Model membrane size-dependent amyloidogenesis of Alzheimer's amyloid-β peptides

Kinoshita, Misaki; Kakimoto, Erina; Terakawa, Mayu S.; Lin, Yuxi; Ikenoue, Tatsuya; So, Masatomo; Sugiki, Toshihiko; Ramamoorthy, Ayyalusamy; Goto, Yuji; Lee, Young Ho

doi:10.1039/c6cp07774a

Cited by 43 publications

(39 citation statements)

References 60 publications

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“…As recently demonstrated peptide-based nanodiscs have additional advantages over MSP-nanodiscs [54]. While Aβ interaction with cell membrane accelerates its aggregation [20,38,39], here we show the solvent exposed charged residues in the peptide belt associated with lipids in the nanodisc play a protective role by delaying Aβ40 aggregation (Fig. 5).…”

Section: Discussionsupporting

confidence: 73%

“…It should also be noted that the presence of small size nanodiscs were found to significantly deaccelerate Aβ40’s aggregation as compared to lipid-free Aβ aggregation. Based on the experimental studies using lipid vesicles, previous studies have shown that Aβ40 aggregation is promoted by very low lipid concentration [20,38,39]. However, as shown in Fig.2c, a very low DMPC concentration in nanodiscs (at 1:1 DMPC:Aβ molar ratio) exhibited a linear correlation between 4F concentration and Aβ40 aggregation (T lag ) kinetics indicating its counter protective role against Aβ40 fibrillation.…”

Section: Resultsmentioning

confidence: 86%

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Nanodisc-Forming Scaffold Protein Promoted Retardation of Amyloid-Beta Aggregation

Sahoo

Genjo

Cox

et al. 2018

Journal of Molecular Biology

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Peptidic nanodiscs are useful membrane mimetic tools for structural and functional studies of membrane proteins, and membrane interacting peptides including amyloids. Here, we demonstrate anti-amyloidogenic activities of a nanodisc-forming 18-residue peptide (denoted as 4F), both in lipid-bound and lipid-free states by using Alzheimer's amyloid-beta (Aβ40) peptide as an example. Fluorescence-based amyloid fibrillation kinetic assays showed a significant delay in Aβ40 amyloid aggregation by the 4F peptide. In addition, 4F-encased lipid nanodiscs, at an optimal concentration of 4F (>20 μM) and nanodisc size (<10 nm), significantly affect amyloid fibrillation. A comparison of experimental results obtained from nanodiscs with that obtained from liposomes revealed a substantial inhibitory efficacy of 4F-lipid nanodiscs against Aβ40 aggregation and were also found to be suitable to trap Aβ40 intermediates. A combination of atomistic molecular dynamics simulations with NMR and circular dichroism experimental results exhibited a substantial change in Aβ40 conformation upon 4F binding through electrostatic and π-π interactions. Specifically, the 4F peptide was found to interfere with the central β-sheet-forming residues of Aβ40 through substantial hydrogen, π-π, and π-alkyl interactions. Fluorescence experiments and coarse-grained molecular dynamics simulations showed the formation of a ternary complex, where Aβ40 binds to the proximity of peptidic belt and membrane surface that deaccelerate amyloid fibrillation. Electron microscopy images revealed short and thick amyloid fibers of Aβ40 formed in the presence of 4F or 4F-lipid nanodsics. These findings could aid in the development of amyloid inhibitors as well as in stabilizing Aβ40 intermediates for high-resolution structural and neurobiological studies.

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Section: Discussionsupporting

confidence: 73%

Section: Resultsmentioning

confidence: 86%

Nanodisc-Forming Scaffold Protein Promoted Retardation of Amyloid-Beta Aggregation

Sahoo

Genjo

Cox

et al. 2018

Journal of Molecular Biology

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“…Numerous reports over the last decade using reconstituted phospholipid vesicles indicate formation of aggregates along off-fibril forming pathways, paving a way for the generation of structurally-diverse oligomers [107–109]. Recently, Aβ42 aggregation on SUV and large unilamellar vesicles (LUV) from POPC lipids showed formation of polymorphic aggregates with distinct biophysical characteristics [110]. In this study, LUVs with high POPC concentrations suppressed amyloid formation that affected fibrillation kinetics, as opposed to those with low POPC concentrations, demonstrating the effect of concentration gradients along the liposome surface in modulating aggregation pathways.…”

Section: Interaction and Modulation Of Aβ Aggregation By Lipidsmentioning

confidence: 99%

Cause and consequence of Aβ – Lipid interactions in Alzheimer disease pathogenesis

Rangachari

Dean

Rana

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Self-templating propagation of protein aggregate conformations is increasingly becoming a significant factor in many neurological diseases. In Alzheimer disease (AD), intrinsically disordered amyloid-β (Aβ) peptides undergo aggregation that is sensitive to environmental conditions. High-molecular weight aggregates of Aβ that form insoluble fibrils are deposited as senile plaques in AD brains. However, low-molecular weight aggregates called soluble oligomers are known to be the primary toxic agents responsible for neuronal dysfunction. The aggregation process is highly stochastic involving both homotypic (Aβ-Aβ) and heterotypic (Aβ with interacting partners) interactions. Two of the important members of interacting partners are membrane lipids and surfactants, to which Aβ shows a perpetual association. Aβ-membrane interactions have been widely investigated for more than two decades, and this research has provided a wealth of information. Although this has greatly enriched our understanding, the objective of this review is to consolidate the information from the literature that collectively showcases the unique phenomenon of lipid-mediated Aβ oligomer generation, which has largely remained inconspicuous. This is especially important because Aβ aggregate "strains" are increasingly becoming relevant in light of the correlations between the structure of aggregates and AD phenotypes. Here, we will focus on aspects of Aβ-lipid interactions specifically from the context of how lipid modulation generates a wide variety of biophysically and biochemically distinct oligomer sub-types. This, we believe, will refocus our thinking on the influence of lipids and open new approaches in delineating the mechanisms of AD pathogenesis. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

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“…Recent studies have proposed that solubility and supersaturation are fundamental factors in understanding protein aggregation in solution. [18][19][20][21][22][23][24][25] Proteins over the solubility limit must form insoluble aggregates such as amyloid fibrils from the thermodynamic point of view. However, apparently soluble proteins prior to the phase transition to insoluble solid states are often detected due to kinetic trapping by the metastability of supersaturation, which is certainly linked to the cause and effect relationship with the nucleation and lag time.…”

Section: Hiv Infections Continue To Be a Major Health Issuementioning

confidence: 99%

“…Recent studies have proposed that solubility and supersaturation are fundamental factors in understanding protein aggregation in solution . Proteins over the solubility limit must form insoluble aggregates such as amyloid fibrils from the thermodynamic point of view.…”

Section: Introductionmentioning

confidence: 99%

Semen‐derived amyloidogenic peptides—Key players of HIV infection

Lee

Ramamoorthy

2018

Protein Science

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Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed.

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Model membrane size-dependent amyloidogenesis of Alzheimer's amyloid-β peptides

Cited by 43 publications

References 60 publications

Nanodisc-Forming Scaffold Protein Promoted Retardation of Amyloid-Beta Aggregation

Nanodisc-Forming Scaffold Protein Promoted Retardation of Amyloid-Beta Aggregation

Cause and consequence of Aβ – Lipid interactions in Alzheimer disease pathogenesis

Semen‐derived amyloidogenic peptides—Key players of HIV infection

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