R E V I E W A R T I C L E
Membrane and surface interactions of Alzheimer’s Ab peptide – insights into the mechanism of cytotoxicity Thomas L. Williams and Louise C. Serpell
School of Life Sciences, University of Sussex, Falmer, East Sussex, UK
Keywords Alzheimer’s disease; amyloid-b peptide; calcein leakage; GM1 ganglioside; membrane bilayers; protein misfolding
Correspondence L. C. Serpell, School of Life Sciences, University of Sussex, Falmer, East Sussex BN1 9QG, UK Fax: +44 (0)1273 678433 Tel: +44 (0)1273 877363 E-mail: l.c.serpell@sussex.ac.uk; T. Williams, Department of Physics, Drexel University, 12-908, 3141 Chestnut Street, Philadelphia, PA 19104, USA Fax: +1 215 895 5934 Tel: +1 215 895 1989 E-mail: tlw55@drexel.edu
Alzheimer’s disease is the most common form of dementia and its patho- logical hallmarks include the loss of neurones through cell death, as well as the accumulation of amyloid fibres in the form of extracellular neuritic pla- ques. Amyloid fibrils are composed of the amyloid-b peptide (Ab), which is known to assemble to form ‘toxic’ oligomers that may be central to disease pathology. Ab is produced by cleavage from the amyloid precursor protein within the transmembrane region, and the cleaved peptide may retain some membrane affinity. It has been shown that Ab is capable of specifically binding to phospholipid membranes with a relatively high affinity, and that modulation of the composition of the membrane can alter both mem- brane–amyloid interactions and toxicity. Various biomimetic membrane models have been used (e.g. lipid vesicles in solution and tethered lipid bilayers) to examine the binding and interactions between Ab and the membrane surfaces, as well as the resulting permeation. Oligomeric Ab has been observed to bind more avidly to membranes and cause greater perme- ation than fibrillar Ab. We review some of the recent advances in studying Ab–membrane interactions and discuss their implications with respect to understanding the causes of Alzheimer’s disease.
(Received 4 April 2011, revised 27 May 2011, accepted 20 June 2011)
doi:10.1111/j.1742-4658.2011.08228.x
Amyloid b assembly and fibrillization
is well established that
Amyloid-b peptide (Ab) accumulation in the brain is one of the pathological hallmarks of Alzheimer’s dis- ease (AD). Ab assembles to form amyloid fibrils that deposit in amyloid plaques in the neuropil [1]. How- ever, the deposition of fibrillar Ab in the brain does not necessarily correlate with the severity or progres- sion of AD [2]. It has been suggested that Ab exerts some of its deleterious effects on cells earlier on during the peptide self-assembly, which may trigger a cascade of processes [3]. Ab is a secreted peptide cleaved from
the transmembrane protein, amyloid precursor protein (APP), whereby cleavage at the C- and N-termini by c- and b-secretase, respectively, results in the release of the Ab peptide [4]. The predominant forms of Ab pep- tide are those with 40 or 42 residues and the relative ratios of these forms are altered in Alzheimer’s patients the 42-residue form [5]. It (Ab42) generally forms fibrils more quickly than the 40-residue form (Ab40) and this may be as a result of the additional hydrophobic isoleucine and alanine at
Abbreviations Ab, amyloid-b peptide; Ab40, amyloid-b peptide1-40; Ab42, amyloid-b peptide1-42; AD, Alzheimer’s disease; AFM, atomic force microscopy; APP, amyloid precursor protein; DMSO, dimethyl sulfoxide; DOPC, 1,2-dioleoyl-sn-glycerol-3-phophocholine; GM1, monosialoganglioside GM1; HFIP, hexafluoroisopropanol; hIAPP, human islet amyloid polypeptide; LUV, large unilamellar vesicles; NMDA, N-methyl D-aspartate; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; POPG, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-(1-glycerol); PrPc, cellular, non-infectious form of prion protein.
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these two residues the C-terminus. Substitution of with hydrophilic amino acids results in a decrease in aggregation kinetics [6]. Two hydrophobic regions of Ab42 at residues 17–21 and 31–42 are considered to be important for fibril structure [7]. Certain residues also play a key role in aggregation because substitution of the phenylalanine20 residue for the hydrophilic glu- tamic acid residue in the Ab sequence reduces the aggregation propensity [8] and the toxic effect of the peptide [9]. The assembly may be driven in part by burial of the hydrophobic regions of the Ab peptide.
investigations
small
of
stabilizes the interacting polypeptide chains without any pre facto chemical modifications, and also has been used experimentally to show the oligomer distri- butions of Ab40 and Ab42. Bitan et al. [12] reported oligomer frequency distributions similar to those found in simulations and concluded that Ab40 and Ab42 oli- gomerize through distinct pathways. Electron micros- copy reveals a difference in the rate of assembly of Ab40 and Ab42 peptides through oligomers, to pro- tofibrils and subsequently to fibrils (Fig. 2A–F). Struc- tural ‘neurotoxic’ Ab40 assemblies have indicated that they contain a high level of b-sheet conformation, similar to fibrils [13].
The fibrillogenesis of Ab is assumed to occur through various pathways and, for Ab42, it has been suggested that pentamer or hexamer paranuclei (Fig. 1A,B) form the basic subunits of the protofibril (Fig. 1C), leading to a beaded chain-like structure as a result of self-association of the paraneuclei [10]. Oligo- mer size distributions have been determined both experimentally and using computer simulations, with both yielding similar frequency distributions. Initially, computer simulations show that both Ab40 and Ab42 have similar size distributions peaking at monomers. As assembly progresses, the mean occurrence probabil- ity for Ab40 peaks at dimers and monotonically decreases. Whereas, Ab42 shows a greater frequency distribution centred around trimers, followed by a sig- nificant decrease in tetramers and another peak at pen- tamers, which monotonically decreases after pentamers [11]. The computer simulations show that Ab40 oligo- mers form a more compact confirmation compared to Ab42 oligomers because of the additional conforma- tional freedom associated with the additional isoleu- [11]. Photo-induced cine and alanine amino acids covalently proteins, of cross-linking
unmodified
A
B
C
several
Amyloid fibrils can be formed in vitro from a broad range of proteins and peptides, and these fibrils share a core structure consisting of a cross-b architecture [14,15]. It has been suggested that fibrillization to form amyloid could be a common feature of all peptides and proteins [16] because, under certain denaturing condi- tions, typically soluble proteins such as insulin can form amyloid-like fibres [17]. Inter- and intramolecular forces have been shown to influence fibrillization and the assembly of amyloid fibres, as well as act to stabilize the fibrils. The hydrophobicity and net charge, as well as a sequence propensity to form secondary structures, have been shown to modulate amyloidogenicity [18,19]. Short peptides are able to form amyloid-like fibrils in vitro and provide an ideal model system for structural studies. X- ray fibre diffraction of amyloid fibrils formed by a cen- tral region of the Ab peptide (11–25) revealed a cross-b arrangement of extended b-strands [20]. Crystal struc- tures of amyloid-like fibrils formed by the peptides with the sequences GNNQQNY and NNQQNY show that the cross-b spine formed in the amyloid fibres consists of a pair of b-sheets, whereby the residue side chains interdigitate to form a steric zipper along the length of the fibre [21]. Structural studies of full-length (40 or 42) residue Ab have been possible using hydrogen ⁄ deute- rium exchange [7], solid-state NMR [22] and electron microscopy [23]. It has been established that Ab assem- bles to form a parallel, in-register structure in which Ab forms two b-strands connected by a b-bend that stack up via hydrogen bonding to form a pair of b-sheets [7,24]. Electron microscopy shows that the fibrils are ‘protofilaments’, which twist composed of around one another to form the mature fibril [25] (Fig. 2). Many of the inter- and intramolecular interac- tions involved in the assembly of amyloidogenic pep- tides may also be involved in the interactions between peptides and surfaces, including membranes [26].
Fig. 1. Discrete molecular dynamics simulations using a four-bead protein model [88]. (A) Ab42 monomer, (B) hexamer and (C) protofi- bril-like assembly comprising 28 Ab42 peptides. N-terminal Asp1 is colour-coded red to highlight the distribution of N-termini in the assembly. Figure adapted from [88], with thanks to Dr Brigita Urbanc.
The preparation of amyloidogenic peptides, espe- cially Ab, can result in experimentally observed differ- ences. It has been shown that the mode of preparation
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A
B
C
D
E
F
G
H
I
Fig. 2. Transmission electron micrographs showing the growth of statically incubated amyloid fibrils. Fibrillogenesis of 100 lM Ab42 (A–C) and Ab40 (D–F) with time, from freshly dissolved (A, D) to 24 h of incubation (B, E) and, finally, after 72 h of incubation (C, F). Ab42 forms long straight fibrils more rapidly than Ab40 at the same starting concentration of peptide. Peptides were incubated at room temperature without agitation. Comparison of fibrils grown with and without lipids: (G) fibrils formed by 100 lM Ab42 alone after 72 h of incubation; (H) 1 mgÆmL)1 LUVs alone; and (I) freshly dissolved Ab42 (10 mM) incubated with 1 mgÆmL)1 LUVs for 72 h. The images show that Ab42 assembles in the presence of LUVs to form long straight amyloid-like fibrils that appear to associate with the membranes. The LUVs remain intact despite the observed leakage of self-quenching dye induced by freshly dissolved Ab42 [31].
including turns and b-hairpins [27,28]. HFIP bonds, contamination has been implicated in inducing mem- brane leakage and cell toxicity [29]. Dimethylsulfoxide (DMSO) is commonly used in the preparation of Ab and other amyloid-forming peptides. However, dissolu- tion of b2-microglobulin in the polar solvent, DMSO, has been shown to cause destruction of the hydrogen bond networks in amyloid fibril aggregates by acting as a strong proton acceptor [30]. Therefore, recent pro- tocols have included a critical step that removes resid- ual solvents [31].
can significantly affect the secondary structure of the peptide, and therefore may alter its fibrillization and assembly characteristics. The pretreatment of amyloi- dogenic peptides has been investigated extensively, and harsh solvents and treatment methods have been employed to render the peptide homogenous, disaggre- gated and unstructured. The addition of trifluoroetha- nol and, more recently, hexafluoroisopropanol (HFIP), has been used to pretreat Ab, aiming to dissagregate the peptide and render it a-helical; however, it has also been shown to promote other intramolecular hydrogen
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Ab interactions with solid surfaces
The assembly of amyloid fibrils in solution and on sur- faces is reviewed in more detail elsewhere [37].
Ab interactions with lipids
leading to alterations
amyloid–membrane
studying
The proteolytic cleavage of the APP from its trans- membrane location results in the release of the Ab peptide, and therefore the soluble peptide may retain affinity for the cellular membrane or certain features of the membrane. Phospholipids are composed of two hydrophobic fatty acids bound to carbon atoms in the glycerol, which in turn is joined to the hydrophobic polar headgroup via a negatively-charged phosphate group. Therefore, phospholipids are amphipathic. The phospholipid bilayer of cellular membranes provides an extensive surface for amyloid interactions and com- prises one of the primary cellular structures that Ab comes into contact with. Plasma membranes have been suggested as a possible target for the cytotoxicity asso- ciated with Ab and therefore in the pathology of AD. The interactions between lipid bilayers and Ab have been studied using a variety of biophysical techniques, including CD, fluorescence spectroscopy, surface plas- mon resonance and atomic force microscopy (AFM). Biomimetic unilamellar vesicles provide a simple sys- interactions tem for because bilayer composition can be stringently regu- lated, and it is possible to encapsulate solute molecules within the aqueous space [31].
Solid surfaces influence the assembly of amyloid-form- ing peptides, and the adsorption of the peptide to the surface can promote fibrillization. Hydrophobicity, surface charge and surface roughness have all been shown to play a role in influencing fibre assembly because the surface may act to increase the local con- centration and modulate the conformation of the pep- tide, in the propensity for association [32]. Hydrophobic surfaces such as nega- tively-charged Teflon have been used to mimic the nonpolar plane of membranes. At physiological pH, Teflon and Ab are both negatively charged, and there- fore electrostatic interactions would suggest partial repulsion between the surface and the peptide. How- ever, at pH 7, it has been shown that Ab40 adsorbs to the nonpolar substrate [33] as a result of protein dehy- dration effects contributing to the adsorption of pep- tides to hydrophobic surfaces [26]. The adsorption of Ab40 and Ab42 to hydrophobic Teflon particles at pH 7 also promotes aggregation and fibrillization of the peptide [32], and adsorption of Ab42 to hydrophobic graphite leads to nucleation-controlled growth of fibrils [34]. Conversely, the adsorption of Ab to hydrophilic silica, which has been used to mimic the polar, charged membrane surface, only occurs when the peptide is positively charged at pH 4 and 7 [35]. This suggests that Ab adsorption to hydrophilic surfaces is mainly driven by electrostatic interactions. The adsorption of Ab42 on hydrophilic mica occurred quickly; however, the aggregation was slow and gradual coalescence was observed [34]. Similar behaviours between surfaces and other amyloid-forming peptides have been observed. Fibrillization of the recombinant amyloidogenic light chain variable domain was observed on negatively- charged mica, although no fibres were apparent on the positively-charged Teflon despite adsorption of peptide on both surfaces, suggesting the significant involvement of electrostatic interactions in assembly [36].
this
and
The influence of surfaces on amyloid fibril formation can also affect fibril morphology. The fibrillization of Ab on hydrophilic mica surfaces lead to the formation of particulate, pseudomicellar aggregates, whereas, at higher concentrations, linear protofibrillar assemblies were formed [34]. Moreover, Ab assembly on highly- ordered pyrolytic graphite results in uniform, elon- gated sheets, with fibre formation being observed in three directions orientated 120o to each other, which is suggested to result from hydrophobic interactions that maximize contact between the carbons in the graphite and the hydrophobic residues within the Ab chain [34].
Simple, one-lipid species vesicles prepared from soy- bean phosphatidylcholine have been used to examine the effect of lipid-induced Ab aggregation using an absorbance assay. It was demonstrated that, in the absence of lipid vesicles, the aggregation of Ab40 fol- lowed typical lag-growth kinetics. In the presence of neutral phosphatidylcholine vesicles, the lag time was delayed and the half-aggregation time increased by 30%, dependent on lipid concentration [38]. Nucle- ation and elongation were also influenced by the pres- ence of neutral lipid surfaces, and appeared to decrease when lipids were incubated with Ab40. Sec- ondary structural changes in Ab conformation as a consequence of lipids have been demonstrated by CD [39]. When solubilized in the hydrophobic solvent, trifluoroethanol, Ab40 and Ab42 show characteristic a-helical structures and, upon dissolution in sodium resulted in the peptide becoming phosphate, unstructured [39]. The presence of various lipids, including egg yolk phosphatidylglycerol, bovine brain phosphatidylserine phosphatidylethanolamine, resulted in a strong 218 nm CD minima indicative of b-sheet structure [39]. It was suggested that the head- group charge of the phospholipids contributes to the
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association between Ab and the membrane via electro- static interactions. The affinity of DMSO-solubilized Ab40 to 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocho- line (POPC) was found to be weaker than for 1-palmi- toyl-2-oleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (POPG) [40], supporting the view that the headgroups mediate binding.
compared
lipids
to
membrane disruption may either be the result of the formation of defects within the lipid bilayer or the for- mation of membrane-spanning channels. We use the term ‘defects’ here to mean the penetration ⁄ permeation of the lipid bilayer by amyloidogenic peptides that results in a noncontinuous membrane surface and the emergence of defects ⁄ holes or deformations within the bilayer structure. By contrast to the conclusion that Ab is able to form pores, Kayed et al. [44] showed that size exclusion chromatography-purified Ab42 oligo- mers (eluting at (cid:2) 90–110 kDa) caused an increased conductance across mixed-lipid bilayers in a concentra- tion-dependent manner. The results were interpreted as showing that conductance was nonselective for differ- ent ions and was inconsistent with specific pore forma- tion [44]. Further studies indicated that Ab42 caused increased conductance by interacting with the mem- brane surface, possibly by spreading the lipid head- groups apart, leading to membrane thinning, and thus a lowering of the membrane dielectric barrier and increased conductance [45]. Recently, however, these studies have been called into question by the results obtained in a study by Capone et al. [29] who sug- gested that membrane thinning was a result of HFIP contamination.
encapsulating
lipid vesicles
Studies using
Moreover, the mass adsorption between Ab40 and POPG was between 50–100% greater than Ab40 mass adsorption to POPC membranes and it appeared that, although POPC binding did not result in aggregation of the Ab peptide, POPG liposomes markedly increased aggregation. Interactions between fresh Ab40 and lipid vesicles of various compositions have shown that the the surface charge and hydrophobicity of membranes can modulate the binding of the Ab to the membrane surface. It was reported that Ab40 preferen- tially bound to negatively-charged phosphatidylglycer- ol membranes and composite membranes containing negatively-charged neutrally- charged membranes. The adsorption of 1 day fibril- lized Ab40 showed slight variations in the binding kinetics compared to fresh Ab. The affinity between fibrillar Ab and negatively-charged membranes is lower than the affinity between fibrillar Ab and neutrally- charged membranes. The electrostatic forces were found to be more significant between fresh Ab and membranes, although hydrophobic forces were consid- ered to be more important between fibrillar Ab and membranes [41].
early oligomeric
calcium ions
self- quenching fluorescent dyes such as calcein and fluores- cein have been used to study the effect of Ab assembly on membrane integrity. The addition of Ab42 to 1,2-dimyristoyl-sn-glycero-3-phosphocholine large uni- lamellar lipid vesicles (LUVs) encapsulating calcein demonstrated that soluble Ab42 causes permeation of the membranes and the release of the encapsulated fluorescent dye [31]. It was also demonstrated that, as the Ab42 peptide assembles into fibres in solution, the propensity to cause membrane permeation decreases, and mature fibres show a lack of ability to cause permeation. Interestingly, early olig- omeric Ab added to the vesicles elongates to form amyloid fibrils that appear to be associated with the membranes on electron microscopy [31] (Fig. 2). This is similar to the damage to 1,2-dioleoyl-sn-glycerol- (DOPC) ⁄ 1,2-dioleoyl-sn-glycerol-3- 3-phosphocholine phosphoserine calcein-loaded vesicles caused by human islet amyloid polypeptide (hIAPP) [46]. This was sug- gested to be caused by mechanical disruption of the lipid membrane as a result of the associated growth of amyloid-like fibrils [46]. Confocal microscopy has been used to observe the release of different sized Alexa Fluor dyes from the aqueous space of giant unilamel- lar vesicles as a result of Ab42-induced permeation. It was reported that the smaller Alexa546 (Mr (cid:2)1300) dye leaked from the membranes before the diffusion of the
AFM studies have been used to monitor the assem- bly of Ab42 on lipid bilayers composed of brain total extract, which provides a physiologically relevant ratio of acidic and neutral phospholipids. In such a study, the peptide was prepared in trifluoroacetic acid fol- lowed by incubation in trifluoroethanol. Small aggre- gates, (cid:2) 5–7 nm in height, initially associated with the membrane and, after 7 h of in situ incubation, small aggregates (cid:2) 5–15 nm in height were observed [42]. Incubation of Ab42 with the bilayers revealed very little membrane disruption. Interestingly, this prepara- tion of Ab42 did not appear to ‘grow’ on the mem- brane bilayer [42]. To investigate the possibility that Ab42 is able to form ion channels, Ab42 was incorpo- rated into planar bilayers. AFM revealed multimeric complexes protruding above the lipid bilayer. The indi- vidual channels showed varying numbers of Ab subun- its, to ranging from a two subunit arrangement rectangular four subunit structures and hexagonal six subunit structures [43]. Electrophysiological records supported the view that the Ab was creating channels that allowed the passage of [43]. it was suggested that the mechanism of Therefore,
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larger Alexa488 (Mr 10 000) dye, whereas the overall shape of the vesicles was maintained [47]. It was sug- gested that Ab is able to influence the cohesion of the components of the membranes [47]. Anisotropy has been used to monitor the effects of Ab39 and Ab40 on the membrane fluidity of POPC and POPG membranes containing fluorescent 1,6-diphenyl-1,3,5-hexatriene dye. Freshly-prepared Ab39 and Ab40 did not have any observable effects to membrane fluidity but, upon oligomerization of the peptides, membrane fluidity was decreased in a time- and concentration-dependent man- ner. This affect was more striking for those peptides assembled at pH 6 rather than neutral pH [48]. This is assumed to be the result of a conformational difference between aggregates of Ab formed at the two different pHs that, in turn, influence the exposure of hydropho- bic regions and association with the membrane [48].
Ab interactions with sterols
treatment with statins, which lower neuronal choles- terol, has been shown to decrease the amount of Ab secreted by neurons. This is probably because both c- and b-secretases are found in cholesterol-rich domains within the membrane and therefore a lowering of cho- lesterol reduces secretase activity [53]. The cholesterol content of membranes may play a role in modulating Ab penetration because > 20% w ⁄ w cholesterol induces a membrane transition from a fluid-disordered to fluid-ordered phase, and Ab25–35 is unable to inter- calate into the membrane bilayer [54,55]. However, using monolayer surface pressure measurements, it was shown that Ab40 spontaneously inserts into monolay- ers containing a 30 mol% cholesterol to phospholipid ratio and, in this context, Ab adopts an a-helical struc- ture. Below this molar ratio, Ab40 prefers to associate with the membrane surface region with a greater b- sheet content [56]. The involvement of cholesterol in Ab secretion and processing appears to be very complex and its involvement in AD has been reviewed [52–56].
The cholesterol
in
the
ratio
nondemented
brains
demonstrated
cells
It was
[61].
to phospholipid ratio has been reported to affect the extent of high-affinity Ab bind- ing to synthetic lipid membranes because pure phos- pholipid mixtures showed very little peptide binding. It was suggested that this increase in peptide-membrane affinity was a result of the involvement of cholesterol in altering membrane fluidity and structure [57]. Oligo- meric, but not monomeric, Ab42 was shown to insert into POPC ⁄ cholesterol membranes. Oligomer insertion was also found to occur in negatively-charged mono- layers but not in the absence of cholesterol [58]. By contrast, cell culture assays using PC-12 and SH-SY5Y cells showed an inverse relationship between choles- terol content and Ab40 surface binding, where choles- terol-depleted higher Ab-cell surface binding [59]. It was suggested that this increase in Ab binding may increase the internalization of Ab to a greater extent because the decreased membrane cholesterol content affects the fluidity and permabiliza- tion of membranes [60]. The inclusion of < 30% cho- lesterol in POPC membranes gave rise to channel activity induced by the addition of Ab40, whereas no channel activity was observed in POPC only mem- branes suggested that cholesterol-rich membranes prevented the fibrillization of Ab40 by increasing the incorporation of the peptide within the membranes.
[51]. Changes
inaccessible
Ab interactions with membrane receptors
The complex nature of biological membranes includes various membrane receptors such as glycolipid and
Cholesterol is a vital component of eukaryotic cell membranes, and influences membrane fluidity, perme- ability and dielectric properties. Cholesterol causes the immobilization of the first few hydrocarbon groups of the phospholipid molecules, making the lipid bilayer less viscoelastic and therefore decreaseing the mem- brane permeability to small water-soluble molecules. Cholesterol also prevents the crystallization of the hydrocarbons and prevents phase shifts within the membrane. In AD, the cholesterol content of certain regions of the brain can be markedly different from the same regions in nondemented brains. In the grey mat- ter of the superior temporal gyrus, the cholesterol to phospholipid mole ratio in AD brains is 0.46 ± 0.08 whereas is 0.66 ± 0.05; however, the cholesterol content in the cerebellum is not significantly different [49]. This reduc- tion of (cid:2) 33% between the cholesterol content of the temporal gyrus of AD brains and nondemented brains could significantly affect the fluidity of the neuronal them more susceptible to membranes and render Ab-induced permeation. Moreover, the decrease in cholesterol ⁄ phospholipid ratio in AD brains may affect the cleavage of APP and cause an elevation in gener- ated Ab [50]. A 4 A˚ decrease in the membrane bilayer width (D-space) could ensure that the cleavage site is more accessible to secretase enzymes, which otherwise may be in cholesterol contents as a result of ageing may also play a role in reduced amyloid degradation because the amyloid degradation pathway may involve the activation of plasmin in cholesterol-rich domains and be inhibited levels are reduced [52]. However, when cholesterol
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Membrane interactions of Alzheimer’s Ab peptide
for
sialic
acid to be
studied. It was shown that neither the ceramide, nor sialic acid moieties could induce the structural transi- tions of Ab40 and Ab42 alone, implying that it is criti- cal associated with the carbohydrate backbone for Ab structural transitions to occur [70]. A small structural transition of Ab42 at pH 6 was observed with ceramide-containing lipid vesicles, and it was suggested that the presence of a hydrogen acceptor in the form of the amide carbonyl and a hydrogen donor in the form of a hydroxyl group on the ceramide was responsible for this structural transi- tion. Fibrillization of Ab40 in the presence and absence of GM1 in the membrane showed that GM1 causes increased Ab fibrillization. Additionally, GM1 decreased the fibrillization lag of Ab40 from 5–6 days to 1 day, with an observed structural transition from a random conformation to b-sheet within 3 h [71]. Elec- trostatic interactions may play a pivotal role in mediat- ing Ab–GM1 interactions (Ab is slightly positively charged and the GM1 headgroup is negatively charged); the pressure exerted on the membrane as a result of Ab40 inserting into GM1-containing mem- branes in a low ionic-strength aqueous environment at pH 5.5 is greater than when the ionic strength sur- rounding the membrane is increased [68]. Increasing the pH to 7.2 (where the Ab is negatively charged) leads to a decrease in Ab insertion pressure because the interaction between the negatively-charged Ab and negatively-charged GM1 becomes repulsive.
glutamate receptors. Both ionotropic glutamate recep- tors such as N-methyl d-aspartate (NMDA) receptors and metabotropic glutamate receptors such as metabo- tropic glutamate receptors have been implicated in the alteration of synaptic activity. The binding of Ab olig- omers to synaptic plasma membranes alters the diffu- sion of metabotropic glutamate receptors and causes abnormal Ca2+ mobilization [62]. Moreover, the administration of Ab42 to cortical neurons was shown to reduce the density of synaptic NMDA receptors on the cortical neuronal membranes, either by promotion of endocytosis of the cell surface receptors or preven- tion of the delivery of the NMDA receptors to the neuronal membranes, which has been shown to reduce both memory and learning [63]. Other receptors reported to bind to Ab oligomers include the cellular, form of prion protein (PrPc). At non-infectious nanomolar concentrations, Ab42 was able to bind to the PrPc receptor of mice engineered to express the PrPc protein, and caused significant synaptic dysfunc- tion [64]. Using surface plasmon resonance, synthetic Ab42 oligomers were shown to bind with a high affinity (Kd = 70 nm) to recombinant human prion protein, whereas Ab42 monomers and mature fibres did not bind to human prion protein receptors [65]. Therefore, the existence of one specific receptor for Ab membrane binding may not be a realistic sugges- tion; Ab may possess varying degrees of affinity to a range of membrane receptors and certain receptors may be more significant in modulating Ab induced toxicity.
functions,
including as cell
Gangliosides are a group of glycosphingolipids com- posed of a hydrophilic sialic acid terminal sugar exposed to the external environment and a hydropho- bic ceramide moiety that is embedded within the mem- brane [66]. Gangliosides have been reported to serve a variety of type-specific markers, as differentiation and developmental markers, and as receptors and mediators of cell adhesion [67], and they comprise 5–10% of the outer membrane leaf- let [68]. The affinity between gangliosides and Ab can vary, with a reported Kd of 1.2 · 10)6 m between Ab42 and disialoganglioside GD1a and 7.7 · 10)7 m between Ab42 and disialoganglioside GT1b, with the highest affinity between Ab42 and monosialoganglio- side GM1 (GM1) with a Kd of 5.2 · 10)7 m [69]. The expression of gangliosides within the membrane bilayer induces structural transitions in Ab. Upon dilution of Ab in NaCl ⁄ Pi, the peptide initially adopts a random structure but, subsequent to the interaction with GM1, the Ab transitions into a a ⁄ b conformation at pH 7 and into a b conformation at pH 6 [70]. In the same study, the significance of the ganglioside moieties was
Gangliosides have also been shown to modulate the permeation of biological membranes and, using dye release assays, the inclusion of GM1 within the bilay- ers resulted in a significantly greater permeation by Ab compared to membranes without GM1 [31]. Exclusion of GM1 from lipid vesicles containing calcein showed a 57% reduction in Ab42-induced membrane perme- ation compared to when GM1 was present within the vesicle membrane [31]. This increase in permeation of GM1-containing membranes was attributed to hydro- phobic interactions between the solvent-exposed aro- matic residue stacks on the glycolipid sugar rings of GM1. This stacking interaction is driven by the net positive charge of the sugar ring in close proximity to the p-electron cloud of the amino acid aromatic ring, where the polar moiety of the GM1 provides a com- plementary surface for the polar amino acids of the Ab to form hydrogen bonds [72]. The permeation of calcein-loaded LUVs has also been shown to be Ab concentration- and pH-dependent, where increasing concentrations of Ab40 resulted in a monotonic increase in the permeation of dye-filled LUVs [70,73] and a 42% reduction in permeation of pH 7 vesicles compared to pH 6 vesicles [73].
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Ab–membrane interactions and permeation: pore formation or detergent effects
to form a more
recognized as a potential mechanism associated with AD, and was shown to be involved in the amyloid cas- cade hypothesis, where elevated Ca2+ was suggested to be a consequence of both tau-phosphorylation and cell death [79]. The formation of Ca2+ channels in lipid bilayers was proposed in AD cytotoxicity because the incorporation of Ab40 into planar phosphatidylserine bilayers formed channels that generated linear current– voltage relationships in symmetrical solutions [80]. The channels were directly observed in planar membranes by AFM, which consisted of an 8–12 nm doughnut- shaped structure with a 1–2 nm internal pore cavity that protrudes (cid:2) 1 nm above the embedded bilayer surface [43,81]. Computational modelling of Ab42 insertion into a lipid bilayer that approximately matches the thickness of DOPC bilayers showed that Ab42 octamers separate into distinct tetrameric units. By achieving this structure, the tetrameric units stabi- lize the membrane-inserted octamer, and lead to the conclusion that the pore formed by the octamer might consist of tetrameric and hexameric b-sheet subunits, which were considered to be consistent with reported AFM studies [82]. The transmembrane pore has been proposed to form between six hexamers, which span the bilayer and merge stable 36-stranded b-barrel arrangement. This model was favoured because it was proposed that the parallel b-barrels formed by the N-terminal segments of the peptide form the lining of the pores and could account for the cationic selectivity observed for metal ions such as Zn2+ [83].
The third proposed model
The mechanism associated with Ab cytotoxicity has not been determined definitively, although the involve- ment of the membrane surface has been implicated as a possible source of Ab-induced toxicity. The solvent exposure of the N-terminal region of Ab has been sug- gested to play a critical role in mediating toxicity. Assembly of Ab42 in the presence of certain C-termi- nal fragments causes the Ab42 N-terminus to be less solvent exposed and significantly reduces cell toxicity, and it was suggested that the N-terminus may play a critical role in mediating Ab-cellular interactions [74]. The membrane may act as an extensive surface for Ab to aggregate and fibrillize, and membranes serve as a primary barrier to Ab entry into the cytosol of cells. Therefore, it is not unexpected that Ab may preferen- tially bind to certain domains or receptors within these membranes. The pre-processing location of APP from the transmembrane region also suggests that Ab may retain certain affinities for the membrane. Therefore, a potential cytotoxic mechanism involving the cytoplas- mic membranes maybe justified. Ab42 has been shown to tightly insert into membranes, with a small portion being peripherally associated with lysosomal mem- branes, leading to destabilization of lysosomal mem- branes and the induction of toxicity [75,76]. The association was shown to be pH-dependent and neu- tralization of the lysosomal pH in differentiated PC12 cells decreased Ab membrane insertion [76]. The amphipathic nature of amyloid oligomers has been suggested to contribute to their capacity to penetrate and insert into membranes, coat or lie on the surface of the membranes, or potentially act as cell-penetrating peptides [77].
surface
Three structurally divergent modes of membrane- mediated toxicity have been proposed for Ab, which include carpeting of the peptide on one leaflet of the membrane surface, resulting in an asymmetric pressure between the two leaflets and the leakage of small mole- cules [78]. This model is believed to be of minor physi- ological relevance for amyloid diseases because it has been demonstrated to cause similar membrane damage for both hIAPP and non-amyloidogenic mouse IAPP [46]. The carpet model was also proposed to explain the exponential leakage kinetics and absence of a lag phase in hIAPP and mouse IAPP-induced LUV permeation [46].
The formation of stable pores and ion channels is the second model proposed for amyloid-induced toxicity. The disruption of Ca2+ homeostasis has been
is based on the deter- gent-like effects of amyloid-forming peptides on lipid membranes. This mechanism of permeation is pro- posed to occur through the membrane association of the amyloid-forming peptides in the form of micelle- like structures. Membrane permeation occurs at high local concentrations of the peptide on the membrane surface, either after the surface is covered with peptide monomers or oligomers, or through the association between membrane-bound amyloid [84]. The initial interaction is electrostatically driven, where the peptide preferentially binds to either the phospholipid head- group or receptors on the membrane surface, which is the peptide so that followed by alignment of the hydrophilic the phospholipid head faces groups. The peptide orientates so that the hydropho- bic residues reside towards the hydrophobic core of the membrane, and this is followed by disintegration of the membrane by disruption of the bilayer curva- ture [84]. The detergent effect results from the surfac- tant-like properties associated with the amphiphilic peptide causing a reduction in membrane surface
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Fig. 3. Schematic diagram that depicts three possible mechanisms of Ab-induced membrane damage: carpeting, pore forma- tion and the detergent effect. Adapted with permission from Butterfield and Lashuel [86].
state and result in nonspecific permeation of the mem- branes; the formation of amyloid-induced pores or ion channels may occur as a result of specific receptor- amyloid-induced permeation.
Concluding remarks
of
the
and
IAPP
leads to cell dysfunction and The mechanism that death caused by amyloidogenic peptides related to dis- ease remains controversial. Effects on organelles and cellular homeostasis mechanisms have been suggested [3]. One way of explaining all of these mechanisms from plasma membrane permeation to mitochondrial dysfunction and lysosomal leakage is the potential effect of oligomers on membranes. Therefore, mem- brane damage could represent a unifying explanation for all different avenues of the toxic effect.
peptide
and
in
We have reported on studies that aimed to examine the mechanisms of Ab-related membrane damage giv- ing weight to the idea that Ab can disrupt membrane integrity. However, any conclusions made regarding the mechanism of membrane disruption by amyloido- genic peptides, such as Ab, are hampered by differ- ences experimental preparation conditions. It may be that several mechanisms are responsible (Fig. 3) and it remains to be seen which of the proposed mechanisms is most important.
tension, where it forms a hole by the removal of lipid from the bilayer, either in the outer leaflet, which results in membrane thinning, or both leaflets, which results in holes [78]. hIAPP has been reported to extract lipids from cellular membranes and be incor- porated into the forming amyloid deposits; confocal microscopy of rhodamine-labelled giant unilamellar vesicles showed a loss of barrier function of the mem- branes and colocalization DOPC ⁄ phosphatidylethanolamine lipids using amy- loid-specific and lipid-specific dyes [85]. Structural analogies and sequence homologies between Ab and IAPP have been reported and it was suggested that Ab may therefore possess an ability to cause lipid extraction of membranes in a similar manner to IAPP [86,87]. The mechanism of toxicity associated with amphiphilic amyloid-forming peptides may not be exclusively related to a single mechanism such as pore formation or detergent-like effects but more likely a collection of these mechanisms (Fig. 3). Each mecha- nism may be involved in the disruption of biological membranes, either at a particular stage during the assembly of the amyloid-forming peptide or during a particular pathway taken during the peptide fibrilliza- tion. As shown with other amphiphilic peptides, the carpet and detergent models may well only occur when the peptide is in its monomeric or small oligomeric
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