Observations that ␤-sheet proteins form amyloid fibrils under at least partially denaturing conditions has raised questions as to whether these fibrils assemble by docking of preformed ␤-structure or by association of unfolded polypeptide segments. By using ␣-helical protein apomyoglobin, we show that the ease of fibril assembly correlates with the extent of denaturation. By contrast, monomeric ␤-sheet intermediates could not be observed under the conditions of fibril formation. These data suggest that amyloid fibril formation from apomyoglobin depends on disordered polypeptide segments and conditions that are selectively unfavorable to folding. However, it is inevitable that such conditions often stabilize protein folding intermediates.

A mirror image phage display approach was used to identify novel and highly specific ligands for Alzheimer's disease amyloid peptide Abeta(1-42). A randomized 12-mer peptide library presented on M13 phages was screened for peptides with binding affinity for the mirror image of Abeta(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 Abeta(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 Abeta 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 Abeta ligand in diagnosis and therapy of Alzheimer's disease are discussed.

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Peptides Peptides U 0400 Selection of D-Amino-Acid Peptides that Bind to Alzheimer's Disease AmyloidPeptide Aβ 1-42 by Mirror Image Phage Display. -(WIESEHAN, K.; BUDER, K.; LINKE, R. P.; PATT, S.; STOLDT, M.; UNGER, E.; SCHMITT, B.; BUCCI, E.; WILLBOLD*, D.; ChemBioChem 4 (2003) 8, 748-753; Forschungszent. Juelich, D-52425 Juelich, Germany; Eng.) -Lindner 42-198