Targeting Prion Protein and Alzheimer's disease Amyloid Peptide by Peptide Ligands

The presently established models of prion propagation are based on the essential role of the host-encoded prion protein (PrP). Development and progression of the disease implies ongoing conversion of its non-pathological isoform PrPC into its pathological isoform PrPSc. Thus, any stabilization of the PrPC conformation should slow down or inhibit conversion of PrPC into PrPSc. We screened a phage displayed peptide library to ultimately identify high affinity ligands that bind to and stabilize PrPC. A similar approach was used to identify ligands that specifically bind to Alzheimer's disease (AD) amyloid peptide Abeta(1–42). Applying a mirror image version of a phage display screening allowed us to ultimately identify a 12mer peptide that binds specifically to Abeta(1–42) and consists solely of D-amino acids (D-pep). D-amino acid peptides are known to be less protease sensitive, more resistant to degradation in animals, and less or even not immunogenic at all, as compared with an L-amino acid 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 who suffered from Alzheimer's disease, amyloid plaques were stained specifically with a fluorescence-labeled derivative of D-pep. D-pep was specific for Abeta plaques and did not stain amyloid deposits. Because such D-peptides are considered to consist of peptides other than A, to be rather protease resistant and mostly non-immunogenic, D-pep may be very suitable for use as a probe for the detection of amyloid plaques in living humans or animal models or to search for compounds that are suitable for AD therapy. D-pep may synthetically be combined with any marker employed for physiological detection or medical imaging techniques. Current studies are aimed to find out whether D-pep or derivatives thereof are able to cross the blood-brain barrier and be used for in vivo diagnostic imaging of living brains. Any AD therapeutic approach directed either against amyloid fibril -secretase activities, will have to rely on correct γ- or β-formation, or monitoring of the cerebral and cerebrovascular amyloid loads.