Influence of gold nanoparticle surface chemistry and diameter upon Alzheimer’s disease amyloid-β protein aggregation
- Kelly A. Moore1,
- Kayla M. Pate2,
- Deborah D. Soto-Ortega1,
- Samuel Lohse5,
- Nicholas van der Munnik2,
- Mihyun Lim3,
- Kaliah S. Jackson4,
- Venetia D. Lyles4,
- Lemeisha Jones4,
- Nisha Glassgow4,
- Vanessa M. Napumecheno4,
- Shanee Mobley4,
- Mark J. Uline1, 2,
- Rahina Mahtab4,
- Catherine J. Murphy5 and
- Melissa A. Moss1, 2Email author
© The Author(s). 2017
Received: 15 August 2016
Accepted: 3 January 2017
Published: 6 February 2017
Deposits 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.
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 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.
These 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.
KeywordsAlzheimer’s disease Amyloid-β protein Protein aggregation Inhibition Gold nanoparticles Aggregate morphology
In 1901, Alois Alzheimer examined a patient experiencing multiple neurological symptoms, including pronounced memory loss , marking the first diagnosis of what is now the most common neurodegenerative disorder, Alzheimer’s disease (AD). Amyloid plaques, comprised of aggregated amyloid-β (Aβ) protein  and found throughout the cerebral cortex , are a pathological hallmark of AD. While monomeric Aβ is inert , Aβ aggregates induce neurotoxicity , inhibit neuronal long-term potentiation [5–7], induce synapse loss , and disrupt memory and complex learned behavior . As a result, halting Aβ aggregation is one promising therapeutic strategy for AD. However, extensive investigation of small molecules and peptides as inhibitors of Aβ aggregation has failed to yield a successful therapeutic, necessitating the exploration of novel therapeutic agents.
Nanoparticles (NPs) have emerged as attractive therapeutic and diagnostic tools with applications in medical imaging, analytics, and drug delivery [10–14]. NPs can be synthesized from a wide range of materials including metals, polymers, and carbon-based molecules [11–14]. Furthermore, the ease with which NP size, shape, and surface properties are controlled [10–14] render NPs an ideal tunable platform for therapeutic applications.
Among the growing body of potential therapeutic applications for NPs is their ability to modulate amyloid protein aggregation [15–19]. Inhibition of Aβ aggregation, specifically, has been reported for NPs ranging in size from <10 nm to several hundred nanometers and exhibiting diverse surface chemistries [20–28]. Moreover, these effects have been observed at picomolar NP concentrations and substoichiometric ratios of NP to protein. While a wide array of small molecules and peptides can disrupt Aβ aggregation [29, 30], none have been as effective as NPs at substoichiometric ratios, thus increasing their potential for delivery of therapeutically effective concentrations to the brain. However, variations in NP size and surface chemistry can result in the contrasting promotion of Aβ aggregation [21, 23, 24, 31–33]. Thus, there exists a need to better understand the impact of NP physiochemical properties upon Aβ aggregation.
Using spherical NPs that vary in surface coating and size, this study investigates the effect that NP surface chemistry, charge, and diameter have upon Aβ aggregation. Gold was selected as the NP core material because gold NPs are readily synthesized, easily functionalized, and highly stable against oxidative dissolution [34–36]. Examination of four NP surface chemistries as well as three different NP diameters revealed that electric charge, surface chemistry, and size all modulate the ability of gold nanospheres to inhibit Aβ aggregation. While NP diameter and surface chemistry impact the extent of inhibition, electric charge determines the ability to influence aggregate morphology. In particular, smaller, anionic NPs are superior inhibitors, halting aggregation at substoichiometric ratios as low as 1:2,000,000 with the protein. Theoretical calculations suggest that such low stoichiometry may be achieved through NP-induced alterations to local solution conditions, including pH and charge density. Together, these findings identify surface-coated gold NPs as potential therapeutic agents for AD and provide insight into the physiochemical properties displayed by NPs that effectively inhibit Aβ aggregation.
Results and discussion
As part of the emergence of NPs in medical applications, development of NPs as inhibitors of amyloid protein aggregation has garnered attention [15–19]. With the ability to vary NP physiochemical properties, including material, size, and charge, NPs offer a tunable platform to modulate amyloid protein aggregation [37, 38]. However, the influence of NP characteristics on protein aggregation is poorly understood [15–17]. This study characterizes the inhibition of Aβ aggregation by gold nanospheres with varying surface chemistry and diameter. A cellular assay was used to probe the neurotoxicity of synthesized NPs, while a fluorescent amyloid-binding dye and transmission electron microscopy (TEM) were employed to characterize NP-induced alterations in Aβ aggregate formation and morphology, respectively. These investigations define a role for NP size, electric charge, and surface chemistry in determining inhibitory capabilities, and a theoretical model provides insight into the possible mechanism of inhibition.
Toxicity of surface-coated gold NPs
Effect of surface-coated gold NPs on ThT fluorescence detection of Aβ1–40 aggregates
18 nm surface-coated gold NPs inhibit Aβ1–40 monomer aggregation and alter fibril morphology
Percent inhibition of Aβ1–40 monomer aggregation observed in the presence of surface-coated NPsa,b
4.3 ± 2.6
0.0 ± 0.0
19 ± 8*
45 ± 4*
47 ± 5*
59 ± 9*
97 ± 2*
99 ± 0*
95 ± 3*
95 ± 3*
92 ± 4*
94 ± 1*
When Aβ1-40 aggregates were formed in the presence of 200 pM citrate-coated (Fig. 4b) or PAH-coated (Fig. 4c) NPs, the quantity of aggregates was reduced compared to the control. These results corroborate the plateau reductions observed via ThT fluorescence. TEM additionally facilitated examination of the influence of CTAB-coated NPs on Aβ1–40 aggregation, for which analysis by ThT fluorescence was precluded. Aggregates formed in the presence of 200 pM CTAB-coated NPs exhibited a reduction in aggregate quantity (Fig. 4e), demonstrating that these NPs can also inhibit Aβ1–40 aggregation. When Aβ1–40 aggregation was stimulated in the presence of 200 pM 18 nm PAA-coated NPs, an absence of filamentous aggregates was observed (Fig. 4g), substantiating the ability of these NPs to abrogate aggregation. Together, TEM results confirm the relative inhibitory capabilities of surface-coated NPs observed by ThT fluorescence as well as the complete inhibition imparted by PAA-coated NPs.
While the most effective inhibitors were NPs coated with anionic PAA, NPs exhibiting both negative and positive surface charges inhibited Aβ aggregation. This observation agrees with previous studies that have described both anionic and cationic NPs as inhibitors of protein aggregation [20, 21, 23–25, 28, 49–55]. Among the NPs examined within the current study, however, those with anionic citrate and PAA coatings were more effective inhibitors than those with cationic CTAB and PAH coatings. This finding aligns with other studies that have observed superior inhibitory capabilities by anionic NPs over cationic NPs [20, 21, 23, 25, 28]. Among anionic NPs, PAA-coated particles exhibited superior inhibitory capabilities over citrate-coated particles. Other studies also report variances in inhibition of amyloid protein aggregation by NPs displaying different surface chemistries with the same electric charge [22, 25]. In comparison to monomeric citrate, polymeric PAA will exhibit molecular reorganization transitions with the local solution environment . These transitions can result in spatially dependent changes to physical parameters that may facilitate inhibition, as discussed in the next section.
TEM images further revealed that NPs with different coatings exert different effects on aggregate morphology. While aggregates formed in the presence of anionic citrate-coated NPs exhibited a morphology similar to the control (Fig. 4b), aggregates formed in the presence of cationic NPs demonstrated altered morphologies. PAH-coated NPs induced the formation of an increased number of thin, elongated aggregate structures (Fig. 4c), while CTAB-coated NPs induced the formation of short, thick associated aggregates (Fig. 4e). Thus, these results demonstrate the ability of cationic, but not anionic, NPs to influence aggregate morphology. Other studies have described similar NP-induced changes in aggregate structure, with a diverse array of morphologies reported [20, 21, 26, 49, 50, 52, 54, 55]. However, these observations are not confined to cationic NPs.
NP size influences inhibition of Aβ1–40 monomer aggregation by PAA-coated gold NPs
Both 8 nm and 18 nm PAA-coated nanospheres were capable of abrogating Aβ aggregation at a substoichiometric ratio of 1:2,000,000. While other studies have proposed NP-protein binding as the mode of aggregation inhibition, this extremely low NP to monomer ratio suggests that these surface-coated NPs are acting via another mechanism. Moreover, TEM images show that NPs did not co-localize with aggregates and that morphological changes were not isolated to regions near NPs. A similar lack of interaction with aggregated protein is also reported for other NP types [20, 50, 54, 59]. These observations suggest a dynamic interaction between NP-localized protein and the bulk solution.
Theoretical calculations indicate that surface charged NPs alter local solution conditions that can influence Aβ aggregation
The strikingly low stoichiometry at which inhibition of Aβ1–40 aggregation by PAA-coated NPs was observed as well as the lack of association between NPs and Aβ aggregates within TEM images suggest that interactions other than sequestration of Aβ1–40 monomer at the NP surface may play a role in the inhibitory capabilities of surface-coated NPs. A potential mechanism that can account for these congruent observations exists in the effect that the curved, charged NP surface has upon local solution conditions, including pH and ionic strength , both of which significantly influence Aβ aggregation [60–62]. Specifically, Aβ aggregation is attenuated in the presence of acidic and basic pH [61, 63–65], while aggregation is promoted by the presence of a higher ionic strength, or charge density [62, 66–70]. Moreover, both solution pH [60, 65, 66, 71] and ionic strength [66, 67, 70] can modulate aggregate morphology. To explore this possibility, a self-consistent molecular field theory (SCMFT) was developed and implemented to describe molecular organization near the curved, charged NP surface. Theoretical calculation of the equilibrium concentrations of solution species allowed for the determination of local solution pH and charge density.
Interestingly, an asymmetry exists about the bulk solution values, with cationic NPs eliciting a more pronounced change in charge density. This asymmetry is a manifestation of differences between counterions that become localized to balance the NP surface charge. The cationic NP surface draws hydroxide and chloride to its surface, with chloride being the predominant species, while the anionic NP surface draws hydronium and Tris to its surface, with Tris predominating. In the latter case, because Tris is in chemical equilibrium with its local environment through the acid dissociation reaction (tr + ⇄ tr + H +), the fraction of Tris that is charged, and hence capable of balancing the anionic NP surface charge, is interdependent upon the local pH environment, thus causing a distinct effect upon molecular organization. This asymmetric magnitude in charge density combined with the opposing changes in both local solution pH and charge density induced by anionic vs. cationic NPs may contribute to the distinct inhibitory effects observed for anionic and cationic NPs, including the stronger inhibitory capabilities of anionic NPs and the ability of cationic, but not anionic, NPs to alter aggregate morphology. Moreover, polymeric PAA can produce steric hindrance that results in a preference for localizing protons over bulky ions, such as Tris. The result is a more pronounced effect on the local pH compared to citrate, congruent with the enhanced effectiveness of PAA-coated vs. citrate-coated NPs.
Overall, theoretical results parallel experimental observations in both the current and prior studies, supporting the hypothesis that inhibition of amyloid aggregation may stem, in part, from NP-induced changes in local solution conditions.
This study provides evidence that electric charge, surface chemistry, and size can modulate the ability of gold nanospheres to inhibit Aβ aggregation. NP surface chemistry and size influence the extent of inhibition, while electric charge defines NP ability to alter aggregate morphology. Overall, PAA-coated NPs 18 nm and smaller are superior inhibitors, abrogating aggregation at substoichiometric ratios as low as 1:2,000,000 with Aβ. Such low stoichiometric ratios coupled with the lack of NP-aggregate association prompted investigation for NP-induced changes in local solution conditions to influence aggregation. A theoretical model describing changes in local solution pH and charge density displays congruencies with experimental observations to support this potential mechanism. Cell viability assays further demonstrated that the most effective NP inhibitors are non-toxic. Together, these findings identify surface-coated gold nanospheres as potential tunable therapeutic agents for the inhibition of Aβ aggregation and provide insight into the physiochemical properties of effective NP inhibitors.
Aβ1–40 was purchased from AnaSpec, Inc. (San Jose, CA). Gold (III) trichloride hydrate HAuCl4 · 3H2O, trisodium citrate, sodium borohydride (NaBH4), ascorbic acid, CTAB, ThT, Triton-X 100, XTT, and all cell culture media and reagents were purchased from Sigma-Aldrich (St. Louis, MO). The polyelectrolytes PAH and PAA were also obtained from Sigma-Aldrich and used without further purification. Sodium chloride (NaCl) was purchased from Fisher Scientific. Uranyl acetate was purchased from Electron Microscopy Sciences (Hatfield, PA).
Surface-coated gold NP synthesis and characterization
Surface-coated gold NPs of average core diameters 8 nm, 18 nm, and 40 nm were synthesized using a previously reported seeded growth method , described in detail within Additional file 1. NPs in their citrate-capped form were either used for experimentation, coated with CTAB, which forms a bilayer on the surface causing the trimethylammonuim headgroup to face the aqueous solvent, or electrostatically over-coated in a layer-by-layer fashion with PAA and PAH . Therefore, at pH 7, the nanomaterials would present either a cationic (CTAB and PAH) or anionic (citrate and PAA) surface. NPs were characterized using TEM and UV–vis absorbance spectroscopy.
Toxicity of surface-coated gold NPs
Potential toxicity of surface-coated NPs was probed in human neuroblastoma SH-SY5Y cells (American Type Culture Collection, Manassus, VA). Cellular reduction of XTT was employed to evaluate cellular metabolic activity following NP exposure. Cells, sustained and prepared for experiments as described in Additional file 1, were incubated (24 h) with NPs (100 pM or 200 pM) diluted into medium, with medium alone (negative control), or with 2% Triton-X 100 in medium (positive control). Following incubation, cells were washed and treated (24 h) with 0.33 mg/mL XTT and 8.3 μmol/L phenozene methyl sulfate. Metabolically active cells reduce XTT to an orange formazan product, for which absorbance (450 nm) was measured using a BioTek Synergy 2 microplate reader (Winooski, VT). Results are reported as a percentage of the negative control following background (medium containing XTT) subtraction.
Aβ1–40 monomer aggregation
Aβ1–40 monomer aggregation assays were performed similar to previously described methods . Briefly, Aβ1–40 monomer, purified via size exclusion chromatography (SEC) as described in Additional file 1, was diluted to 40 μM in 40 mM Tris–HCl (pH 8.0) and agitated (vortex, 800 rpm, 25 °C) alone (control) or with 20-200 pM NPs. Periodically, a 20 μL aliquot was removed and combined with 140 μL of 10 μM ThT, an amyloid-binding dye that yields a shifted, enhanced florescence upon recognition of the characteristic β-sheet structure of fibrillar Aβ aggregates. Fluorescence (excitation = 450 nm, emission = 470-500 nm) was evaluated using a Perkin-Elmer LS-45 luminescence spectrometer (Waltham, MA). Fluorescence values were calculated as the integrated area under the emission curve with baseline (ThT alone) subtraction and plotted vs. aggregation time.
ThT detection of Aβ1–40 aggregates in the presence of surface-coated gold NPs
To ensure that NPs do not compromise ThT detection, ThT fluorescence was evaluated for 5 μM Aβ1–40 pre-formed fibrils, prepared as described in Additional file 1, in the presence of 8.75 μM ThT and 5-200 pM NPs (concentrations congruent with those of diluted samples used to monitor aggregation). ThT fluorescence was measured after 2 h incubation. Compromised ThT detection was evaluated as a decrease in ThT fluorescence relative to that observed for fibrils in the absence of NPs and expressed as the fraction of ThT fluorescence observed for the control.
Morphological evaluation of Aβ1–40 aggregates
To evaluate Aβ1–40 aggregate morphology, monomer aggregation reactions were prepared for TEM following the time point at which the control reaction reached equilibrium (assessed via ThT). As described previously , a 10 μL sample was placed on a 300 mesh formvar-carbon supported copper grid (Electron Microscopy Sciences, Hatfield, PA). After 3 min, the sample was wicked away from the bottom side of the grid using filter paper. Sample application was repeated twice, and grids were allowed to air dry (24 h). Gridded samples were stained (10 min) with 2% aqueous uranyl acetate, excess stain was wicked away, and grids were allowed to dry (24 h). Imaging was performed using a JEOL 200CX TEM (Tokyo, Japan) with an accelerating voltage of 120 kV. Blinded observation of samples with random selection of grid areas was implemented to reduce bias.
Using GraphPad Prism 5 software (San Diego, CA), the effect of NPs on aggregation was evaluated using a one-way analysis of variance (ANOVA) with Dunnett’s post-test, and the effect of NPs on ThT detection was evaluated using a two-way ANOVA with Bonferroni post-test. p < 0.05 was considered significant.
A SCMFT was developed and parameterized to model the equilibrium molecular organization near the interface of surface-coated NPs suspended in 40 mM Tris–HCl (pH 8.0). The NP surface was modeled as a sphere bearing a fixed surface charge where spherical symmetry was imposed. Five mobile species (water, hydronium, hydroxide, chloride, and Tris) were accounted for explicitly to capture the solvent environment. The chemical equilibrium of Tris is integrated into the model and made dependent upon the local solvent environment. The concentration of chloride was parameterized to achieve electroneutrality within the bulk solution. The SCMFT is expressed mathematically as a dimensionless free energy functional. The equilibrium molecular organization is determined through the minimization of this functional. Further details can be found in Additional file 1. This model was used to predict the molecular organization near the NP surface, from which the pH and charge density were determined a function of distance from the NP surface. Calculations were performed for 18 nm NPs with surface charges ranging from 4 to −4 e/nm2.
Analysis of variance
Bovine serum albumin
Self-consistent molecular field theory
Size exclusion chromatography
Transmission electron microscopy
This work was supported by the National Science Foundation’s Research at Undergraduate Institutions Program (RUI, CHE-0701406 to R.M., C.J.M., and M.A.M.) and the Faculty Early Career Development Program (CAREER, CBET-0644826 to M.A.M.).
Availability of data and materials
The datasets acquired and analyzed during the current study are available from the corresponding author on reasonable request.
KAM, DDS-O, RM, CJM, and MAM designed the study. SL, KSJ, VDL, LJ, NG, VMN, and SM synthesized and characterized the surface-coated gold NPs. KAM, DDS-O, ML, and KSJ characterized inhibitory properties of the surface-coated gold NPs. KP performed studies to determine toxicity of the surface-coated gold NPs. NvdM and MJU conceptualized and implemented the theoretical model. KAM, KP, and MAM wrote the manuscript. MU, RM, CJM, and MAM supervised various aspects of the project. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
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