A D-enantiomeric peptide interferes with heteroassociation of amyloid-beta oligomers and prion protein

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide. One AD hallmark is the aggregation of beta-amyloid (A beta) into soluble oligomers and insoluble fibrils. Several studies have reported that oligomers rather than fibrils are the most toxic species in AD progression. A beta oligomers bind with high affinity to membrane-associated prion protein (PrP), leading to toxic signaling across the cell membrane, which makes the A beta-PrP interaction an attractive therapeutic target. Here, probing this interaction in more detail, we found that both full-length, soluble human (hu) PrP(23-230) and huPrP(23-144), lacking the globular C-terminal domain, bind to A beta oligomers to form large complexes above the megadalton size range. Following purification by sucrose density-gradient ultracentrifugation, the A beta and huPrP contents in these heteroassemblies were quantified by reversed-phase HPLC. The A beta:PrP molar ratio in these assemblies exhibited some limited variation depending on the molar ratio of the initial mixture. Specifically, a molar ratio of about four A beta to one huPrP in the presence of an excess of huPrP(23-230) or huPrP(23-144) suggested that four A beta units are required to form one huPrP-binding site. Of note, an A beta-binding all-D-enantiomeric peptide, RD2D3, competed with huPrP for A beta oligomers and interfered with A beta-PrP heteroassembly in a concentration-dependent manner. Our results highlight the importance of multivalent epitopes on A beta oligomers for A beta-PrP interactions and have yielded an all-D-peptide-based, therapeutically promising agent that competes with PrP for these interactions.