Rationally Designed Peptoid Inhibitors of Amyloid-ß Oligomerization.

While plaques comprised of fibrillar Aß aggregates are hallmarks of Alzheimer's disease, soluble Aß oligomers present higher neurotoxicity. Thus, one therapeutic approach is to prevent the formation of Aß oligomers and reduce their associated harmful effects. We have proposed a peptoid mimic of the Aß hydrophobic KLVFF core as an ideal candidate aggregation inhibitor due to its ability to evade proteolytic degradation via repositioning of the side chain from the α-carbon to the amide nitrogen. This peptoid, JPT1, utilizes chiral sidechains to achieve a helical structure, while C-terminal addition of two phenylalanine residues places aromatic groups on two sides of the helix with spacing designed to facilitate interaction with amyloid ß-sheet structure. We have previously shown that JPT1 modulates Aß fibril formation. Here, we demonstrate that JPT1 also modulates Aß oligomerization, and we explore the role of the charge on the linker between the KLVFF mimic and the extended aromatic residues. Additionally, we demonstrate that peptoid-induced changes in Aß oligomerization correlate with attenuation of oligomer-induced nuclear factor-κB activation in SH-SY5Y human neuroblastoma cells. These findings support the therapeutic potential of peptoids to target early stages of Aß aggregation and impact the associated Aß-induced cellular response.

Influence of gold nanoparticle surface chemistry and diameter upon Alzheimer's disease amyloid-ß protein aggregation.

BACKGROUND: Deposits of aggregated amyloid-ß protein (Aß) are a pathological hallmark of Alzheimer's disease (AD). Thus, one therapeutic strategy is to eliminate these deposits by halting Aß aggregation. While a variety of possible aggregation inhibitors have been explored, only nanoparticles (NPs) exhibit promise at low substoichiometric ratios. With tunable size, shape, and surface properties, NPs present an ideal platform for rationally designed Aß aggregation inhibitors. In this study, we characterized the inhibitory capabilities of gold nanospheres exhibiting different surface coatings and diameters. RESULTS: Both NP diameter and surface chemistry were found to modulate the extent of aggregation, while NP electric charge influenced aggregate morphology. Notably, 8 nm and 18 nm poly(acrylic acid)-coated NPs abrogated Aß aggregation at a substoichiometric ratio of 1:2,000,000. Theoretical calculations suggest that this low stoichiometry could arise from altered solution conditions near the NP surface. Specifically, local solution pH and charge density are congruent with conditions that influence aggregation. CONCLUSIONS: These findings demonstrate the potential of surface-coated gold nanospheres to serve as tunable therapeutic agents for the inhibition of Aß aggregation. Insights gained into the physiochemical properties of effective NP inhibitors will inform future rational design of effective NP-based therapeutics for AD.

Rationally designed peptoids modulate aggregation of amyloid-beta 40.

Alzheimer's disease (AD) is the most common form of dementia and the sixth leading cause of death in the United States. Plaques composed of aggregated amyloid-beta protein (Aß) accumulate between the neural cells in the brain and are associated with dementia and cellular death. Many strategies have been investigated to prevent Aß self-assembly into disease-associated ß-sheet amyloid aggregates; however, a promising therapeutic has not yet been identified. In this study, a peptoid-based mimic of the peptide KLVFF (residues 16-20 of Aß) was tested for its ability to modulate Aß aggregation. Peptoid JPT1 includes chiral, aromatic side chains to induce formation of a stable helical secondary structure that allows for greater interaction between the aromatic side chains and the cross ß-sheet of Aß. JPT1 was found to modulate Aß40 aggregation, specifically decreasing lag time to ß-sheet aggregate formation as well as the total number of fibrillar, ß-sheet structured aggregates formed. These results suggest that peptoids may be able to limit the formation of Aß aggregates that are associated with AD.