Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity

The deposition of A beta peptide in the brain is the key event in Alzheimer disease progression. Therefore, the prevention of A beta self assembly into disease-associated oligomers is a logical strategy for treatment. p stacking is known to provide structural stability to many amyloids; two phenylalanine residues within the A beta 14-23 self recognition element are in such an arrangement in many solved structures. Therefore, we targeted this structural stacking by substituting these two phenylalanine residues with their D-enantiomers. The resulting peptides were able to modulate A beta aggregation in vitro and reduce A beta cytotoxicity in primary neuronal cultures. Using kinetic analysis of fibril formation, electron microscopy and dynamic light scattering characterization of oligomer size distributions, we demonstrate that, in addition to altering fibril structural characteristics, these peptides can induce the formation of larger amorphous aggregates which are protective against toxic oligomers, possibly because they are able to sequester the toxic oligomers during co-incubation. Alternatively, they may alter the surface structure of the oligomers such that they can no longer interact with cells to induce toxic pathways.