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 (Aβ) accumulate between the neural cells in the brain and are associated with dementia and cellular death. Many strategies have been investigated to prevent Aβ self-assembly into disease-associated β-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 Aβ) was tested for its ability to modulate Aβ 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 β-sheet of Aβ. JPT1 was found to modulate Aβ40 aggregation, specifically decreasing lag time to β-sheet aggregate formation as well as the total number of fibrillar, β-sheet structured aggregates formed. These results suggest that peptoids may be able to limit the formation of Aβ aggregates that are associated with AD.

BackgroundDeposits of aggregated amyloid-β protein (Aβ) are a pathological hallmark of Alzheimer’s disease (AD). Thus, one therapeutic strategy is to eliminate these deposits by halting Aβ 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 Aβ aggregation inhibitors. In this study, we characterized the inhibitory capabilities of gold nanospheres exhibiting different surface coatings and diameters.ResultsBoth 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 Aβ 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.ConclusionsThese findings demonstrate the potential of surface-coated gold nanospheres to serve as tunable therapeutic agents for the inhibition of Aβ aggregation. Insights gained into the physiochemical properties of effective NP inhibitors will inform future rational design of effective NP-based therapeutics for AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13036-017-0047-6) contains supplementary material, which is available to authorized users.

Alzheimer's disease (AD), the most common form of dementia, is characterized by extracellular plaques in the brain created when monomeric amyloid-b (Ab) protein aggregates into fibrillar structures. Soluble Ab aggregates, including oligomers that form along the reaction pathway, are believed to be the more toxic species and can increase the production of reactive oxygen species (ROS). Polyphenols have been suggested as a complimentary AD therapeutic based on epidemiological evidence that polyphenol-rich diets correlate with a reduced incidence of AD. In particular, many flavonoids, a subclass of polyphenols, have the ability to inhibit Ab aggregation. Alternatively, polyphenols can counter Ab-induced cellular responses by neutralizing ROS through their antioxidant properties. This study sought to identify polyphenols that can reduce Ab-induced apoptosis by inhibiting Ab aggregation and/or reducing ROS. Polyphenols investigated include quercetin (QUE), rhamnetin (RHA), isorhamnetin (IRHA), and tamarixetin (TAM). Using SDS-PAGE and Western blot to evaluate oligomer size, only IRHA was unable to reduce Ab oligomers 250-100 kDa in size, while QUE reduced these oligomers by 88.3 5 2.4%. All compounds reduced Ab oligomers <100 kDa in size, although IRHA was still the weakest inhibitor. Antioxidant capabilities were quantified in vitro relative to Trolox, a vitamin E analog. All compounds tested exhibited antioxidant capability similar to Trolox. To assess the effect of anti-aggregation and antioxidant properties on Ab-induced apoptosis, human neuroblastoma cells were stained using TUNEL, which identifies breaks in the DNA strand. Polyphenols with anti-aggregation properties successfully reduced apoptosis, and it is hypothesized that antioxidant activity will also have a protective effect.