Selection of D-Amino-Acid Peptides That Bind to Alzheimer's Disease Amyloid Peptide Aβ_1–42 by Mirror Image Phage Display

Graphical Abstract

A peptide through the looking glass: The mirror image phage display technique was used to identify a peptide consisting of D-amino acids that binds specifically to fibrils formed by the amyloid peptide Aβ found in plaques and leptomeningeal vessels. Fluorescent labeling of this peptide allowed it to be used as a probe for such fibrils (see picture). This highly specific Aβ ligand could be useful for the diagnosis of, and development of treatment for Alzheimer's disease.

Abstract

A mirror image phage display approach was used to identify novel and highly specific ligands for Alzheimer's disease amyloid peptide Aβ(1–42). A randomized 12-mer peptide library presented on M13 phages was screened for peptides with binding affinity for the mirror image of Aβ(1–42). After four rounds of selection and amplification the peptides were enriched with a dominating consensus sequence. The mirror image of the most representative peptide (D-pep) was shown to bind Aβ(1–42) with a dissociation constant in the submicromolar range. Furthermore, in brain tissue sections derived from patients that suffered from Alzheimer's disease, amyloid plaques and leptomeningeal vessels containing Aβ amyloid were stained specifically with a fluorescence-labeled derivative of D-pep. Fibrillar deposits derived from other amyloidosis were not labeled by D-pep. Possible applications of this novel and highly specific Aβ ligand in diagnosis and therapy of Alzheimer's disease are discussed.