Differential effects of silver and iron oxide nanoparticles on IAPP amyloid aggregation

Wang, Miaoyi; Käkinen, Aleksandr; Pilkington, Emily H.; Davis, Thomas P.; Ke, Pu Chun

doi:10.1039/c6bm00764c

Cited by 57 publications

(42 citation statements)

References 39 publications

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“…Gold nanoparticles appear to be excellent antiamyloid agents and can act as fibrillization probes through binding with amyloid cysteines . Gladytz et al proposed that the amyloid aggregation of IAPP and prion protein SUP35 hinged on a balance between peptide–nanoparticle and peptide–peptide interactions, a statement supported by our observations with iron oxide and silver nanoparticles coated with citrate and polyethylene glycol (PEG) …”

Section: Introductionsupporting

confidence: 79%

Mitigation of Amyloidosis with Nanomaterials

et al. 2019

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Amyloid fibrils were considered a major culprit for cell degeneration till the 1990s. [5] Recent studies, however, have implicated the oligomers as the most toxic species. This toxicity is believed to arise from the interactions of the oligomers with cell membranes, proteins, chaperones, organelles, biometals, and small ligands to induce membrane damage, endoplasmic reticulum stress, and reactive oxygen species (ROS) [6] (Figure 1). The ambiguity surrounding the exact cause of oligomer toxicity originates from the transient and heterogeneous nature of the aggregation species, compounded by the coexistence of primary and secondary nucleation, [7] the kinetics of fibrillar association, dissociation, and fragmentation, and the polymorphism of amyloid fibrils, driven by thermodynamic transitions. It has now been verified that the crystalline form, rather than the fibrils, is the most stable state of amyloid proteins. [8] Here, we outline the biophysical foundation of amyloid aggregation, and summarize current mitigation strategies involving nanomaterial and multifunctional nanomaterial composite inhibitors in silico, in vitro, and in vivo. We note the occasional divergence between protein aggregation and toxicity, and discuss the implications of the protein "corona" [9] enriched on amyloid fibrils in a biological milieu. This presentation highlights the structural and physicochemical attributes of nanomaterials and multifunctional nanocomposites for targeting amyloidosis. In Silico Mitigation of Amyloidosis with NanomaterialsUnderstanding the aggregation pathways and uncovering the structures and dynamics of oligomeric intermediates are crucial for the design of antiamyloid strategies. The heterogeneous and Amyloidosis is a biophysical phenomenon of protein aggregation with biological and pathogenic implications. Among the various strategies developed to date, nanomaterials and multifunctional nanocomposites possessing certain structural and physicochemical traits are promising candidates for mitigating amyloidosis in vitro and in vivo. The mechanisms underpinning protein aggregation and toxicity are introduced, and opportunities in materials science to drive this interdisciplinary field forward are highlighted. Advancement of this emerging frontier hinges on exploitation of protein self-assembly and interactions of amyloid proteins with nanoparticles, intracellular and extracellular proteins, chaperones, membranes, organelles, and biometals.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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Section: Introductionsupporting

confidence: 79%

Mitigation of Amyloidosis with Nanomaterials

et al. 2019

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“…The fibrils appeared softer, with a persistence length of 458 ± 13 nm based on FiberApp statistical analysis, 33 compared with that of 2,885 ± 60 nm for the IAPP control. 34 Below the CMC, LPC remodelled amyloid fibrils into filaments of thinner width (Fig. 1D).…”

Section: Resultsmentioning

confidence: 97%

Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

Xing

Pilkington

Wang

et al. 2017

Phys. Chem. Chem. Phys.

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Amyloid aggregation of human islet amyloid polypeptide (IAPP) is a hallmark of type 2 diabetes (T2D), a metabolic disease and a global epidemic. Although IAPP is synthesized in pancreatic β-cells, its fibrils and plaques are found in the extracellular space indicating a causative transmembrane process. Numerous biophysical studies have revealed that cell membranes as well as model lipid vesicles promote the aggregation of amyloid-β (associated with Alzheimer’s), α-synuclein (associated with Parkinson’s) and IAPP, through electrostatic and hydrophobic interactions between the proteins/peptides and lipid membranes. Using a thioflavin T kinetic assay, transmission electron microscopy, circular dichroism spectroscopy, discrete molecular dynamics simulations as well as free energy calculations here we show that micellar lysophosphatidylcholine (LPC), the most abundant lysophospholipid in the blood, inhibited the amyloid aggregation of IAPP through nonspecific interactions while elevating the α-helical peptide secondary structure. This surprising finding suggests a native protective mechanism against IAPP aggregation in vivo.

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“…These amyloids were characterized by a central nucleation “core”, ranging from smaller clusters of 50–150 nm to micrometers in diameter. Fibrils of low persistence (average of 891.9 nm compared with that of 2,885 ± 60 nm for the IAPP control 6,7 ) and contour length (<1,350 nm) were additionally observed radiating out from the core, forming the full stelliform structure of ∼0.5 μm in diameter for smaller cores and micrometers in diameter for larger cores with some macroscopic aggregates visible in solution (Figure 4A).…”

Section: Results and Discussionmentioning

confidence: 99%

“…Aggregation inhibition with the use of small molecules as well as metal, carbon, and polymeric nanoparticles (NPs) 6−9 has been a major strategy against amyloid-mediated toxicity. Polymeric NPs, specifically, have been explored as protein aggregation inhibitors utilizing their tunable hydrophobicity as well as their capacity for initiating H-bonding.…”

Section: Introductionmentioning

confidence: 99%

Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation

Pilkington

Lai

et al. 2017

Biomacromolecules

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Protein aggregation into amyloid fibrils is a ubiquitous phenomenon across the spectrum of neurodegenerative disorders and type 2 diabetes. A common strategy against amyloidogenesis is to minimize the populations of toxic oligomers and protofibrils by inhibiting protein aggregation with small molecules or nanoparticles. However, melanin synthesis in nature is realized by accelerated protein fibrillation to circumvent accumulation of toxic intermediates. Accordingly, we designed and demonstrated the use of star-shaped poly(2-hydroxyethyl acrylate) (PHEA) nanostructures for promoting aggregation while ameliorating the toxicity of human islet amyloid polypeptide (IAPP), the peptide involved in glycemic control and the pathology of type 2 diabetes. The binding of PHEA elevated the β-sheet content in IAPP aggregates while rendering a new morphology of “stelliform” amyloids originating from the polymers. Atomistic molecular dynamics simulations revealed that the PHEA arms served as rodlike scaffolds for IAPP binding and subsequently accelerated IAPP aggregation by increased local peptide concentration. The tertiary structure of the star nanoparticles was found to be essential for driving the specific interactions required to impel the accelerated IAPP aggregation. This study sheds new light on the structure–toxicity relationship of IAPP and points to the potential of exploiting star polymers as a new class of therapeutic agents against amyloidogenesis.

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Differential effects of silver and iron oxide nanoparticles on IAPP amyloid aggregation

Cited by 57 publications

References 39 publications

Mitigation of Amyloidosis with Nanomaterials

Mitigation of Amyloidosis with Nanomaterials

Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation

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