Designed Cell-Penetrating Peptide Inhibitors of Amyloid-beta Aggregation and Cytotoxicity

Amyloid proteins and peptides are a major contributing factor to the development of various neurodegenerative disorders, including Alzheimer's and prion diseases. Previously, a designed cell-penetrating peptide (CPP) comprising a hydrophobic signai sequence followed by a prion protein (PrP)-derived polycationic sequence (PrP23-28: KKRPKP) was shown to have potent anti-prion properties. Here, we extend this approach toward the amyloid-beta (A beta) peptide amyloid formation, which is associated with Alzheimer's disease. We characterized the interactions of the CPP with A beta using complementary in vitro and in silico experiments. We report that the CPP stabilizes A beta in a non-amyloid state and inhibits A beta-induced neurotoxicity. Moreover, replacing PrP23-28 with a corresponding segment from A beta results in a construct with similar CPP functionality and antagonism of A beta aggregation and neurotoxicity. Our findings reveal a general underlying principle for inhibition of pathogenic protein aggregation that may facilitate the design of CPP-based therapeutics for amyloid diseases.