title: Design and evaluation of a 6-mer amyloid-beta protein derived phage display library for molecular targeting of amyloid plaques in Alzheimer's disease: Comparison with two cyclic heptapeptides derived from a randomized phage display library.
abstract: Amyloid plaques are the main molecular hallmark of Alzheimer's disease. Specific carriers are needed for molecular imaging and for specific drug delivery. In order to identify new low molecular weight amyloid plaque-specific ligands, the phage display technology was used to design short peptides that bind specifically to amyloid-beta protein, which is the principal component of amyloid plaques. For this purpose, a phage display library was designed from the amino acid sequence of amyloid-beta 1-42. Then, the diversity was increased by soft oligonucleotide-directed mutagenesis. This library was screened against amyloid-beta 1-42 and several phage clones were isolated. Their genomes were sequenced to identify the displayed peptides and their dissociation constants for amyloid-beta 1-42 binding were evaluated by ELISA. The two best peptides, which are derived from the C-terminus hydrophobic domain of amyloid-beta 1-42 that forms a beta-strand in amyloid fibers, were synthesized and biotinylated. After confirming their binding affinity for amyloid-beta 1-42 by ELISA, the specific interaction with amyloid plaques was validated by immunohistochemistry on brain sections harvested from a mouse model of Alzheimer's disease. The thioflavin T aggregation assay has furthermore shown that our peptides are able to inhibit the amyloid fiber formation. They are not toxic for neurons, and some of them are able to cross the blood-brain barrier after grafting to a magnetic resonance imaging contrast agent. To conclude, these peptides have high potential for molecular targeting of amyloid plaques, either as carriers of molecular imaging and therapeutic compounds or as amyloid fiber disrupting agents.
authors.affiliation: Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau 19, B-7000 Mons, Belgium. Lionel.Larbanoix@umons.ac.be
authors.forename: Lionel
authors.initials: L
authors.lastname: Larbanoix
authors.forename: Carmen
authors.initials: C
authors.lastname: Burtea
authors.forename: Emilie
authors.initials: E
authors.lastname: Ansciaux
authors.forename: Sophie
authors.initials: S
authors.lastname: Laurent
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mahieu
authors.forename: Luce
authors.initials: L
authors.lastname: Vander Elst
authors.forename: Robert N
authors.initials: RN
authors.lastname: Muller
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D019921:Biotinylation; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D003287:Contrast Media; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007700:Kinetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D017422:Sequence Analysis, DNA; D013844:Thiazoles / Q000032:analysis
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D003287:Contrast Media; D010446:Peptide Fragments; D019151:Peptide Library; D010456:Peptides, Cyclic; D013844:Thiazoles; C009462:thioflavin T