Abstract
The amyloid-β (Aβ) peptides are key molecules in Alzheimer’s disease (AD) pathology. They interact with cellular membranes, and can bind metal ions outside the membrane. Certain oligomeric Aβ aggregates are known to induce membrane perturbations and the structure of these oligomers—and their membrane-perturbing effects—can be modulated by metal ion binding. If the bound metal ions are redox active, as e.g., Cu and Fe ions are, they will generate harmful reactive oxygen species (ROS) just outside the membrane surface. Thus, the membrane damage incurred by toxic Aβ oligomers is likely aggravated when redox-active metal ions are present. The combined interactions between Aβ oligomers, metal ions, and biomembranes may be responsible for at least some of the neuronal death in AD patients.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
The amyloid-β peptides and Alzheimer’s disease
The amyloid β peptides (Aβ) are considered to be key players in the molecular mechanism(s) behind Alzheimer´s disease (AD) [1,2,3]. The peptides are 39–43 residues long and derived by proteolytic cleavage from the transmembrane protein amyloid-β precursor protein (AβPP). The amino acid sequence of the 42 residues long peptide [i.e., Aβ(1–42)] is shown in Fig. 1. The N-terminal segment 1–16 is relatively hydrophilic with six charged residues. After residue 16, the peptide is more hydrophobic, particularly the segments comprising residues 17–21 and 30–42, where the last segment belongs to the transmembrane part of AβPP. Although the Aβ peptides are generally unstructured in aqueous solution, the two hydrophobic segments may form a transient hairpin structure with residues 22–29 as a turn [1]. The Aβ peptides form amyloid material in aqueous solution in a self-aggregation process that ends in formation of insoluble fibrils with a well-defined amyloid structure. The hairpin conformation of the monomers is likely an important structural motif in this aggregation process [1]. Heterogeneous intermediate stages involve so-called oligomeric forms that typically consist of 2–60 Aβ monomers. The structures of these oligomers are different from fibrils and less well understood [3,4,5]. The oligomeric aggregates are generally considered to be the most cell-toxic Aβ species, especially those formed by the Aβ(1–42) peptide, and to be the major initiators of the AD disease mechanism(s) [4,5,6].
The structural and other properties of possibly toxic Aβ oligomers will depend on the surrounding environment [7]. Here, we discuss two important environmental parameters: metal ions and membranes. Membrane is a wide term that in this context ranges from biomimetic model membranes to biomembranes in general, including cellular plasma and organellar membranes. The lipid composition of biomembranes varies between different organelles, cell types, and even organisms. It is very challenging to mimic the complex and dynamic features of a living membrane in vitro or in silico, including regulation of the lipid phase and membrane asymmetry. Thus, model membranes with reduced complexity are often used in biophysical and molecular studies [8]. Most of the studies on interactions with metal ions and model membranes have been carried out for monomeric Aβ, but oligomeric aggregates likely have similar (although perhaps not identical) interactions. Here, we discuss mainly how Aβ could interact in parallel with both metal ions and membranes, and how such parallel interactions could be relevant for the AD disease mechanism(s). It should be pointed out that these interactions may be important also for the Aβ antimicrobial activity, which appears to benefit the host organisms (including humans) [9,10,11].
Aβ metal binding
AD patients are known to display altered metal homeostasis [12], and the insoluble plaques found in the brains of AD patients—which are a hallmark of AD pathology and which to a large part consist of aggregated Aβ peptides [3, 13]—are known to contain high levels of elements such as Ca, Cu, Fe, and Zn [14, 15]. The Aβ monomers are known to bind metal ions [2, 16] and the N-terminal Aβ segment (i.e., aa 1–16) displays several residues with a high propensity for metal ion binding (i.e., three His, one Tyr, and four negatively charged amino acids; cf. Figure 1) [2]. At neutral pH, Zn(II) and Cu(II) ions have been shown to bind to the His6, His13, and His14 residues as well as to the N-terminus of the monomeric Aβ peptide [17,18,19], displaying Kd values around 1–50 nM for Aβ/Cu(II) and 0.1–1 µM for Aβ/Zn(II) interactions [20, 21]. At lower pH, alternative binding ligands have been observed [20]. Metal ions such as Fe(II) [22], Mn(II) [23], and Pb(IV) [24] also display binding sites that mainly involve the Aβ histidines, possibly in combination with the negatively charged Asp and Glu residues [23] or the Tyr10 residue [24]. Different interactions have been observed for different ions of the same metal, e.g., Cu(I)/Cu(II) and Pb(II)/Pb(IV) ions [24, 25]. As many different metal ions can bind the Aβ N-terminal part with similar coordination ligands and binding affinities, binding competition between different metal ions with different properties—such as redox-active and non-redox-active ions—might be of biological relevance in AD pathology.
While binding of metal ions is known to affect Aβ aggregation [16, 26,27,28,29], for example, by reducing the net charge of the complex and thereby reducing the electrostatic repulsion between two Aβ peptides, this aggregation will in turn affect the peptides’ metal-binding properties: bringing several Aβ peptides together in aggregates arguably increase their capacity for metal coordination, as several Aβ N-termini then may wrap around a single metal ion. For example, Ca(II) ions display no specific binding to Aβ monomers, but exhibit profound interaction with Aβ aggregates [30]. The brain contains ions of several d-block transition metals, and the in vivo concentrations of Cu, Fe, and Zn ions are in the range for relevant Aβ interactions [31]. Metal ions are, however, tightly regulated in biological systems and the freely available metal ion pool is consequently limited. Metal–Aβ interactions therefore most likely occur in certain locations, such as the synaptic cleft, where Cu and Zn ions are secreted in close proximity to the AβPP and Aβ proteins. In addition to metal ions, cationic molecules such as polyamines may interact with the N-terminal part of Aβ and induce similar effects as bound metal ions [32, 33].
Redox reactions and Aβ toxicity
There is strong evidence that oxidative stress is involved at an early stage in AD development [34]. The brain has a high consumption of dioxygen and is a vulnerable target for deleterious oxidative stress reactions. Redox-active metal ions like those of Cu and Fe are known to interact with molecular oxygen to form so-called reactive oxygen species (ROS), typically transient free radicals like the superoxide anion (\(O_{2}^{{ -^{ \bullet } }}\)) and hydroxyl radicals (\(HO^{ \bullet }\)) that are harmful to living cells. By redox cycling in the presence of a reducing agent, Cu and Fe ions can catalyze the formation of the free radicals from dioxygen and hydrogen peroxide [35]. Manganese ions are also redox active, but the concentration of Mn in the brain is much lower than the Cu and Fe concentrations. When ROS are not readily detoxified by antioxidants, they can react with almost all biomolecules in living cells, including lipids in the cell membrane. Some in vitro studies indicate that ROS species formed under controlled chemical conditions can penetrate through bilayer vesicle membranes [36, 37].
Compared to free available Cu ions in aqueous solution, Aβ/Cu(II) complexes decrease the ROS formation [35]. Notably, it has been reported that the murine Aβ peptide, where three N-terminal residues are substituted, binds Cu ions with a higher affinity and generates even less ROS compared to the human Aβ peptide [38]. The transient Aβ/Cu(II) and Aβ/Cu(I) coordination modes facilitate electron transfer and redox cycling via Fenton and Haber–Weiss reactions involving an in-between state [35]. In addition to various biomolecules in the cell, the Aβ peptide itself is also a target for molecular modifications induced by oxidative stress. The N-terminal residues in close proximity to the metal-binding site are exposed to hydroxyl radicals that can oxidize in particular Asp and the aromatic side-chains of Tyr, Phe, and His residues.
As the amyloid plaques in AD brains contain increased concentrations of Cu and Fe ions, i.e., in the millimolar range [15], it stands to reason that ROS are generated around these plaques. Cells and molecules around these plaques will therefore suffer oxidative damage, and this is one possible mechanism for AD cell toxicity. The aggregated Aβ peptides in these plaques have been shown to contain dityrosine cross-links [39, 40], which typically are formed as a result of oxidative stress. Whether these cross-links mostly form before, after, or during the Aβ aggregation process in AD brains is still unknown [39]. In vitro studies using Cu ions and hydrogen peroxide to induce dityrosine have shown that cross-linked Aβ dimers display slower self-aggregation [41], and thus spend longer time in the oligomeric and likely neurotoxic states. It is, however, unclear if dityrosine-linked Aβ peptides are more or less toxic than native Aβ. Nevertheless, chemical modifications of the Aβ peptides, induced by ROS that has been generated by redox-active metal ions, are a possible factor in AD neuronal death.
Aβ interactions with membranes and membrane mimetica: pores and leakage
Biomembranes are another factor known to affect Aβ aggregation and amyloid formation [42], and both increased and decreased fibrillation rates have been observed [43, 44]. Interactions between Aβ peptides and membranes, by various mechanisms, have been suggested to be important for AD pathology [45, 46]. Interactions with membrane models typically induce changes in the Aβ secondary structure, as demonstrated with, e.g., large unilamellar vesicles (LUVs), bicelles, planar lipid membranes, and micelles of detergents such as SDS [8, 47,48,49,50]. The local Aβ concentration can increase when the peptides bind to a membrane, which might facilitate Aβ self-interactions on the membrane surface [9, 10]. A balance seems to exist between peptide insertion into the membrane, which stabilizes the secondary structure of the hydrophobic parts of Aβ, and surface-catalyzed aggregation [51]. This balance likely varies with the lipid composition and other factors in the local environment.
In many molecular studies of Aβ aggregation, micelle-forming surfactants/detergents have been used in otherwise aqueous solvents, to achieve a simple membrane-mimetic environment [8, 52]. For example, in the presence of sodium dodecyl sulfate (SDS) micelles, the more hydrophobic parts of the peptide insert into the micelle as two α-helical regions 16–24 and 29–35, held together by the unstructured 25–28 loop [49]. The N-terminal segment (residues 1–15) is left free outside the micelle, and is able to bind metal ions like in an aqueous solution and with similar binding affinity [53, 54]. Figure 2 shows a schematic picture of how the Aβ peptide is located partly inside and partly outside of the surface of an SDS micelle, and how it is able to bind a metal ion with ligands in the N-terminal segment of the peptide.
Several models of membrane-induced toxicity have been proposed for Aβ, including leakage through pore structures, by membrane thinning, or by mechanical disruption of the membrane by growing Aβ aggregates [51, 55, 56]. Aggregated Aβ species appear to be more capable of reacting with the membrane than monomeric Aβ. A two-step model for membrane disruption has been presented, where an initial formation of cationic-specific pores is followed by general membrane damage by a detergent-like mechanism [57]. As the Aβ concentration reaches the critical limit required to damage the membrane, the overall membrane conductance increases in the presence of the oligomers, possibly due to pores being formed across the membrane. This is called the “barrel-stave model” or general membrane leakage [58, 59]. Although the formation of cell-toxic oligomeric states is influenced by the presence of membranes, the oligomers that are formed conversely affect the properties of nearby membranes. It has, for example, been proposed that Aβ can recruit cholesterol and ganglioside lipids as these specifically bind to the peptide [60, 61], effectively forming a lipid–peptide microdomain with altered membrane properties.
Membrane pore formation and metal ions
A specific type of membrane disturbance would be formation of membrane pores allowing passage of certain molecules (e.g.. small molecules, ions of calcium and other metals) in and out of the cell. Such pores, which could be rather heterogeneous in terms of size and properties, have been identified by a number of methods, including single-channel electrical recording, atomic force microscopy and molecular dynamic modeling, using both biological and artificial model membranes [56, 62,63,64]. Protocols for preparation of relatively homogenous β-barrel pores, formed by Aβ(1–42) but not Aβ(1–40), have recently been presented [4, 5]. It has been shown that certain metal ions, such as Zn(II), may bind to the Aβ aggregates and block pore leakage [57, 65]. One in vivo study showed that addition of Zn(II) or removal of Ca(II) ions inhibited Aβ toxicity, while addition of Cd(II) ions (which are known inhibitors of native calcium channels) or antioxidants did not [66, 67]. This might be related to Zn(II) but not Cd(II) ions displaying specific binding to the Aβ N-terminal region [18, 24], as another study showed that various ions and molecules that interact specifically with the Aβ His13 and His14 residues could block leakage in planar lipid bilayers, and stop cytotoxicity in rat neurons [68], thus indicating similar mechanisms in artificial and biological membranes. Zinc ions have interestingly also been shown to block the leakage caused by truncated Aβ peptides that lack the metal-binding domain, such as Aβ(17–42) [69]. This indicates different ion specificity for the channel, in addition to the suggested histidine gating. Thus, Ser26 has been proposed as an important cation-binding residue in the internal channel opening [61]. Zn(II) or Cu(II) ion binding has been shown to structurally convert the C-terminal part of Aβ into a helical conformation inside the membrane, thus preventing formation of the β-sheet structures considered important for aggregation [70]. Binding to other metal ions has also been shown to affect the structure of Aβ species in membranes and their related cytotoxicity [71]. Metal ion bridges between oligomeric species might bring together and stabilize pore structures in the membrane environment [70, 72]. Binding of redox-active metal ions capable of generating oxygen radicals could lead to stabilization of pore structures—cell toxic or not—e.g., via formation of ROS-induced covalent dityrosine cross-links (see discussion above) [41, 73]. Thus, in addition to modulating the toxic activity of oligomeric pore structures, Cu and Fe ions bound to Aβ aggregates located halfway into a membrane may add additional damage by generating high concentration of ROS species just outside the membrane surface. Even though these ions will generate less ROS when bound to Aβ species than in their free form, the local concentration of Cu and Fe ions could be rather high around Aβ aggregates, as a large number of Aβ N-termini—ready to attract metal ions—would be positioned outside the membrane/aggregate surface (Fig. 2).
Possible pathways for toxic mechanisms related to Aβ interactions with membranes and metal ions are shown in Fig. 3. The metal-related effects are: promoting aggregation by coordinating more than one Aβ peptide (A, E), generating ROS that is harmful in general and in particular creates dityrosine-linked Aβ dimers (B), and blocking calcium leakage by binding to the Aβ pore (H). The membrane-related effects are: inducing changes in Aβ secondary structure (D), promoting general Aβ aggregation (D, E) and in particular formation of calcium-leaking Aβ pores (F). These effects may occur simultaneously or in sequence according to various pathways. It should be stressed that in our opinion, there are likely multiple toxic/harmful factors involved in the neuronal death observed in AD brains.
Concluding remarks
Recent research has shown many similarities between the amyloid formation and cell toxic mechanisms of different amyloidogenic peptides and proteins, such as Aβ, α-synuclein, and the islet amylin polypeptide (IAPP/amylin) [7, 74,75,76,77,78,79]. Common concepts may be membrane-perturbing oligomeric states and harmful oxidative stress caused by binding of redox-active Cu and Fe ions. For the Aβ peptides, the membrane activity may be related to a potential physiological role as an antimicrobial agent [9, 10]. Further studies are needed to more precisely pinpoint the role(s) of membranes and metals in the mechanisms of AD and other amyloid diseases.
References
Abelein A, Abrahams JP, Danielsson J et al (2014) The hairpin conformation of the amyloid β peptide is an important structural motif along the aggregation pathway. J Biol Inorg Chem 19:623–634. https://doi.org/10.1007/s00775-014-1131-8
Wärmländer S, Tiiman A, Abelein A et al (2013) Biophysical studies of the amyloid beta-peptide: interactions with metal ions and small molecules. ChemBioChem 14:1692–1704. https://doi.org/10.1002/cbic.201300262
Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608. https://doi.org/10.15252/emmm.201606210
Serra-Batiste M, Ninot-Pedrosa M, Bayoumi M et al (2016) Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments. Proc Natl Acad Sci 113:10866–10871. https://doi.org/10.1073/pnas.1605104113
Österlund N, Moons R, Ilag LL et al (2019) Native Ion Mobility-Mass Spectrometry reveals the formation of β-barrel shaped amyloid-β hexamers in a membrane-mimicking environment. JACS 141:10440–10450. https://doi.org/10.1021/jacs.9b04596
Lee SJC, Nam E, Lee HJ et al (2017) Towards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitors. Chem Soc Rev 46:310–323. https://doi.org/10.1039/c6cs00731g
Owen MC, Gnutt D, Gao M et al (2019) Effects of in vivo conditions on amyloid aggregation. Chem Soc Rev 48:3946–3996. https://doi.org/10.1039/c8cs00034d
Österlund N, Luo J, Wärmländer SKTS, Gräslund A (2018) Membrane-mimetic systems for biophysical studies of the amyloid-β peptide. Biochim Biophys Acta Proteins Proteom 1867:492–501. https://doi.org/10.1016/j.bbapap.2018.11.005
Gosztyla ML, Brothers HM, Robinson SR (2018) Alzheimer’s amyloid-β is an antimicrobial peptide: a review of the evidence. J Alzheimer’s Dis 62:1495–1506. https://doi.org/10.3233/JAD-171133
Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3:238–250. https://doi.org/10.1038/nrmicro1098
Moir RD, Lathe R, Tanzi RE (2018) The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimer’s Dement 14:1602–1614. https://doi.org/10.1016/j.jalz.2018.06.3040
Gerhardsson L, Lundh T, Londos E, Minthon L (2011) Cerebrospinal fluid/plasma quotients of essential and non-essential metals in patients with Alzheimer’s disease. J Neural Transm 118:957–962. https://doi.org/10.1007/s00702-011-0605-x
Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890. https://doi.org/10.1016/S0006-291X(84)80190-4
Miller LM, Wang Q, Telivala TP et al (2006) Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with β-amyloid deposits in Alzheimer’s disease. J Struct Biol 155:30–37. https://doi.org/10.1016/j.jsb.2005.09.004
Lovell MA, Robertson JD, Teesdale WJ et al (1998) Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci 158:47–52. https://doi.org/10.1016/S0022-510X(98)00092-6
Tiiman A, Palumaa P, Tõugu V (2013) The missing link in the amyloid cascade of Alzheimer’s disease—metal ions. Neurochem Int 62:367–378. https://doi.org/10.1016/j.neuint.2013.01.023
Sarell CJ, Syme CD, Rigby SEJ, Viles JH (2009) Copper(II) binding to amyloid-β fibrils of Alzheimer’s disease reveals a picomolar affinity: stoichiometry and coordination geometry are independent of Aβ oligomeric form. Biochemistry 48:4388–4402. https://doi.org/10.1021/bi900254n
Danielsson J, Pierattelli R, Banci L, Gräslund A (2007) High-resolution NMR studies of the zinc-binding site of the Alzheimer’s amyloid β-peptide. FEBS J 274:46–59. https://doi.org/10.1111/j.1742-4658.2006.05563.x
Dorlet P, Gambarelli S, Faller P, Hureau C (2009) Pulse EPR spectroscopy reveals the coordination sphere of copper(II) Ions in the 1–16 amyloid-β peptide: a key role of the first two N-terminus residues. Angew Chemi Int Ed 48:9273–9276. https://doi.org/10.1002/anie.200904567
Faller P, Hureau C (2009) Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-beta peptide. Dalton Trans. https://doi.org/10.1039/b813398k
Tõugu V, Karafin A, Palumaa P (2008) Binding of zinc(II) and copper(II) to the full-length Alzheimer’s amyloid-β peptide. J Neurochem 104:1249–1259. https://doi.org/10.1111/j.1471-4159.2007.05061.x
Bousejra-Elgarah F, Bijani C, Coppel Y et al (2011) Iron(II) binding to amyloid-β, the Alzheimer’s peptide. Inorg Chem 50:9024–9030. https://doi.org/10.1021/ic201233b
Wallin C, Kulkarni YS, Abelein A et al (2016) Characterization of Mn(II) ion binding to the amyloid-β peptide in Alzheimer’s disease. J Trace Elem Med Biol 38:183–193. https://doi.org/10.1016/j.jtemb.2016.03.009
Wallin C, Sholts SB, Österlund N et al (2017) Alzheimer’s disease and cigarette smoke components: effects of nicotine, PAHs, and Cd(II), Cr(III), Pb(II), Pb(IV) ions on amyloid-β peptide aggregation. Sci Rep 7:14423. https://doi.org/10.1038/s41598-017-13759-5
Alies B, Badei B, Faller P, Hureau C (2012) Reevaluation of copper(I) affinity for amyloid-beta peptides by competition with ferrozine—an unusual copper(I) indicator. Chem A Eur J 18:1161–1167. https://doi.org/10.1002/chem.201102746
Faller P, Hureau C, Berthoumieu O (2013) Role of Metal Ions in the Self-assembly of the Alzheimer’s amyloid-β peptide. Inorg Chem 52:12193–12206. https://doi.org/10.1021/ic4003059
Abelein A, Gräslund A, Danielsson J (2015) Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation. Proc Natl Acad Sci 112:5407–5412. https://doi.org/10.1073/pnas.1421961112
Hane F, Leonenko Z (2014) Effect of metals on kinetic pathways of amyloid-β aggregation. Biomolecules 4:101–116. https://doi.org/10.3390/biom4010101
Hane F, Tran G, Attwood SJ, Leonenko Z (2013) Cu2+ affects amyloid-β (1-42) aggregation by increasing peptide-peptide binding forces. PLoS ONE 8:e59005. https://doi.org/10.1371/journal.pone.0059005
Brännström K, Öhman A, Lindhagen-Persson M, Olofsson A (2013) Ca 2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner. Biochem J 450:189–197. https://doi.org/10.1042/bj20121583
Wallin C, Luo J, Jarvet J et al (2017) The amyloid-β peptide in amyloid formation processes: interactions with blood proteins and naturally occurring metal ions. Isr J Chem 57:674–685. https://doi.org/10.1002/ijch.201600105
Luo J, Mohammed I, Wärmländer SKTS et al (2014) Endogenous polyamines reduce the toxicity of soluble Aβ peptide aggregates associated with Alzheimer’s disease. Biomacromol 15:1985–1991. https://doi.org/10.1021/bm401874j
Luo J, Yu CH, Yu H et al (2013) Cellular polyamines promote amyloid-Beta (Aβ) peptide fibrillation and modulate the aggregation pathways. ACS Chem Neurosci 4:454–462. https://doi.org/10.1021/cn300170x
Tönnies E, Trushina E (2017) Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheimers Dis 57:1105–1121. https://doi.org/10.3233/JAD-161088
Cheignon C, Tomas M, Bonnefont-Rousselot D et al (2018) Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 14:450–464. https://doi.org/10.1016/j.redox.2017.10.014
Fortier CA, Guan B, Cole RB, Tarr MA (2009) Covalently bound fluorescent probes as reporters for hydroxyl radical penetration into liposomal membranes. Free Radic Biol Med 46:1376–1385. https://doi.org/10.1016/j.freeradbiomed.2009.02.023
Gamliel A, Afri M, Frimer AA (2008) Determining radical penetration of lipid bilayers with new lipophilic spin traps. Free Radic Biol Med 44:1394–1405. https://doi.org/10.1016/j.freeradbiomed.2007.12.028
Eury H, Bijani C, Faller P, Hureau C (2011) Copper(II) coordination to amyloid β: murine versus human peptide. Angew Chemi Int Ed 50:901–905. https://doi.org/10.1002/anie.201005838
Al-Hilaly YK, Williams TL, Stewart-Parker M et al (2013) A central role for dityrosine crosslinking of amyloid-β in Alzheimer’s disease. Acta Neuropathol Commun 1:83. https://doi.org/10.1186/2051-5960-1-83
Hensley K, Maidt ML, Yu Z et al (2018) Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation. J Neurosci 18:8126–8132. https://doi.org/10.1523/jneurosci.18-20-08126.1998
Williams TL, Serpell LC, Urbanc B (2016) Stabilization of native amyloid β-protein oligomers by copper and hydrogen peroxide induced cross-linking of unmodified proteins (CHICUP). Biochim Biophys Acta Proteins Proteom 1864:249–259. https://doi.org/10.1016/j.bbapap.2015.12.001
Shabestari MH, Meeuwenoord NJ, Filippov DV, Huber M (2016) Interaction of the amyloid β peptide with sodium dodecyl sulfate as a membrane-mimicking detergent. J Biol Phys 42:299–315. https://doi.org/10.1007/s10867-016-9408-5
Hellstrand E, Sparr E, Linse S (2010) Retardation of Aβ fibril formation by phospholipid vesicles depends on membrane phase behavior. Biophys J 98:2206–2214. https://doi.org/10.1016/j.bpj.2010.01.063
Lindberg DJ, Wesén E, Björkeroth J et al (2017) Lipid membranes catalyse the fibril formation of the amyloid-β (1–42) peptide through lipid-fibril interactions that reinforce secondary pathways. Biochim Biophys Acta Biomembr 1859:1921–1929. https://doi.org/10.1016/j.bbamem.2017.05.012
Kotler SA, Walsh P, Brender JR, Ramamoorthy A (2014) Differences between amyloid-β aggregation in solution and on the membrane: insights into elucidation of the mechanistic details of Alzheimer’s disease. Chem Soc Rev 43:6692–6700. https://doi.org/10.1039/C3CS60431D
Demuro A, Parker I, Stutzmann GE (2010) Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem 285:12463–12468. https://doi.org/10.1074/jbc.R109.080895
Terzi E, Hölzemann G, Seelig J (1997) Interaction of Alzheimer β-amyloid peptide(1-40) with lipid membranes. Biochemistry 36:14845–14852. https://doi.org/10.1021/bi971843e
Henry S, Bercu NB, Bobo C et al (2018) Interaction of Aβ 1-42 peptide or their variant with model membrane of different composition probed by infrared nanospectroscopy. Nanoscale 10:936–940. https://doi.org/10.1039/c7nr07489a
Jarvet J, Danielsson J, Damberg P et al (2007) Positioning of the Alzheimer Aβ(1-40) peptide in SDS micelles using NMR and paramagnetic probes. J Biomol NMR 39:63–72. https://doi.org/10.1007/s10858-007-9176-4
Österlund N, Kulkarni YS, Misiaszek AD et al (2018) Amyloid-β Peptide Interactions with Amphiphilic Surfactants: electrostatic and Hydrophobic Effects. ACS Chem Neurosci 9:1680–1692. https://doi.org/10.1021/acschemneuro.8b00065
Bokvist M, Lindström F, Watts A, Gröbner G (2004) Two Types of Alzheimer’s β-amyloid (1-40) Peptide Membrane Interactions: aggregation Preventing Transmembrane Anchoring Versus Accelerated Surface Fibril Formation. J Mol Biol 335:1039–1049. https://doi.org/10.1016/j.jmb.2003.11.046
Coles M, Bicknell W, Watson AA et al (1998) Solution structure of amyloid β-peptide(1–40) in a water–micelle environment. Is the membrane-spanning domain where we think it is? †, ‡. Biochemistry 37:11064–11077. https://doi.org/10.1021/bi972979f
Tiiman A, Luo J, Wallin C et al (2016) Specific binding of Cu(II) ions to amyloid-beta peptides bound to aggregation-inhibiting molecules or SDS micelles creates complexes that generate radical oxygen species. J Alzheimer’s Dis 54:971–982. https://doi.org/10.3233/JAD-160427
Lindgren J, Segerfeldt P, Sholts SB et al (2013) Engineered non-fluorescent Affibody molecules facilitate studies of the amyloid-beta (Aβ) peptide in monomeric form: low pH was found to reduce Aβ/Cu(II) binding affinity. J Inorg Biochem 120:18–23. https://doi.org/10.1016/j.jinorgbio.2012.11.005
Khondker A, Alsop RJ, Rheinstädter MC (2017) Membrane-accelerated amyloid-β aggregation and formation of cross-β sheets. Membr (Basel) 7:49. https://doi.org/10.3390/membranes7030049
Bode DC, Baker MD, Viles JH (2016) Ion channel formation by amyloid-β42 oligomers but not amyloid-β40 in cellular membranes. J Biol Chem 292:1404–1413. https://doi.org/10.1074/jbc.M116.762526
Sciacca MFM, Kotler SA, Brender JR et al (2012) Two-step mechanism of membrane disruption by Aβ through membrane fragmentation and pore formation. Biophys J 103:702–710. https://doi.org/10.1016/j.bpj.2012.06.045
Kagan BL, Azimov R, Azimova R (2004) Amyloid peptide channels. J Membr Biol 202:1–10. https://doi.org/10.1007/s00232-004-0709-4
Quist A, Doudevski I, Lin H et al (2005) Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci 102:10427–10432. https://doi.org/10.1073/pnas.0502066102
Kakio A, Nishimoto SI, Yanagisawa K et al (2001) Cholesterol-dependent formation of GM1 ganglioside-bound amyloid β-protein, an endogenous seed for Alzheimer amyloid. J Biol Chem 276:24985–24990. https://doi.org/10.1074/jbc.M100252200
Fantini J, Di Scala C, Yahi N et al (2014) Bexarotene blocks calcium-permeable ion channels formed by neurotoxic Alzheimer’s β-amyloid peptides. ACS Chem Neurosci 5:216–224. https://doi.org/10.1021/cn400183w
Lin HAI, Bhatia R, Lal R (2001) Amyloid β protein forms ion channels: implications for Alzheimer’s disease pathophysiology. Faseb J 15:2433–2444. https://doi.org/10.1096/fj.01-0377com
Strodel B, Lee JWL, Whittleston CS, Wales DJ (2010) Transmembrane structures for Alzheimer’s Aβ1-42 oligomers. J Am Chem Soc 132:13300–13312. https://doi.org/10.1021/ja103725c
Demuro A, Smith M, Parker I (2011) Single-channel Ca2+ imaging implicates Aβ 1–42 amyloid pores in Alzheimer’s disease pathology. J Cell Biol 195:515–524. https://doi.org/10.1083/jcb.201104133
Kawahara M, Arispe N, Kuroda Y, Rojas E (1997) Alzheimer’s disease amyloid beta-protein forms Zn(2+)-sensitive, cation-selective channels across excised membrane patches from hypothalamic neurons. Biophys J 73:67–75. https://doi.org/10.1016/S0006-3495(97)78048-2
Zhu YJ, Lin H, Lal R (2000) Fresh and nonfibrillar amyloid β protein(1–40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AβP-channel-mediated cellular toxicity. FASEB J 14:1244–1254. https://doi.org/10.1096/fasebj.14.9.1244
Bhatia R, Lin H, Lal R (2000) Fresh and globular amyloid β protein (1–42) induces rapid cellular degeneration: evidence for AβP channel-mediated cellular toxicity. FASEB J 14:1233–1243. https://doi.org/10.1096/fasebj.14.9.1233
Arispe N, Diaz JC, Flora M (2008) Efficiency of histidine-associating compounds for blocking the Alzheimer’s Aβ channel activity and cytotoxicity. Biophys J 95:4879–4889. https://doi.org/10.1529/biophysj.108.135517
Jang H, Arce FT, Ramachandran S et al (2010) Truncated beta-amyloid peptide channels provide an alternative mechanism for Alzheimer’s disease and down syndrome. Proc Natl Acad Sci U S A 107:6538–6543. https://doi.org/10.1073/pnas.0914251107
Curtain CC, Ali F, Volitakis I et al (2001) Alzheimer’s disease amyloid-β binds copper and zinc to generate an allosterically ordered Membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem 276:20466–20473. https://doi.org/10.1074/jbc.M100175200
Granzotto A, Suwalsky M, Zatta P (2011) Physiological cholesterol concentration is a neuroprotective factor against β-amyloid and β-amyloid-metal complexes toxicity. J Inorg Biochem 105:1066–1072. https://doi.org/10.1016/j.jinorgbio.2011.05.013
Miller Y, Ma B, Nussinov R (2012) Metal binding sites in amyloid oligomers: complexes and mechanisms. Coord Chem Rev 256:2245–2252. https://doi.org/10.1016/j.ccr.2011.12.022
Smith DP, Smith DG, Curtain CC et al (2006) Copper-mediated amyloid-β toxicity is associated with an intermolecular histidine bridge. J Biol Chem 281:15145–15154. https://doi.org/10.1074/jbc.M600417200
Chiti F, Dobson CM (2017) Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annu Rev Biochem 86:27–68. https://doi.org/10.1146/annurev-biochem-061516-045115
Brender JR, Krishnamoorthy J, Messina GML et al (2013) Zinc stabilization of prefibrillar oligomers of human islet amyloid polypeptide. Chem Commun 49:3339–3341. https://doi.org/10.1039/c3cc40383a
Dong X, Svantesson T, Sholts SB et al (2019) Copper ions induce dityrosine-linked dimers in human but not in murine islet amyloid polypeptide (IAPP/amylin). Biochem Biophys Res Commun 510:520–524. https://doi.org/10.1016/j.bbrc.2019.01.120
Borsarelli CD, Falomir-Lockhart LJ, Ostatná V et al (2012) Biophysical properties and cellular toxicity of covalent crosslinked oligomers of α-synuclein formed by photoinduced side-chain tyrosyl radicals. Free Radic Biol Med 53:1004–1015. https://doi.org/10.1016/j.freeradbiomed.2012.06.035
Al-Hilaly YK, Biasetti L, Blakeman BJF et al (2016) The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy bodies in Parkinson’s disease. Sci Rep 6:39171. https://doi.org/10.1038/srep39171
Tiwari MK, Leinisch F, Sahin C et al (2018) Early events in copper-ion catalyzed oxidation of α-synuclein. Free Radic Biol Med 121:38–50. https://doi.org/10.1016/j.freeradbiomed.2018.04.559
Krüger DM, Kamerlin SCL (2017) Micelle maker: an online tool for generating equilibrated micelles as direct input for molecular dynamics simulations. ACS Omega 2:4524–4530. https://doi.org/10.1021/acsomega.7b00820
Kok WM, Cottam JM, Ciccotosto GD et al (2013) Synthetic dityrosine-linked β-amyloid dimers form stable, soluble, neurotoxic oligomers. Chem Sci 4:4449–4454. https://doi.org/10.1039/c3sc22295k
Acknowledgments
Open access funding provided by Stockholm University. This work was supported by grants from the Magnus Bergvall Foundation to SW, from the Lawski foundation to NÖ, and from the Olle Engkvist Foundation and the Swedish Research Council to AG.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Wärmländer, S.K.T.S., Österlund, N., Wallin, C. et al. Metal binding to the amyloid-β peptides in the presence of biomembranes: potential mechanisms of cell toxicity. J Biol Inorg Chem 24, 1189–1196 (2019). https://doi.org/10.1007/s00775-019-01723-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-019-01723-9