Probing the interplay between amyloidogenic proteins and membranes using lipid monolayers and bilayers

https://doi.org/10.1016/j.cis.2013.10.015Get rights and content

Highlights

  • Lipid mono- and bilayers are useful models for studying membrane/protein interactions.

  • Membranes promote amyloidogenic protein conformational change and aggregation.

  • Electrostatic and hydrophobic interactions and crowding favor aggregation.

  • Amyloidogenic protein/membrane interactions induce permeability changes.

  • Several possible models of permeabilization are presented.

Abstract

Many degenerative diseases such as Alzheimer's and Parkinson's involve proteins that have a tendency to misfold and aggregate eventually forming amyloid fibers. This review describes the use of monolayers, bilayers, supported membranes, and vesicles as model systems that have helped elucidate the mechanisms and consequences of the interactions between amyloidogenic proteins and membranes. These are twofold: membranes favor the formation of amyloid structures and these induce damage in those membranes. We describe studies that show how interfaces, especially charged ones, favor amyloidogenic protein aggregation by several means. First, surfaces increase the effective protein concentration reducing a three-dimensional system to a two-dimensional one. Second, charged surfaces allow electrostatic interactions with the protein. Anionic lipids as well as rafts, rich in cholesterol and gangliosides, prove to play an especially important role. Finally, these amphipathic systems also offer a hydrophobic environment favoring conformational changes, oligomerization, and eventual formation of mature fibers. In addition, we examine several models for membrane permeabilization: protein pores, leakage induced by extraction of lipids, chaotic pores, and membrane tension, presenting illustrative examples of experimental evidence in support of these models. The picture that emerges from recent work is one where more than one mechanism is in play. Which mechanism prevails depends on the protein, its aggregation state, and the lipid environment in which the interactions occur.

Introduction

Several clinical syndromes, described as amyloid diseases, including Alzheimer's and Parkinson's, are caused by the aggregation of specific proteins and peptides. Amyloidogenic proteins or peptides of different amino acid compositions share a tendency to aggregate in a similar way. These similarities provide support for the hypothesis that amyloid aggregate interaction with membranes and/or receptors can be associated with a shared basic form of the aggregates rather than with the type of protein or peptide that forms the aggregates, as reviewed in [1]. Amyloidogenic proteins show similar pathways of fibrillization, including the formation of prefibrillar oligomers characterized by globular structures typically of few nanometers. These oligomers evolve into linear or annular structures, which then form insoluble fibrillar aggregates (Fig. 1). Amyloid fibrils (Fig. 2) have lengths in the micron range, diameters in the nanometer range, and, in tissues, they form clusters easily observed by optical microscopy after staining. This assembly of proteins or peptides into mature amyloid fibrils is a multistep process typical of a nucleation–polymerization pathway. Initially, the process is characterized by a lag phase, during which monomers oligomerize and form aggregation nuclei. These nuclei act as aggregation seeds and elongate into a variety of intermediates eventually evolving into mature fibrils characterized by a cross-β core structure [1], [2]. Following the aggregation kinetics of β2-microglobulin, a protein associated with dialysis-related amyloidosis, Yoshimura et al. showed that, under different experimental conditions, the protein follows two different aggregation pathways: either the formation of crystal-like amyloid fibrils or amorphous aggregates. Comparing the aggregation kinetics they found that only the first pathway is characterized by a sigmoidal profile [3]. Monte Carlo simulations show that a simple model involving molecules with two internal states may account for the sigmoidal profile generally observed in amyloid fibril aggregation [4].

It is generally accepted that in most cases the toxicity of amyloids is related to the existence of various intermediate structures that precede fibril formation and are characterized by a marked polymorphism [5], [6]. For the first time the X-ray derived atomic structure of a small toxic oligomer of αB crystallin has been determined and has been found to consist of six antiparallel beta strands [7]. The structure of Aβ aggregates, the main component of senile plaques in Alzheimer's disease, has been elucidated using a variety of techniques [8], [9], [10]. In addition, it has been shown that the same protein, in different environmental conditions (i.e. pH, temperature, solvent composition, ionic strength), may form aggregates of different toxicities [11], [12] or of different structures [13].

Lipid membranes are known to catalyze the formation of amyloid aggregates and the biophysical properties of the lipids themselves may be of particular importance in determining the properties of the aggregates [14], [15]. Significantly, it has been shown that in pathogenic conditions such as Alzheimer's disease, the composition of phospholipids in the brain is altered [16]. Conversely, disruption of membrane integrity caused by aggregate–membrane interaction results from both protein aggregate and membrane properties.

Despite the intense work in this field, a clear characterization of the amyloid intermediates and of the mechanism of their interaction with membranes is far from complete. In this review we focus on the importance of model systems (monolayers and bilayers) in elucidating the interplay between membrane-catalyzed oligomer formation and oligomer–membrane interactions that cause perturbation and disruption of the typical barrier properties of the cell membrane, eventually leading to cell death.

A lipid monolayer at the air–water interface or a self-assembled monolayer on solid support (SAM) is a basic model of a single membrane leaflet [17]. Therefore, such a simple model system can be employed to study the interactions occurring at the surface of biological membranes, and in particular to probe the interactions with amyloidogenic proteins. Lipid bilayers (BLMs), supported lipid bilayers (sBLMs), and vesicles are well-defined membrane model systems often amenable to molecular scale characterization techniques. By providing a variety of lipid environments they give insight into the modulating effects of membranes on protein aggregation, while measurements of ionic conductance, surface morphology and fluorescence leakage shed light on protein disruptive effects on membranes.

Section snippets

Protein aggregation in a membrane environment: The relevance of interfaces

The study of membrane-assisted fibrillogenesis (Fig. 3) has been inspired by many important questions with medical and physiological relevance, as amyloid aggregates exert their cytotoxic activity at cell membranes rather than in bulk [18]. The most intriguing questions raised in these studies are related to the role of membranes (in particular their lipid composition or the presence of lipid rafts) in determining oligomer formation and to the forces involved in oligomer–surface interactions. A

Monolayer destabilization

Interactions of amyloidogenic proteins with monolayers can result in protein insertion into the monolayer, altering its structure and behavior. Several factors, such as lipid headgroup charge, hydrocarbon chain packing, monolayer surface pressure and the presence of ions in the subphase modulate protein/monolayer interaction.

Protein insertion into a lipid monolayer results in an expansion of the surface pressure–area isotherm as compared to that of the pure lipid. Such effects have been

Conclusions

Work in the past decade has solidified several salient points in the interactions between amyloidogenic proteins and membranes. The interactions are mutual in that membranes catalyze the formation of protein aggregates, which then destroy the integrity of the membrane that led to their formation. In most cases it is these oligomers rather than mature amyloid fibers that are the toxic species. Both electrostatic interactions with the lipid headgroups and hydrophobic interactions with the

Acknowledgments

This work was partially supported by the University of Genova (Fondi di Ateneo) and a Faculty Research Fellowship Award and sabbaticals from Saint Lawrence University to N. Marano. HypF-N was a kind gift from the labs of Fabrizio Chiti and Massimo Stefani (University of Florence).

References (132)

  • M. Sani et al.

    Lipid matrix plays a role in Abeta fibril kinetics and morphology

    FEBS Lett

    (2011)
  • M. Stefani

    Structural features and cytotoxicity of amyloid oligomers: implications in Alzheimer's disease and other diseases with amyloid deposits

    Prog Neurobiol

    (2012)
  • S. Rocha et al.

    Peptide–surfactant interactions: consequences for the amyloid-beta structure

    Biochem Biophys Res Commun

    (2012)
  • C. Cecchi et al.

    A protective role for lipid raft cholesterol against amyloid-induced membrane damage in human neuroblastoma cells

    Biochim Biophys Acta-Biomembr

    (2009)
  • G. Gorbenko et al.

    Protein aggregation in a membrane environment

    Adv Protein Chem Struct Biol

    (2011)
  • Y.A. Domanov et al.

    Islet amyloid polypeptide forms rigid lipid–protein amyloid fibrils on supported phospholipid bilayers

    J Mol Biol

    (2008)
  • M. Zhu et al.

    Surface-catalyzed amyloid fibril formation

    J Biol Chem

    (2002)
  • A. Relini et al.

    Collagen plays an active role in the aggregation of beta2-microglobulin under physiopathological conditions of dialysis-related amyloidosis

    J Biol Chem

    (2006)
  • D. Xiao et al.

    Amphiphilic adsorption of human islet amyloid polypeptide aggregates to lipid/aqueous interfaces

    J Mol Biol

    (2012)
  • L. Nault et al.

    Human insulin adsorption kinetics, conformational changes and amyloidal aggregate formation on hydrophobic surfaces

    Acta Biomater

    (2013)
  • A. Relini et al.

    The two-fold aspect of the interplay of amyloidogenic proteins with lipid membranes

    Chem Phys Lipids

    (2009)
  • K. Matsuzaki

    Physicochemical interactions of amyloid [beta]-peptide with lipid bilayers

    Biochim Biophys Acta-Biomembr

    (2007)
  • P.T. Wong et al.

    Amyloid-β membrane binding and permeabilization are distinct processes influenced separately by membrane charge and fluidity

    J Mol Biol

    (2009)
  • B.D. van Rooijen et al.

    Lipid bilayer disruption by oligomeric α-synuclein depends on bilayer charge and accessibility of the hydrophobic core

    Biochim Biophys Acta-Biomembr

    (2009)
  • H. Ahyayauch et al.

    Binding of beta-amyloid (1–42) peptide to negatively charged phospholipid membranes in the liquid-ordered state: modeling and experimental studies

    Biophys J

    (2012)
  • H. Ding et al.

    β-Amyloid (1–40) peptide interactions with supported phospholipid membranes: a single-molecule study

    Biophys J

    (2012)
  • L. Kjaer et al.

    The influence of vesicle size and composition on alpha-synuclein structure and stability

    Biophys J

    (2009)
  • B.D. van Rooijen et al.

    Membrane binding of oligomeric alpha-synuclein depends on bilayer charge and packing

    FEBS Lett

    (2008)
  • G. De Franceschi et al.

    Structural and morphological characterization of aggregated species of alpha-synuclein induced by docosahexaenoic acid

    J Biol Chem

    (2011)
  • J. Varkey et al.

    Alpha-synuclein oligomers with broken helical conformation form lipoprotein nanoparticles

    J Biol Chem

    (2013)
  • C. Canale et al.

    Natively folded HypF-N and its early amyloid aggregates interact with phospholipid monolayers and destabilize supported phospholipid bilayers

    Biophys J

    (2006)
  • M. Engel et al.

    Islet amyloid polypeptide inserts into phospholipid monolayers as monomer

    J Mol Biol

    (2006)
  • C. Lee et al.

    How type II diabetes-related islet amyloid polypeptide damages lipid bilayers

    Biophys J

    (2012)
  • P. Calvez et al.

    Parameters modulating the maximum insertion pressure of proteins and peptides in lipid monolayers

    Biochimie

    (2009)
  • G. Thakur et al.

    Surface chemistry of lipid raft and amyloid Aβ (1–40) Langmuir monolayer

    Colloids Surf B Biointerfaces

    (2011)
  • J. Fantini et al.

    Molecular basis for the glycosphingolipid-binding specificity of alpha-synuclein: key role of tyrosine 39 in membrane insertion

    J Mol Biol

    (2011)
  • L. Mapelli et al.

    Toxic effects of expanded ataxin-1 involve mechanical instability of the nuclear membrane

    Biochim Biophys Acta (BBA) — Mol Basis Dis

    (2012)
  • G. Valincius et al.

    Soluble amyloid beta-oligomers affect dielectric membrane properties by bilayer insertion and domain formation: implications for cell toxicity

    Biophys J

    (2008)
  • T. Mirzabekov et al.

    Pore formation by the cytotoxic islet amyloid peptide amylin

    J Biol Chem

    (1996)
  • R. Kayed et al.

    Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases

    J Biol Chem

    (2004)
  • F. Chiti et al.

    Protein misfolding, functional amyloid, and human disease

    Annu Rev Biochem

    (2006)
  • Y. Yoshimura et al.

    Distinguishing crystal-like amyloid fibrils and glass-like amorphous aggregates from their kinetics of formation

    Proc Natl Acad Sci U S A

    (2012)
  • R. Gaspari et al.

    Aggregation phenomena in a system of molecules with two internal states

    Phys Rev E

    (2007)
  • V.N. Uversky

    Mysterious oligomerization of the amyloidogenic proteins

    FEBS J

    (2010)
  • A. Laganowsky et al.

    Atomic view of a toxic amyloid small oligomer

    Science

    (2012)
  • J.C. Stroud et al.

    Toxic fibrillar oligomers of amyloid-β have cross-β structure

    Proc Natl Acad Sci U S A

    (2012)
  • A. Petkova et al.

    Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils

    Science

    (2005)
  • S. Campioni et al.

    A causative link between the structure of aberrant protein oligomers and their toxicity

    Nat Chem Biol

    (2010)
  • M. Kosicek et al.

    Phospholipids and Alzheimer's disease: alterations, mechanisms and potential biomarkers

    Int J Mol Sci

    (2013)
  • H. Möwald

    Surfactant layers at water surfaces

    Rep Prog Phys

    (1993)
  • Cited by (40)

    • Aβ<inf>1-42</inf> peptide toxicity on neuronal cells: A lipidomic study

      2022, Journal of Pharmaceutical and Biomedical Analysis
    • Membrane-mimetic systems for biophysical studies of the amyloid-β peptide

      2019, Biochimica et Biophysica Acta - Proteins and Proteomics
      Citation Excerpt :

      Planar lipid layers have proven to be useful membrane models. The three main versions, i.e., monolayers, free-standing bilayers, and supported bilayers, have different pros and cons [76]. The monolayers are the simplest to prepare and use, but also the least similar to biological membranes.

    • Influence of self-assembly on the performance of antimicrobial peptides

      2018, Current Opinion in Colloid and Interface Science
      Citation Excerpt :

      For such effects, rafts, rich in cholesterol and gangliosides, play an important role as well, since amyloid formation may be favored by a locally higher binding of net cationic amyloidic peptides, in analogy to the effects of anionic charge density for raft-devoid membranes. Moreover, lipid membranes provide a hydrophobic environment favoring conformational changes, oligomerization, and subsequent fiber formation [77,78]. In addition to such effects of the polar headgroup, also acyl group properties and presence of sterols may affect peptide binding, incorporation, and amyloid formation through effects on membrane phase behavior and mechanical properties.

    View all citing articles on Scopus
    View full text