Identification of prion protein-derived peptides of potential use in Alzheimer's disease therapy

Soluble form of the prion protein (PrP) has been previously shown to interact with amyloid-beta (A beta) peptides, suppressing their fibrillization as well as toxicity, which indicates that this protein may play a protective role in Alzheimer's disease (AD). The shortest known PrP fragment retaining all of these properties corresponds to physiologically generated proteolytic polypeptide PrP23-110/111, called N1. Here we have identified two N1 derived synthetic peptides, encompassing residues 23-50 (PrP23-50) and 90-112 (PrP90-112), which bind to A beta 1-42 protofibrillar oligomers as well as amyloid fibrils. We found that, akin to N1, the abovementioned synthetic peptides not only reduce the initial rate of A beta fibrillization, but also alter the aggregation pathway of A beta, inhibiting formation of protofibrillar oligomers and facilitating amorphous aggregation. Furthermore, our data show that N1, PrP23-50 and PrP90-112 protect cultured hippocampal neurons from neurotoxic effects of A beta oligomers, preventing oligomers-induced retraction of neurites and loss of cell membrane integrity. The above PrP fragments can also attenuate neuronal intake of A beta. Our results strongly suggest that synthetic peptides such as PrP23-50 and PrP90-112 can be useful in designing a novel class of therapeutics in AD.