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Acceleration and inhibition of amyloid-β fibril formation by peptide-conjugated fluorescent-maghemite nanoparticles

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Abstract

The formation of amyloid aggregates by association of peptides into ordered structures is hallmark of certain neurodegenerative disorders. Exploring the effect of specific nanoparticles on the formation of amyloid fibrils may contribute toward a mechanistic understanding of the aggregation processes, leading to design nanoparticles that modulate the formation of toxic amyloid plaques. Uniform maghemite (γ-Fe2O3) magnetic nanoparticles, containing fluorescein covalently encapsulated within (F-γ-Fe2O3), were prepared. These F-γ-Fe2O3 nanoparticles of 14.0 ± 4.0 nm were then coated with human serum albumin (HSA) via a precipitation process. Covalent conjugation of the spacer arm succinimidyl polyethylene glycol succinimidyl ester (NHS–PEG–NHS) to the F-γ-Fe2O3~HSA nanoparticles was then accomplished by interacting the primary amine groups of the HSA coating with excess NHS–PEG–NHS molecules. Covalent conjugation of the peptides amyloid-β 40 (Aβ40) or Leu-Pro-Phe-Phe-Asp (LPFFD) onto the surface of the former fluorescent nanoparticles was then performed, by interacting the terminal activated NHS groups of the PEG derivatized F-γ-Fe2O3~HSA nanoparticles with primary amino groups of the peptides. Kinetics of the Aβ40 fibrillation process in the absence and presence of varying concentrations of the Aβ40 or LPFFD conjugated nanoparticles were also elucidated. The non-peptide conjugated fluorescent nanoparticles do not affect the Aβ40 fibrillation process significantly. However, the Aβ40-conjugated nanoparticles (F-γ-Fe2O3~HSA–PEG–Aβ40) accelerate the fibrillation process while the LPFFD-conjugated nanoparticles (F-γ-Fe2O3~HSA–PEG–LPFFD) inhibit it. By applying MRI and fluorescence imaging techniques simultaneously these bioactive fluorescent magnetic iron oxide nanoparticles can be used as an efficient tool to study and control the Aβ40 amyloid fibril formation process.

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Acknowledgments

The authors thank Dr Judith Grinblat, Luba Burlaka, and Gregory Vishninsky (Bar-Ilan University, Israel) for their help in obtaining the HR/TEM images. These studies were partially supported by a BSF (Israel-USA Binational Science Foundation) grant, and by a Minerva Grant (Microscale and Nanoscale Particles and Films).

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  1. Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, 52900, Ramat-Gan, Israel

    Hadas Skaat, Gilead Shafir & Shlomo Margel

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  1. Hadas Skaat
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  2. Gilead Shafir
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Correspondence to Shlomo Margel.

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Fig. S1 TEM image of the F-γ-Fe2O3~HSA–PEG–Aβ40 nanoparticles 120.0 h after incubation in PBS at 37 °C

11051_2011_276_MOESM2_ESM.tif

Fig. S2 Kinetics of the Aβ40 fibrils formation in PBS at 37 °C in the absence (a) and in the presence of 100.0% (w/wAβ40) (b) of the F-γ-Fe2O3~HSA nanoparticles

11051_2011_276_MOESM3_ESM.tif

Fig. S3 ThT fluorescence intensity versus time of the 100.0% (w/wAβ40) F-γ-Fe2O3~HSA–PEG–Aβ40 nanoparticles in the absence (a) and in the presence (b) of the dissolved Aβ40 in PBS at 37 °C

11051_2011_276_MOESM4_ESM.tif

Fig. S4 HRTEM images (a–c) representing higher magnifications of the inset c image shown in Fig. 9. Exposure of the Aβ40 protofibrils-coated γ-Fe2O3 nanoparticles to the electron beam for an extended period of time causes their gradual destruction (a, b), leaving only the inorganic crystalline γ-Fe2O3 nanoparticles (c)

Supplementary material 5 (TIFF 2897 kb)

Supplementary material 6 (TIFF 2717 kb)

11051_2011_276_MOESM7_ESM.tif

Fig. S5 TEM image of the Aβ40 fibrils labeled with 10.0% (w/wAβ40) of the F-γ-Fe2O3~HSA–PEG–Aβ40 nanoparticles, 60.0 h after the initiation of the fibrillation process. The nanoparticles were added before the onset the fibril formation, as described in the “Experimental” part

11051_2011_276_MOESM8_ESM.tif

Fig. S6 TEM image of the Aβ40 fibrils labeled with 10.0% (w/wAβ40) of the F-γ-Fe2O3~HSA–PEG–LPFFD nanoparticles, 160.0 h after the initiation of the fibrillation process. The nanoparticles were added before the onset the fibril formation, as described in the “Experimental” part

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Skaat, H., Shafir, G. & Margel, S. Acceleration and inhibition of amyloid-β fibril formation by peptide-conjugated fluorescent-maghemite nanoparticles. J Nanopart Res 13, 3521–3534 (2011). https://doi.org/10.1007/s11051-011-0276-4

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