Targeting the Toxic Oligomers of Amyloidogenic Proteins by Self-assembled Cyclic D,L-α-Peptides: Potential Application for Alzheimer’s and Parkinson’s Diseases

Protein misfolding and aggregation is the fundamental cause of more than 20 amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Although peptides and proteins of various sequences can self-assemble into toxic amyloid structures, they share 
common three-dimensional features that may promote their
cross-reaction. Given the significant structural and biochemical similarities between 
amyloids and the architecture of self-assembled cyclic D,L-α-
peptides, we hypothesized that the latter may bind and stabilize
the nontoxic forms of different amyloids, thereby preventing their aggregation into
 toxic forms. By screening an unbiased library of six-residue cyclic D,L-α-peptides and optimizing the activity of a lead peptide, we found one cyclic D,L-α-peptide (CP-2) that interacts strongly with Alzheimer’s disease associated Amyloid beta (Aβ) and inhibits its aggregation and toxicity. Further studies including Thioflavin T assays, electron microscopy, and circular dichroism spectroscopy, collectively suggest that CP-2 could also effectively cross-interact with Parkinson’s disease associated α-synuclein (α-syn), prevent its aggregation, and remodels its fibrils to non-toxic amorphous species, through an “off pathway” mechanism. NMR studies show that CP-2 interacts with the N-terminal and the non-Aβ component region of α-syn, which are responsible for α-syn’s membrane interactions and self-assembly, and so changes its conformation. Dot-blot and cell survival assays suggest that CP-2 reduces the amount of toxic α-syn oligomers and protects PC-12 and SH-SY5Y cells from α-syn induced toxicity. Moreover, CP-2 permeates cells through endosomes/lysosomes, co-localizes with intracellular a-syn and reduces its accumulation and toxicity in neuronal cells overexpressing α-syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.