Misfolding of the Aβ protein and its subsequent aggregation into toxic oligomers are related to Alzheimer's disease. Although peptides of various sequences can self-assemble into amyloid structures, these structures share common three-dimensional features that may promote their cross-reaction. Given the significant similarities between amyloids and the architecture of self-assembled cyclic D,L-α-peptide, we hypothesized that the latter may bind and stabilize a nontoxic form of Aβ, thereby preventing its aggregation into toxic forms. By screening a focused 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 Aβ and inhibits its aggregation. In transmission electron microscopy, optimized thioflavin T and cell survival assays, CP-2 inhibits the formation of Aβ aggregates, entirely disassembles preformed aggregated and fibrillar Aβ, and protects rat pheochromocytoma PC12 cells from Aβ toxicity, without inducing any toxicity by itself. Using various immunoassays, circular dichroism spectroscopy, photoinduced cross-linking of unmodified proteins (PICUP) combined with SDS/PAGE, and NMR, we probed the mechanisms underlying CP-2's antiamyloidogenic activity. NMR spectroscopy indicates that CP-2 interacts with Aβ through its self-assembled conformation and induces weak secondary structure in Aβ. Upon coincubation, CP-2 changes the aggregation pathway of Aβ and alters its oligomer distribution by stabilizing small oligomers (1-3 mers). Our results support studies suggesting that toxic early oligomeric states of Aβ may be composed of antiparallel β-peptide structures and that the interaction of Aβ with CP-2 promotes formation of more benign parallel β-structures. Further studies will show whether these kinds of abiotic cyclic D,L-α-peptides are also beneficial as an intervention in related in vivo models.
The biocompatible and biodegradable properties of protein microspheres and the recent advances in their preparation have generated considerable interest of utilizing these core-shell structures for drug delivery and diagnostic applications. However, effective targeting of protein microspheres to desirable cells or loci still remains a challenge. Here, we describe for the first time a facile one-pot sonochemical approach for covalent modification of protein microspheres made from serum albumin; the surface of which is covalently decorated with a short recognition peptide to target amyloid-β (Aβ) as the main pathogenic protein in Alzheimer's disease (AD). The microspheres were characterized for their morphology, size, and entrapment efficacy by electron microscopy, dynamic light scattering and confocal microscopy. Fluorescence-activated cell-sorting analysis and Thioflavin-T binding assay demonstrated that the conjugated microspheres bind with high affinity and selectivity to Aβ, sequester it from the medium and reduce its aggregation. Upon incubation with Aβ, the microspheres induced formation of amorphous aggregates on their surface with no apparent fibrillar structure. Moreover, the microspheres directly reduced the Aβ-induced toxicity toward neuron like PC12 cells. The conjugated microspheres are smaller than unmodified microspheres and remained stable throughout the incubation under physiological conditions.
We extend to you a warm and sunny Aloha in celebration of the 23 rd American Peptide Symposium and the 6 th International Symposium. The meeting theme, Peptides Across the Pacific, embraced the spirit of the scientific and social program. Peptides Across the Pacific encompassed the important role that peptide science currently plays in so many disciplines and explored the potential impact peptides can make in scientific fields that have yet to realize the utility of these wonderful molecules.The scientific program for 2013 was framed by distinguished lectures delivered by two renowned peptide chemists.
Accumulation and aggregation……of amyloid-b (Ab) in the brain is the primary pathogenic event in Alzheimer's disease (AD). Thus reducing the level of Ab in the brain is considered to be a promising strategy for AD therapy. In their Full Paper on page 11171 ff., S. Rahimipour et al. describe sonochemically prepared protein microspheres, the surfaces of which are modified with an Ab recognition peptide. The microspheres can bind with high affinity and selectivity to Ab, sequester it from the medium, inhibit its aggregation, and directly reduce its toxicity toward neuron-like cells.
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