title: Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity.
abstract: The deposition of Aβ peptide in the brain is the key event in Alzheimer disease progression. Therefore, the prevention of Aβ self assembly into disease-associated oligomers is a logical strategy for treatment. π stacking is known to provide structural stability to many amyloids; two phenylalanine residues within the Aβ 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 Aβ aggregation in vitro and reduce Aβ 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.
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jitendra
authors.initials: J
authors.lastname: Kumar
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Risa
authors.initials: R
authors.lastname: Namsechi
authors.affiliation: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta, Canada; Neurosciences and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Sim
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism*; D011487:Protein Conformation; D055503:Protein Multimerization / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates