Rationally Designed Peptoids Modulate Aggregation of Amyloid-Beta 40

Alzheimer's disease (AD) is the most common form of dementia and the sixth leading cause of death in the United States. Plaques composed of aggregated amyloid-beta protein (A beta) accumulate between the neural cells in the brain and are associated with dementia and cellular death. Many strategies have been investigated to prevent A beta self-assembly into disease-associated beta-sheet amyloid aggregates; however, a promising therapeutic has not yet been identified. In this study, a peptoid-based mimic of the peptide KLVFF (residues 16-20 of A beta) was tested for its ability to modulate A beta aggregation. Peptoid JPT1 includes chiral, aromatic side chains to induce formation of a stable helical secondary structure that allows for greater interaction between the aromatic side chains and the cross beta-sheet of A beta. JPT1 was found to modulate A beta 40 aggregation, specifically decreasing lag time to beta-sheet aggregate formation as well as the total number of fibrillar, beta-sheet structured aggregates formed. These results suggest that peptoids may be able to limit the formation of A beta aggregates that are associated with AD.