(7e) Aromatic Peptides Selectively Target and Remodel Soluble Oligomers of Amyloid ß

The misfolding of specific proteins of unrelated sequence into similar toxic aggregates is the hallmark of several conformational disorders, and much effort has focused on identifying molecules that inhibit and reverse protein aggregation. Little is known about how peptides can be used to selectively target and remodel toxic protein aggregates relative to non-toxic conformational isoforms. We find that aromatic-repeat peptides possess striking activity for rapidly remodeling mature toxic soluble oligomers and fibrils of the Aβ42 peptide associated with Alzheimer’s disease into insoluble, benign aggregates. Importantly, peptides repetitive in non-aromatic amino acids are inactive for remodeling Aβ oligomers and fibrils. Interestingly, aromatic-repeat peptides do not remodel Aβ non-toxic oligomers (which are indistinguishable in size and morphology relative to toxic Aβ oligomers) nor do they accelerate the aggregation of monomeric Aβ peptide, revealing they are specific for remodeling toxic Aβ aggregates. Moreover, we find that aromatic peptides active for remodeling Aβ soluble oligomers and fibrils do so by converting them into aggregated conformers with strikingly similar structural properties as non-toxic oligomers formed in the absence of aromatic peptides. We expect our findings will guide the design of novel biomolecules that selectively target and remodel toxic aggregates of Aβ and other misfolded proteins.