrils is a critical step in the pathogenesis of Alzheimer's disease. Here, we show that peptides incorporating a short Aβ fragment (KLVFF; Aβ) can bind full-length Aβ and prevent its assembly into amyloid fibrils. Through alanine substitution, it was demonstrated that amino acids Lys, Leu, and Phe are critical for binding to Aβ and inhibition of Aβ fibril formation. A mutant Aβ molecule, in which these residues had been substituted, had a markedly reduced capability of forming amyloid fibrils. The present data suggest that residues Aβ serve as a binding sequence during Aβ polymerization and fibril formation. Moreover, the present KLVFF peptide may serve as a lead compound for the development of peptide and non-peptide agents aimed at inhibiting Aβ amyloidogenesis in vivo.