Testing synthetic amyloid-β aggregation inhibitor using single molecule atomic force spectroscopy

Hane, Francis; Lee, Brenda Yasie; Petoyan, Anahit; Rauk, Arvi; Leonenko, Zoya

doi:10.1016/j.bios.2013.10.060

Cited by 21 publications

(21 citation statements)

References 27 publications

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“…Moreover, the design principle by molecular dynamics studies suggests that the strong binding affinity between the artificially designed peptides and the critical regions of Aβ often lead to potential hits of Aβ inhibitors. Guided by this design principle, several peptide inhibitors have been found to interfere with Aβ aggregation . Other screening methods such as phage display have been used to screen and design different cyclic and non‐natural peptide as Aβ inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Design of a Molecular Hybrid of Dual Peptide Inhibitors Coupled on AuNPs for Enhanced Inhibition of Amyloid β‐Protein Aggregation and Cytotoxicity

Xiong

Zhao

Dong

et al. 2017

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Aggregation of amyloid-β protein (Aβ) is a pathological hallmark of Alzheimer's disease (AD), so the inhibition of Aβ aggregation is an important strategy for the prevention and treatment of AD. Herein, we proposed to design molecular hybrids of peptide inhibitors by combining two peptide inhibitors, VVIA and LPFFD, into single sequences and examined their effects on Aβ aggregation and cytotoxicity. The hybrid peptides exhibit increased but moderate inhibitory activity as compared to their two precursors. By conjugating the peptides onto gold nanoparticles (AuNPs), however, the inhibition activity of the corresponding peptide@AuNPs against Aβ aggregation and cytotoxicity is greatly improved. Among them, VVIACLPFFD (VCD10)@AuNP is the most effective, which increases cell viability from 48% to 82% at a dosage as low as 0.1 nmol L (NPs) or 40 nmol L (peptide). The superior capacity of VCD10@AuNPs is considered due to its branched dual-inhibitor sequence, and its special surface orientation and conformation. These structural features promote its synergetic interactions with Aβ on AuNP surface, leading to strong inhibitions of Aβ oligomerization and fibrillation and the cytotoxicity caused by the aggregation species. The findings suggest that potent inhibitors can be derived by hybridization of multiple peptide inhibitors with the hybrid products coupled onto nanoparticles.

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Section: Introductionmentioning

confidence: 99%

Design of a Molecular Hybrid of Dual Peptide Inhibitors Coupled on AuNPs for Enhanced Inhibition of Amyloid β‐Protein Aggregation and Cytotoxicity

Xiong

Zhao

Dong

et al. 2017

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“…It allows AFM to be used as a mechanical nanosensor (Wang et al, 2015), or as a micromechanical transducer for the construction of biosensors (Lavrik et al, 2004). Furthermore, modified AFM tip biosensor has been used in numerous studies, including the analysis of Alzheimer's disease process (Hane et al, 2014), as mechanical sensor in the study of cell penetration by nanoneedles (Obataya et al, 2005), in cell-based biosensing of drug effects (Wang et al, 2009) and in study of growth factor effects on epidermal cells (Zhang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing

Pešl

Přibyl

Aćimović

et al. 2016

Biosensors and Bioelectronics

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Cardiomyocyte contraction and relaxation are important parameters of cardiac function altered in many heart pathologies. Biosensing of these parameters represents an important tool in drug development and disease modeling. Human embryonic stem cells and especially patient specific induced pluripotent stem cell-derived cardiomyocytes are well established as cardiac disease model.. Here, a live stem cell derived embryoid body (EB) based cardiac cell syncytium served as a biorecognition element coupled to the microcantilever probe from atomic force microscope thus providing reliable micromechanical cellular biosensor suitable for whole-day testing. The biosensor was optimized regarding the type of cantilever, temperature and exchange of media; in combination with standardized protocol, it allowed testing of compounds and conditions affecting the biomechanical properties of EB. The studied effectors included calcium , drugs modulating the catecholaminergic fight-or-flight stress response such as the beta-adrenergic blocker metoprolol and the beta-adrenergic agonist isoproterenol. Arrhythmogenic effects were studied using caffeine. Furthermore, with EBs originating from patient's stem cells, this biosensor can help to characterize heart diseases such as dystrophies.

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“…22–23 Using AFM as a technique to image smaller structures such as monomers, dimers, and other small oligomers is highly desirable but carries with it significant challenges. The details of the AFM methods we use are given in Supporting Information.…”

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confidence: 99%

Amyloid β-Protein Assembly and Alzheimer’s Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation

et al. 2016

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Evidence suggests that oligomers of the 42-residue form of the amyloid β-protein (Aβ), Aβ42 play a critical role in the etiology of Alzheimer’s disease (AD). Here we use high resolution atomic force microscopy to directly image populations of small oligomers of Aβ42 that occur at the earliest stages of aggregation. We observe features that can be attributed to monomer and to relatively small oligomers, including dimers, hexamers, and dodecamers. We discovered that Aβ42 hexamers and dodecamers quickly become the dominant oligomers after peptide solubilization, even at low (1 μM) concentrations and short (5 min) incubation times. Soon after (≥10 min), dodecamers are observed to seed the formation of extended, linear pre-protofibrillar β-sheet structures. The pre-protofibrils are a single Aβ42 layer in height and can extend several hundred nanometers in length. To our knowledge this is the first report of structures of this type. In each instance the pre-protofibril is associated off center with a single layer of a dodecamer. Protofibril formation continues at longer times, but is accompanied by the formation of large, globular aggregates. Aβ40, by contrast, does not significantly form the hexamer or dodecamer but instead produces a mixture of smaller oligomers. These species lead to the formation of a branched chain-like network rather than discrete structures.

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Testing synthetic amyloid-β aggregation inhibitor using single molecule atomic force spectroscopy

Cited by 21 publications

References 27 publications

Design of a Molecular Hybrid of Dual Peptide Inhibitors Coupled on AuNPs for Enhanced Inhibition of Amyloid β‐Protein Aggregation and Cytotoxicity

Design of a Molecular Hybrid of Dual Peptide Inhibitors Coupled on AuNPs for Enhanced Inhibition of Amyloid β‐Protein Aggregation and Cytotoxicity

Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing

Amyloid β-Protein Assembly and Alzheimer’s Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation

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