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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.

The "amyloid cascade hypothesis," linking self-assembly of the amyloid-␤ protein (A␤) to the pathogenesis of Alzheimer's disease, has led to the emergence of inhibition of A␤ self-assembly as a prime therapeutic strategy for this currently unpreventable and devastating disease. The complexity of A␤ selfassembly, which involves multiple reaction intermediates related by nonlinear and interconnected nucleation and growth mechanisms, provides multiple points for inhibitor intervention. Although a number of small-molecule inhibitors of A␤ selfassembly have been identified, little insight has been garnered concerning the point at which these inhibitors intervene within the A␤ assembly process. In the current study, a julolidine derivative is identified as an inhibitor of A␤ self-assembly. To gain insight into the mechanistic action of this inhibitor, the inhibition of fibril formation from monomeric protein is assessed quantitatively and compared with the inhibition of two distinct mechanisms of growth for soluble A␤ aggregation intermediates. This compound is observed to significantly inhibit soluble aggregate growth by lateral association while having little effect on soluble aggregate elongation via monomer addition. In addition, inhibition of soluble A␤ aggregate association exhibits an IC 50 with a somewhat lower stoichiometric ratio than the IC 50 determined for inhibition of fibril formation from monomeric A␤. This quantitative comparison of inhibition within multiple A␤ self-assembly assays suggests that this compound binds the lateral surface of on-pathway intermediates exhibiting a range of sizes to prevent their association with other aggregates, which is required for further assembly into mature fibrils.Alzheimer's disease (AD) is currently the most common type of dementia, affecting an estimated 5.2 million Americans (Alzheimer's Association, 2008). As the life expectancy in the United States and other postindustrialized nations increases, AD presents a burgeoning epidemic. AD initially affects short-term memory and progresses to include pervasive cognitive and emotional dysfunction. These manifested symptoms are hypothesized to result from a cascade of events initiated by the self-assembly of monomeric amyloid-␤ protein (A␤), leading first to the formation of soluble aggregates and later progressing into larger insoluble fibrils, which ultimately deposit in the extracellular space of the brain parenchyma. This "amyloid cascade hypothesis" is supported by experimental evidence (Walsh and Selkoe, 2007), including genetic correlations, transgenic animal models, and cell culture studies, and has established the inhibition of A␤ self-assembly as a prime therapeutic strategy in the fight against AD.Several small molecules that inhibit the in vitro formation of amyloid fibrils from monomeric A␤ have been identified (Findeis, 2000;Hamaguchi et al., 2006;LeVine, 2007). Studies using quantitative measures of inhibition assembled from light scattering measurements, thioflavin T (ThT) fluorescence, or immun...

Cerebrovascular accumulation of amyloid-β protein (Aβ) aggregates in Alzheimer's disease (AD) is proposed to contribute to disease progression and brain inflammation as a result of Aβ-induced increases in endothelial monolayer permeability and stimulation of the endothelium for cellular adhesion and transmigration. These deficiencies facilitate the entry of serum proteins and monocyte-derived microglia into the brain. In the current study, a role for nuclear factor-κB (NF-κB) in the activation of cerebral microvascular endothelial cells by Aβ is explored.Quantitative immunocytochemistry is employed to demonstrate that Aβ(1-40) preparations containing isolated soluble aggregates elicit the most pronounced activation and nuclear translocation of NF-κB. This rapid and transient response is observed down to physiological Aβ concentrations and parallels phenotypic changes in endothelial monolayers that are selectively elicited by soluble Aβ(1-40) aggregates. While monomeric and fibrillar preparations of Aβ(1-40) also activated NF-κB, this response was less pronounced, limited to a small cell population, and not coupled with phenotypic changes. Soluble Aβ(1-40) aggregate stimulation of endothelial monolayers for adhesion and subsequent transmigration of monocytes as well as increases in permeability were abrogated by inhibition of NF-κB activation. Together, these results provide additional evidence indicating a role for soluble Aβ aggregates in the activation of the cerebral microvascular endothelium and implicate the involvement of NF-κB signaling pathways in Aβ stimulation of endothelial dysfunction associated with AD.

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