A novel pathway for amyloids self-assembly in aggregates at nanomolar concentration mediated by the interaction with surfaces

Banerjee, Siddhartha; Hashemi, Mohtadin; Lv, Zhengjian; Maity, Sibaprasad; Rochet, Jean‐Christophe; Lyubchenko, Yuri L.

doi:10.1038/srep45592

Cited by 46 publications

(62 citation statements)

References 41 publications

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“…The quantitative analysis of the number and sizes of aggregates shown in Fig. 1b demonstrate that these parameters increase gradually over time, which is similar to our earlier results obtained for Aβ42 aggregation on mica surface 10 . To characterize the role of electrostatics in the aggregation of Aβ42 on POPC, we performed experiments in the presence of 150 mM NaCl.…”

Section: Resultssupporting

confidence: 89%

“…We used time-lapse AFM to directly visualize the aggregation process of Aβ42 protein on supported lipid bilayers formed from 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS) using the approaches described in [10][11][12][13] . A solution of 10 nM Aβ42 was placed on top of the SLBs, assembled on the mica substrate, and imaged at room temperature.…”

Section: Resultsmentioning

confidence: 99%

“…Protein solution was prepared as described previously 10 . Briefly, measured amount of Aβ42 was dissolved and sonicated for 5 min in 100 µl of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) to remove any preformed oligomers.…”

Section: Preparation Of Aβ42 Solutionmentioning

confidence: 99%

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Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

Banerjee

Hashemi

Zagorski

et al. 2019

Preprint

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The assembly of polypeptides and proteins into nanoscale aggregates is a phenomenon observed in a vast majority of proteins. Importantly, aggregation of amyloid β (Aβ) proteins is considered as a major cause for the development of Alzheimer's disease. The process depends on various conditions and typical test-tube experiments require high protein concentration that complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here we demonstrate that Aβ42 monomers at the membrane bilayer are capable of self-assembling into aggregates at physiologically low concentrations, and the membrane in this aggregation process plays a role of a catalyst. We applied all-atom molecular dynamics to demonstrate that the interaction with the membrane surface dramatically changes the conformation of Aβ42 protein. As a result, the misfolded Aβ42 rapidly assembles into dimers, trimers and tetramers, so the on-surface aggregation is the mechanism by which amyloid oligomers are produced and spread.Self-assembly is a widely spread phenomenon in biology and the assembly of proteins into nanoaggerates with various morphologies is a phenomenon of a special attention for decades. Evidence strongly suggests that the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), is due to the self-assembly of amyloid β (Aβ) and α-synuclein oligomers, respectively 1 . These oligomers appear to disrupt the cell homeostasis, by various mechanisms, resulting in the early stages of neurodegenerative diseases 2-4 . The amyloid cascade hypothesis (ACH) 5 is the major model that describes the pathology of AD and other neurodegenerative diseases 5-9 . However, several orders higher concentrations of Aβ compared with that found in vivo are required for the spontaneous aggregation of Aβ, which challenges the validity of ACH. We have discovered that amyloid proteins and peptides are capable of assembling into aggregates at nanomolar concentration range if the process occurs at the surface-liquid interface 10,11 . In the present study, we monitored the aggregation of Aβ42 at its physiologically relevant low concentration (10 nM) on supported lipid bilayers (SLBs) formed by 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-snglycero-3-phospho-L-serine (POPS).Direct time-lapse AFM imaging revealed Aβ42 aggregation on the bilayer surfaces, while no self-assembly of Aβ42 was detected in bulk solution. We performed computational modeling of the aggregation process on the membrane surfaces to demonstrate that interaction of Aβ42 dramatically changes the conformation of Aβ42 monomers. Moreover, membrane-bound Aβ42 proteins trigger the assembly of dimers, trimers, and tetramers, propagating the misfolded states of the Aβ42 molecules. Thus, interaction with membranes results in the transition of Aβ42 into the aggregation-prone, misfolded conformations. Such conformations have not been reported in

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

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Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

Banerjee

Hashemi

Zagorski

et al. 2019

Preprint

Self Cite

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“…Results demonstrated that the assembly of proteins into aggregates took place at a low protein concentrations, while no aggregation was detected in bulk solution (17). Importantly, time-lapse AFM experiments in liquid did not reveal fast mobility of molecules at the mica-liquid interface (17). These data were also in line with observations performed using time-lapse high-speed AFM (18,19).…”

Section: Main Textsupporting

confidence: 80%

“…AFM has been used to directly observe the accelerated aggregation of amyloid peptides and the alpha-synuclein (α-Syn) protein on mica surfaces. Results demonstrated that the assembly of proteins into aggregates took place at a low protein concentrations, while no aggregation was detected in bulk solution (17). Importantly, time-lapse AFM experiments in liquid did not reveal fast mobility of molecules at the mica-liquid interface (17).…”

Section: Main Textmentioning

confidence: 93%

A molecular model of the surface-assisted protein aggregation process

Pan

Banerjee

Zagorski

et al. 2018

Preprint

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The importance of cell surfaces in the self-assembly of proteins is widely accepted. One biologically significant event is the assembly of amyloidogenic proteins into aggregates, which leads to neurodegenerative disorders like Alzheimer's and Parkinson's. The interaction of amyloidogenic proteins with cellular membranes appears to dramatically facilitate the aggregation process. Recent findings indicate that, in the presence of surfaces, aggregation occurs at physiologically low concentrations, suggesting interaction with surfaces plays a critical role in the disease-prone aggregation process. However, the molecular mechanisms behind onsurface aggregation remain unclear. Here we provide a theoretical model that offers a molecular explanation. According to this model, monomers transiently immobilized to surfaces increase the local monomer protein concentration and thus work as nuclei to dramatically accelerate the entire aggregation process. This theory was verified by experimental studies, using mica surfaces, to examine the aggregation kinetics of amyloidogenic-synuclein protein (α-Syn) and non-amyloidogenic cytosine deaminase APOBEC3G (A3G).

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Dynamics of Amyloid Formation from Simplified Representation to Atomistic Simulations

Nguyen

Tufféry

Derreumaux

2022

Methods in Molecular Biology

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Amyloid fibril formation is an intrinsic property of short peptides, non-disease proteins and proteins associated neurodegenerative diseases. Aggregates of the Aβ and tau proteins, the α-synuclein protein, and the prion protein are observed in the brain of Alzheimer's, Parkinson's and prion disease patients, respectively. Due to the transient short-range and long-range interactions of all species and their high aggregation propensities, the conformational ensemble of these devastating proteins, the exception being for the monomeric prion protein, remains elusive by standard structural biology methods in bulk solution and in lipid membranes. To overcome these limitations, an increasing number of simulations using different sampling methods and protein models have been performed. In this article, we first review our main contributions to the field of amyloid protein simulations aimed at understanding the early aggregation steps of short linear amyloid peptides, the conformational ensemble of the Aβ40/42 dimers in bulk solution, and the stability of Aβ aggregates in lipid membrane models. Then we focus on our studies on the interactions of amyloid peptides/inhibitors to prevent aggregation, and long amyloid sequences, including new results on a monomeric tau construct.

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A novel pathway for amyloids self-assembly in aggregates at nanomolar concentration mediated by the interaction with surfaces

Cited by 46 publications

References 41 publications

Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

A molecular model of the surface-assisted protein aggregation process

Dynamics of Amyloid Formation from Simplified Representation to Atomistic Simulations

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