Charged surfactants induce a non-fibrillar aggregation pathway of amyloid-beta peptide

Research Article

Received: 25 January 2013 Revised: 30 May 2013 Accepted: 17 June 2013 Published online in Wiley Online Library

(wileyonlinelibrary.com) DOI 10.1002/psc.2535

Charged surfactants induce a non-fibrillaraggregation pathway of amyloid-beta peptideJoana A. Loureiro, Sandra Rocha and Maria do Carmo Pereira*

The amyloid β-peptide with a sequence of 42 amino acids is the major constituent of extracellular amyloid deposits inAlzheimer's disease plaques. The control of the peptide self-assembly is difficult to achieve because the process is fast andis affected by many variables. In this paper, we describe the effect of different charged and non-charged surfactants onAβ(1-42) fibrillation to define common alternate aggregation pathways. The characterization of the peptide-surfactantinteractions by ultra-structural analysis, thioflavin T assay and secondary structure analysis, suggested that chargedsurfactants interact with Aβ(1-42) through electrostatic interactions. Charged micelles slow down the aggregation processand stabilize the peptide in the oligomeric state, whereas non-charged surfactants promote the Aβ(1-42) fibril formation.Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.

Keywords: beta amyloid; surfactants; aggregation; oligomers; Alzheimer

* Correspondence to: Maria do Carmo Pereira, LEPAE, Department of ChemicalEngineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias,4200-465 Porto, Portugal. E-mail: [email protected]

LEPAE, Department of Chemical Engineering, Faculty of Engineering, Universityof Porto, Rua Roberto Frias, Porto, Portugal

Introduction

Evidences support a direct association between the degree ofdementia of patients that have Alzheimer's disease (AD) and theconcentration of soluble aggregates of the amyloid-β (Aβ) peptide[1–3]. The aggregation process of the Aβ peptide leads to theformation of insoluble fibrils, which accumulate in senile plaques,deposits that characterize AD [4,5]. The more abundant sequencesof the peptide have 40 (~90%), Aβ(1-40), and 42 (~10%), Aβ(1-42),amino acids [6]. The peptide with 42 amino acids is more toxicand it is the major component of the neuritic plaques found inAD [7,8]. The smaller aggregated intermediates, the Aβ oligomers,are considered one of the more toxic species [1]. The control ofAβ oligomerization is difficult to achieve, because the process is fastand is affected by many variables [9]. For its study, problems arisefrom the difficulty of obtaining stable and reproducible oligomersparticularly of the sequence with 42 amino acids. It has beendemonstrated that the surfactant sodium dodecyl sulfate (SDS) isable to induce, at specific conditions, a non-fibrillar state of thepeptide [10,11]. The use of surfactants could provide a standardprocedure for obtaining oligomeric assemblies of Aβ and forgetting new insights into the oligomerization process [12]. Theconcentration of the surfactant in solution determines its effecton Aβ aggregation [10,13–20]. The interactionmechanism betweensurfactants and Aβ may well be generalized as it has beensuggested for the case of globular proteins [21,22]. There is alreadyan indication of identical impacts of different charged surfactantson the secondary structure of Aβ(1-40) [16,18–20,23]. Also, bothnon-ionic and zwitterionic surfactants have similar effects on theaggregation of Aβ(1-40) [24]. In this paper, we describe the effectof different charged surfactants and a non-ionic surfactant onAβ(1-42) fibrillation to characterize their interaction mechanismand to define common alternate aggregation pathways. The studywas performed using different concentrations of the surfactants,below and above their critical micelle concentration (CMC) andby characterizing the ultra-structure of the aggregates, their bind-ing to thioflavin T (ThT) and their secondary structure.

J. Pept. Sci. 2013

Material and Methods

Peptide and Surfactant Solutions

Aβ42 solution

Aβ42 (amyloid-β peptide 1-42, purity >95.22%, MW 4514.14, SelleckChemicals) (Houston, Texas, USA) was dissolved in HFIP (1,1,1,3,3,3-hexafluoro-2-propanol, ≥99.8%, Sigma-Aldrich) (Germany) at 1mg/mLconcentration to improve peptide solubility and disaggregatepreformed agglomerates. HFIP was evaporated with nitrogen flowand the peptide film was dissolved in DMSO (dimethyl sulfoxide formolecular biology, ≥99.9%, FW 78.13, Sigma-Aldrich) at 9mg/mLconcentration [25,26].

Surfactants

Stock solutions of surfactants were prepared by dissolvingCTAC (cetyltrimethylammonium chloride, 25wt% solution in water,MW 320.01, Sigma-Aldrich); OG (octyl β-D-glucopyranoside,≥98%, MW 292.37, Sigma-Aldrich) or SDS (sodium dodecylsulfate, ≥ 98.5%, MW 288.38, Sigma-Aldrich) in either 10mM Hepesbuffer, pH7.4 (HEPES hemisodium salt, ≥99%, Sigma-Aldrich) or phos-phate buffered saline, pH7.4 (PBS, 10mM phosphate buffer, 2.7mMpotassium chloride and 137mM sodium chloride, Sigma-Aldrich).

Measurement of Critical Micelle Concentration

The CMC of the surfactants was determined using surface tensionmeasurements at room temperature. The measurements wereperformed both in Hepes buffer and PBS buffer. Surface tensionmethod was carried out using the hanging drop method [27]by using an optical contact angle system (OCA 15 plus).

Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.

LOUREIRO, ROCHA AND PEREIRA

Transmission Electron Microscopy

Aβ peptide (100μM) was incubated at 37 °C with CTAC (0.5 and1.4mM), SDS (4 and 14mM) or OG (10 and 29.8mM) in 10mMHepes buffer, pH 7.4, or in PBS, for 6 days. Five microliters of eachsample were placed on carbon-formvar coated 400 mesh spacinggrids and left to adsorb for 5min. Negative staining wasperformed with 2% filtered aqueous solution of uranyl acetatefor 45 s. The grids were visualized using a Jeol JEM 1400 (Tokyo,Japan) electron microscope at 80 kV.

Thioflavin T Binding Assay

Thioflavin T is a classic amyloid dye that is commonly used toprobe Aβ fibril formation because of its strong fluorescenceemission upon binding to amyloid fibril structures [25]. It isassumed that the intensity of fluorescence is proportional tothe quantity of amyloid fibrils [28]. ThT assay was carried outfor the same samples that were analyzed by transmissionelectron microscopy (TEM). ThT stock solution was prepared byadding 8mg of ThT to 10ml of either Hepes buffer or PBS [25].This solution was filtered through a 0.2μm syringe filter anddiluted (1ml of ThT stock solution in 50ml of buffer) before eachmeasurement (ThT working solution). An aliquot of 20μl of eachsample was mixed with 1ml of ThT working solution, stirred for1min, and the fluorescence intensity was measured using aPerkin Elmer LS 50B (Waltham, Massachusetts, USA) fluorescencespectrometer, averaging over 60 s. Upon binding to amyloid fi-brils, the ThT has an excitation maximum at 450 nm and en-hanced emission at 482 nm. The spectra were subtracted to thecontrols (ThT working solution and surfactants). For kinetic studies,the samples containing Aβ and CTAC (0.5mM and 1.4mM) or SDS(4mM and 14mM) in PBS buffer were diluted and added to ThTworking solution immediately after preparation leading to the fol-lowing final concentrations: 12.5μM of Aβ peptide, 62.5μM and0.175mM of CTAC; 0.5mM and 1.75mM of SDS. The samples wereplaced on a 96-well plate and the fluorescence intensity wasmeasured using a Biotek Synergy (Winooski, Vermont, USA) 2fluorescence spectrometer after stirring 30s at 37°C every 15 minduring 2days. The measurements were performed with a 420/50 nm excitation filter and a 485/20 nm emission filter.

Theoretical Kinetic Model

The kinetic data obtained from the ThT assay were fitted usingthe model proposed by Hellstrand et al. that describes protein

Table 1. Properties of the surfactants that were used in this study

Surfactant CMCd in Hepese (mM) [1] CMC in PBSf (m

CTACa 0.9 ± 0.2 0.19 ± 0.02

SDSb 6.9 ± 0.3 1.4 ± 0.2

OGc 22.4 ± 0.1 22.2 ± 0.5

acetyltrimethylammonium chloride;bsodium dodecyl sulfate;coctyl β-D-glucopyranoside;dcritical micelle concentration;e10mM sodium HEPES buffer, pH 7.4;fphosphate buffered saline, 10mM phosphate buffer, 2.7mM potassium ch

For OG, R is the radius of the cylinder, and L is its length.

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aggregation [29]. This model provides the time at half comple-tion of the aggregation process, t1/2, which is estimated by fittinga sigmoidal function (Eqn 1) to each parameter.

F tð Þ ¼ F0 þ A

1þ exp �k t � t1=2� �� (1)

The fitted parameters were t1/2, the elongation rate constant, k,the amplitude, A, and the baseline before aggregation, F0. The lagtime, tlag, is the interception between the time axis and thetangent with slope k from the midpoint of the fitted sigmoidalcurve. By this definition, tlag was calculated from the fittedparameter as described by Eqn 2,

tlag ¼ t1=2 � 2

k(2)

Attenuated Total Reflectance–Fourier Transform InfraredSpectroscopy

Attenuated Total Reflectance–Fourier Transform Infrared Spec-troscopy (ATR-FTIR) spectra were recorded using a BrukerAlpha-P spectrophotometer (Germany). Measurements wereperformed using the same solutions used in the TEM experiments.Buffer or surfactant solution spectrumwas subtracted to the Aβ(1-42)sample spectra and the resulting baseline smoothed. All spectrawere recorded by averaging 200 scans at a resolution of 4 cm�1.

Results

The aggregation of Aβ(1-42) was studied in the presence ofsurfactants by ultra-structural analysis at a peptide concentrationof 100μM and surfactant concentrations below and above theCMC. The CMC values for the surfactants at the given bufferconditions used in the experiments were determined by surfacetension and are listed in Table 1. In the case of chargedsurfactants, the CMC decreases drastically in the presence of salts.

The ultra-structural analysis shows that both the cationicsurfactant (CTAC) and the anionic surfactant (SDS) promote, inHepes buffer and at concentrations below the CMC, the aggrega-tion of Aβ(1-42). In these solution conditions, the surfactants leadto the formation of amyloid-like, unbranched fibrils similar to thatobserved for the peptide alone (Figure 1). These fibrils have anaverage diameter of 21 nm. The attached negative-staining agent

M) Size of the micelle (nm) Shape of the micelle

4.8 spherical

4.8 spherical

R = 1.3; L = 9.6 cylinder

loride and 137mM sodium chloride, pH 7.4;

ean Peptide Society and John Wiley & Sons, Ltd. J. Pept. Sci. 2013

Figure 2. The surfactants' effect on Aβ(1–42) fibril content as monitoredby thioflavin T (ThT) fluorescence. The Aβ(1-42) concentration was100μM. The samples were incubated at 37 °C in the presence or absenceof surfactants in 10mM Hepes buffer, pH7.4. The studied surfactantconcentrations were all above the critical micelle concentration (CMC)[cetyltrimethylammonium chloride (CTAC), 1.4mM; sodium dodecylsulfate(SDS), 14.0mM; octadecyl β-D-glucopyranoside (OG), 29.8mM].

Figure 1. Transmission electron microscopy images of the effect of dif-ferent surfactants, cetyltrimethylammonium chloride (CTAC) and sodiumdodecylsulfate (SDS), on Aβ(1–42) aggregation. The Aβ(1-42) concentrationwas 100μM. The samples were incubated for 6 days at 37 °C in the pres-ence or absence of surfactants in a 10mM Hepes buffer, pH 7.4 or10mM phosphate buffer, 137mM NaCl. The studied surfactant concentra-tions were below and above the critical micelle concentration (CMC)(CTAC 0.5mM and 1.4mM; SDS 4mM and 14mM) in Hepes buffer andabove the CMC (CTAC, 1.4mM; SDS, 14mM) in PBS buffer. The scale barcorresponds to 400 nm.

NON AGGREGATION OF AMYLOID-BETA PEPTIDE

(uranyl acetate) is estimated to increase by approximately 1 nmthe size of the fibrils. The obtained values for Aβ(1-42) fibril sizeare concordant with that presented in the literature [30,31]. Inthe case of Aβ(1-42) incubated with the charged surfactants at mi-cellar concentrations (concentration above the CMC), only smallaggregates are observed, indicating that they inhibited the Aβfibrillogenesis. The aggregates were similar to that observed forthe peptide in the initial state (Figure 1, time= 0 h). Comparableresults were obtained for surfactant micellar concentrations inthe presence of salt (PBS buffer).

J. Pept. Sci. 2013 Copyright © 2013 European Peptide Society and Joh

A significant binding to ThT is observed for Aβ(1-42) incubatedalone. The fluorescence intensity at 450 nm, which is thecharacteristic excitation maximum observed upon ThT binding,increased after 1 day incubation time at 37 °C; for the samplescontaining OG, the non-ionic surfactant, the fluorescence inten-sity of ThT was higher than that observed for Aβ alone (Figure 2),whereas for the mixtures of Aβ(1-42) and charged micelles the in-tensity of fluorescence was low and maintained close to that ofthe Aβ starting point. These results reveal that charged micellesshow significant inhibition of Aβ fibril formation.

The Aβ(1-42) aggregation kinetics in surfactant environmentwas studied for SDS and CTAC at two different concentrationsclose to their CMC by means of ThT fluorescence (Figure 3). TheAβ(1-42) concentration was kept at 12.5μM, which was signifi-cantly above the critical concentration below which fibrils cannotform (0.2μM) [29]. The lag time, tlag, and the time at half comple-tion of the aggregation process, t1/2, were obtained by fitting asigmoidal function to each kinetic trace according to the modelpresented by Hellstrand et al. [29]. Both parameters were affectedby the presence of surfactants and were significantly longer forAβ(1-42) incubated with SDS than for Aβ(1-42) alone (Figure 3). Also,the ThT fluorescence plateau decreased.

The increase of surfactant concentrations slowed down thefibril formation and the higher value of t1/2 was obtained forthe highest concentrations of SDS (1.75mM). In the case of CTACat 0.18mM, the fluorescence intensity was below the noise level,and thus it was not possible to calculate the tlag and t1/2,suggesting a stronger inhibitory action.

The t1/2 of the aggregation process was approximately fourtimes higher in the case of the sample with SDS 1.75mM whencompared with the peptide alone. SDS at 0.50mM induced aninhibitory effect of 0.37 days (approximately 9 h).

The non-ionic surfactant OG promoted the Aβ(1-42) aggregationboth at submicellar and micellar concentrations (and either inHepes or PBS buffer) (Figure 4). The fibrils had a differentmorphology and to confirm if they were of the amyloid type,their secondary structure was analyzed by ATR-FTIR spectros-copy. The spectra of Aβ(1-42) in the presence of OG below andabove the CMC in PBS buffer were similar to that of the Aβ(1-42)incubated alone (Figure 4). These spectra are characterized by a

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Figure 3. Concentration dependence of charged surfactants (cetyltrimethylammonium chloride, CTAC; and sodium dodecylsulfate, SDS) in Aβ(1–42)fibril formation in phosphate buffer, 137mM NaCl, pH 7.4. (A) and (C) kinetics of aggregation monitored using thioflavin T (ThT) fluorescence. Datafor two different surfactant concentration close to the CMC (CTAC, 52.50μM and 0.18mM; SDS, 0.5mM and 1.75mM) with 100μM Aβ(1–42). Aβ(1–42) alonewas presented with a red solid line, Aβ(1–42) with lowest surfactant concentrations at blue and Aβ(1–42) with the highest surfactant concentrations atgreen. (B) and (D) fitting of equation 1 to Aβ(1–42) alone kinetic points, with data points as red triangles and the fitted curve as a solid line; Aβ(1–42) inthe presence of lowest surfactant concentrations with data points as blue squares and the fitted curve as a solid line; and Aβ(1–42) in the presence ofhighest surfactant concentrations with data points as green circles and the fitted curve as a solid line. The values for t1/2 were obtained by the fitand tlag was achieved by the Eqn 2.


band in the Amide I region with a maximum intensity at1624 cm�1, which is assigned to β-sheet-rich amyloid fibrils [32].

Discussion

Our results indicate that charged surfactant monomers interactwith Aβ(1-42) through electrostatic interactions. This will causethe exposure of peptide hydrophobic parts that will promotehydrophobic interactions between peptide molecules, whicheventually lead to the peptide aggregation (Figure 5). Chargedmicelles will also interact electrostatically with Aβ(1-42). The


concentration of charged micelles is high enough for surround-ing the Aβ(1-42) peptide molecules inducing consequently anelectrostatic repulsion between the peptide-micelle structures(Figure 5) favoring a non-aggregated state.

This study confirms the fibrillation-inhibiting effect of chargedmicelles. Other charged nanoparticles (NPs) were shown to havealso a fibrillation-inhibiting effect [33–35]. Liao et al. used bareand carboxyl conjugated gold nanoparticles (AuNPs) to inhibitthe formation of fragmented fibrils and spherical oligomers. Theyshowed that the negative surface potential of AuNPs is essentialfor the interactions between the peptide (Aβ(1-40)) and the AuNPsand as a result of this interaction the peptide fibrillation is


Figure 4. Effect of non-charged surfactants in Aβ(1–42) aggregation. Transmission electron microscopy (TEM) images and Fourier transform infraredspectroscopy (FTIR) spectra of the Aβ(1–42) in presence of monomer and micelles of octyl β-D-glucopyranoside surfactant (respectively 10.0mM and29.8mM). In the TEM analysis, the samples were incubated for 2 days at 37 °C in presence of the surfactant in 10mM Hepes buffer or 10mM PBS buffer,pH 7.4. The scale bar corresponds at 400nm. In the FTIR spectra the peptide was incubated for 2 days at 37 °C in PBS buffer, 137mM NaCl, pH 7.4.


inhibited [33]. Saraiva et al. demonstrated that fluorinated NPs pro-mote an increase in the α-helical content of the Aβ(1-42) peptide andhave an antioligomeric effect [34]. Sulfonated and sulfated polysty-rene NPs, which are negatively charged polymeric nanostructures,also affected the conformation of Aβ and induced an unorderedstate, delaying the peptide oligomerization [35].

The effect of non-charged surfactants below the CMC on Aβ(1-42)may be explained by the presence of more hydrophobic molecules(monomers) in solution that favors hydrophobic interactions(Figure 5). The OG micelles in solution behave as inert bodies andact as nuclei of aggregation.

Our previous studies with Aβ(1-40) fragment suggest that the pep-tide shows a low content of β-sheet structures in the presence ofmicelles of charged surfactants, SDS and CTAC [20]. On the con-trary, the presence of these surfactants below the CMC induces aβ-sheet conformation. The presence of OG at concentrations above


the CMC leads to a β-sheet conformation as opposed to what isobserved in the case of charged micelles [20].

A dual effect of cationic surfactants (alkylammonium bromides)on Aβ(1-40) structure has also been reported, as the alkylammoniumbromide surfactants favored the Aβ fibril formation at concentra-tions below the CMC and delay the fibril formation at concentra-tions above their CMC [16]. Cao et al. found that cationic Geminisurfactant hexamethylene-1,6-bis (dodecyl dimethylammoniumbromide) (C12C6C12Br2) micelles delay the formation of Aβ(1-40)fibrils [18]. The interaction of charged and zwitterionic surfactantswith the Aβ-peptide fragment (1-28) demonstrated that thepromotion and stabilization of α-helix secondary structure arehighly dependent on the surface charge of micelles [13].

The aggregation kinetics of the peptide is also significantlyaffected by the presence of salt ions [31]. Ions may concentratenon-specifically in the vicinity of oppositely charged peptide


Figure 5. Schematic representation of the possible mechanism for the interactions of Aβ(1-42) with the charged and nonionic surfactants at monomericor micelle concentrations. Experimental data shows that the peptides in presence of charged micelles do not aggregate, but aggregate in the presenceof monomers. The Aβ in presence of nonionic monomers and micelles reach a complete aggregation.


groups, increasing the apparent dielectric constant of water andpromoting stronger electrostatic interactions between peptide–peptide molecules. Alternatively, ions may interact specifically withcharged or polar chemical groups of the peptide chain [36,37].The aggregationmechanism of Aβ peptides is still very much de-

batable because studies performed under different conditions leadto different proposed mechanisms. The fast aggregation kineticsand the different aggregation stages of peptide samples are obsta-cles for uniform and generalized studies. The use of surfactants maycontribute to a better understanding of the peptide aggregationand above all may allow the study of the fibrillation process at con-ditions that can easily be reproduced.

Acknowledgements

This work was financed by FCT and FEDER through COMPETE: re-search projects PTDC/QUI-BIQ/102827/2008, PTDC/QUI-BIQ/118076/2010, and PTDC/QUI-BIQ/115449/2009.

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Charged surfactants induce a non-fibrillar aggregation pathway of amyloid-beta peptide