Alzheimer's amyloid-beta intermediates generated using polymer-nanodiscs

Sahoo, Bikash R.; Genjo, Takuya; Bekier, Michael E.; Cox, S. F. J.; Stoddard, Andrea K.; Ivanova, Magdalena I.; Yasuhara, Kazuma; Fierke, Carol A.; Wang, Yanzhuang; Ramamoorthy, Ayyalusamy

doi:10.1039/c8cc07921h

Cited by 77 publications

(68 citation statements)

References 25 publications

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“…As another benefit, the polymer-based nanodiscs lack spectroscopic signals that overlap with those of the protein of interest. This nanodisc technology was previously applied to the analysis of the oligomer formation by amyloidogenic peptides such as human islet amyloid polypeptide [ 7 ] and amyloid-β peptide [ 8 ] in the membrane.…”

Section: Artificial Membrane Systems That Simulate the Environment Ofmentioning

confidence: 99%

New lipid membrane technologies for reconstitution, analysis, and utilization of ‘living’ membrane proteins

Morigaki

2020

BIOPHYSICS

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Section: Artificial Membrane Systems That Simulate the Environment Ofmentioning

confidence: 99%

New lipid membrane technologies for reconstitution, analysis, and utilization of ‘living’ membrane proteins

Morigaki

2020

BIOPHYSICS

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“…Some amyloid oligomeric conformers were more toxic than amyloid fibrils [ 37 , 38 , 39 ]. Different oligomers showed different structures and toxicities [ 40 , 41 ]. Thus, amyloid fibrils with different structures may reflect variable toxicity, aggregation pathways, and surrounding microenvironments in different patients and symptoms [ 1 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

“…X-ray crystallography demonstrated the fibril structures of amyloidogenic protein fragments [ 43 , 44 ] and oligomers of Aβ peptides [ 45 , 46 , 47 , 48 ]. NMR studies reported the high-resolution structural details of membrane-bound amyloid oligomers [ 41 , 49 , 50 ]. Solution- and solid-state NMR was used to investigate the monomer and transient intermediate structures in Aβ assemblies [ 16 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ].…”

Section: Introductionmentioning

confidence: 99%

High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways

Watanabe‐Nakayama

Sahoo

Ramamoorthy

et al. 2020

IJMS

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Individual Alzheimer’s disease (AD) patients have been shown to have structurally distinct amyloid-β (Aβ) aggregates, including fibrils, in their brain. These findings suggest the possibility of a relationship between AD progression and Aβ fibril structures. Thus, the characterization of the structural dynamics of Aβ could aid the development of novel therapeutic strategies and diagnosis. Protein structure and dynamics have typically been studied separately. Most of the commonly used biophysical approaches are limited in providing substantial details regarding the combination of both structure and dynamics. On the other hand, high-speed atomic force microscopy (HS-AFM), which simultaneously visualizes an individual protein structure and its dynamics in liquid in real time, can uniquely link the structure and the kinetic details, and it can also unveil novel insights. Although amyloidogenic proteins generate heterogeneously aggregated species, including transient unstable states during the aggregation process, HS-AFM elucidated the structural dynamics of individual aggregates in real time in liquid without purification and isolation. Here, we review and discuss the HS-AFM imaging of amyloid aggregation and strategies to optimize the experiments showing findings from Aβ and amylin, which is associated with type II diabetes, shares some common biological features with Aβ, and is reported to be involved in AD.

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“…Nucleation theory is widely applied to direct the crystallization of small molecule polymorphs, and nucleation driven control over amyloid structure has been used to 5 produce fibrils of sufficient purity for X-ray crystallography and solid-state NMR spectroscopy through repeated seeding (17,39). In addition to amyloid seeds, prior work has shown that exogenous materials, including nanoparticles, polymers, and small molecules can act as nucleants that influence the kinetics of amyloid aggregation (40)(41)(42)(43)(44). While the effect of these agents on the kinetics of amyloid formation has been widely studied, it is generally unclear how changing aggregation conditions dictates the structure of the resulting amyloid fibrils.…”

Section: Introductionmentioning

confidence: 99%

Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

Lucas

Pan

Verbeke

et al. 2020

Preprint

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The aggregation of Amyloid-b (Ab) is associated with the onset of Alzheimer's Disease (AD) and involves a complex kinetic pathway as monomers self-assemble into fibrils. A central feature of amyloid fibrils is the existence of multiple structural polymorphs, which complicates the development of disease-relevant structure-function relationships. Developing these relationships requires new methods to control fibril structure. In this work, we demonstrate that mesoporous silicas (SBA-15) functionalized with hydrophobic (SBA-PFDTS) and hydrophilic groups (SBA-PEG) direct the aggregation kinetics and resulting structure of Ab1-40 fibrils. The hydrophilic SBA-PEG had little effect on amyloid kinetics while as-synthesized and hydrophobic SBA-PFDTS accelerated aggregation kinetics. Subsequently, we quantified the relative population of fibril structures formed in the presence of each material using electron microscopy. Fibrils formed from Ab1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, Ab1-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter cross-over distances that were more structurally representative of fibrils found in AD patient-derived samples. Overall, these results suggest that mesoporous silicas and other exogenous materials are promising scaffolds for the de novo production of specific fibril polymorphs of Ab1-40 and other amyloidogenic proteins. Significance StatementA major challenge in understanding the progression of Alzheimer's Disease lies in the various fibril structures, or polymorphs, adopted by Amyloid-b (Ab). Heterogenous fibril populations may be responsible for different disease phenotypes and growing evidence suggests that Ab fibrils formed in vitro are structurally distinct from patient-derived fibrils. To help bridge 3 this gap, we used surface-functionalized mesoporous silicas to influence the formation of Ab1-40 fibrils and evaluated the distribution of resulting fibril polymorphs using electron microscopy (EM). We found that silicas modified with hydrophobic surfaces resulted in fibril populations with shorter cross-over distances that are more representative of Ab fibrils observed ex vivo. Overall, our results indicate that mesoporous silicas may be leveraged for the production of specific Ab polymorphs.

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Alzheimer's amyloid-beta intermediates generated using polymer-nanodiscs

Cited by 77 publications

References 25 publications

New lipid membrane technologies for reconstitution, analysis, and utilization of ‘living’ membrane proteins

New lipid membrane technologies for reconstitution, analysis, and utilization of ‘living’ membrane proteins

High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways

Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

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