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  • 1.
    Abelein, Axel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Juri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Institute of Chemical Physics and Biophysics, Estonia.
    Luo, Jinghui
    Tiiman, Ann
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway2014In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, no 4-5, p. 623-634Article, review/survey (Refereed)
    Abstract [en]

    The amyloid beta (A beta) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the A beta peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the A beta peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of A beta complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.

  • 2.
    Abelein, Axel
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ionic Strength Modulation of the Free Energy Landscape of A beta(40) Peptide Fibril Formation2016In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 21, p. 6893-6902Article in journal (Refereed)
    Abstract [en]

    Protein misfolding and formation of cross-beta structured amyloid fibrils are linked to, many neurodegenerative disorders. Although recently developed,quantitative approaches have started to reveal the molecular nature of self-assembly and fibril formation of proteins and peptides, it is yet unclear how these self-organization events are precisely modulated by microenvironmental factors, which are known to strongly affect the macroscopic aggregation properties. Here, we characterize the explicit effect of ionic strength on the microscopic aggregation rates of amyloid beta peptide (A beta 40) self-association, implicated in Alzheimer's disease. We found that physiological ionic strength accelerates A beta 40 aggregation kinetics by promoting surface-catalyzed secondary nucleation reactions. This promoted catalytic effect can be assigned to shielding of electrostatic repulsion between Monomers on the fibril surface or between the fibril surface itself and monomeric peptides. Furthermore, we observe the formation of two different beta-structured states with =similar but distinct spectroscopic features, which can be assigned to an off-pathway immature state (F-beta*) and a mature stable State (F-beta), where salt favors formation of the F-beta fibril morphology. Addition of salt to preformed F-beta* accelerates transition to F-beta, underlining the dynamic nature of A beta 40 fibrils in solution. On the basis of,these results we suggest a model where salt decreases the free-energy barrier for A beta 40 folding to the F-beta state, favoring the buildup of the mature fibril morphology while omitting competing, energetically less favorable structural states.

  • 3.
    Danielsson, J
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Andersson, A
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, J
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, A
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    15N relaxation study of the amyloid beta-peptide structural propensities and persistence length.2006In: Magn Reson Chem, ISSN 0749-1581, Vol. 44, no S1, p. S114-21Article in journal (Refereed)
    Abstract [en]

    The dynamics of monomeric Alzheimer A(1-40) in aqueous solution was studied using heteronuclear NMR experiments. 15N NMR relaxation rates of amide groups report on the dynamics in the peptide chain and make it possible to estimate structural propensities from temperature-dependent relaxation data and chemical shifts change analysis. The persistence length of the polypeptide chain was determined using a model in which the influence of neighboring residue relaxation is assumed to decay exponentially as a function of distance. The persistence length of the A(1-40) monomer was found to decrease from eight to three residues when temperature was increased from 3 to 18 °C. At 3 °C the peptide shows structural propensities that correlate well with the suggested secondary structure regions of the peptide to be present in the fibrils, and with the -helical structure in membrane-mimicking systems. Our data leads to a structural model for the monomeric soluble -peptide with six different regions of secondary structure propensities. The peptide has two regions with -strand propensity (residues 16-24 and 31-40), two regions with high PII-helix propensity (residues 1-4 and 11-15) and two unstructured regions with higher mobility (residues 5-10 and 25-30) connecting the structural elements. Copyright © 2006 John Wiley & Sons, Ltd.

  • 4. Dong, Xiaolin
    et al.
    Svantesson, Teodor
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sholts, Sabrina B.
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Copper ions induce dityrosine-linked dimers in human but not in murine islet amyloid polypeptide (IAPP/amylin)2019In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 510, no 4, p. 520-524Article in journal (Refereed)
    Abstract [en]

    Dysregulation and aggregation of the peptide hormone IAPP (islet amyloid polypeptide, a.k.a. amylin) into soluble oligomers that appear to be cell-toxic is a known aspect of diabetes mellitus (DM) Type 2 pathology. IAPP aggregation is influenced by several factors including interactions with metal ions such as Cu(II). Because Cu(II) ions are redox-active they may contribute to metal-catalyzed formation of oxidative tyrosyl radicals, which can generate dityrosine cross-links. Here, we show that such a process, which involves Cu(II) ions bound to the IAPP peptide together with H2O2, can induce formation of large amounts of IAPP dimers connected by covalent dityrosine cross-links. This cross-linking is less pronounced at low pH and for murine IAPP, likely due to less efficient Cu(II) binding. Whether IAPP can carry out its hormonal function as a cross-linked dimer is unknown. As dityrosine concentrations are higher in blood plasma of DM Type 2 patients - arguably due to disease-related oxidative stress - and as dimer formation is the first step in protein aggregation, generation of dityrosine-linked dimers may be an important factor in IAPP aggregation and thus relevant for DM Type 2 progression.

  • 5.
    Lundberg, Pontus
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Magzoub, Mazin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindberg, Mattias
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hällbrink, Mattias
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Eriksson, L. E. Göran
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cell membrane translocation of the N-terminal (1-28) part of the prion protein2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 299, no 1, p. 85-90Article in journal (Refereed)
    Abstract [en]

    The N-terminal (1-28) part of the mouse prion protein (PrP) is a cell penetrating peptide, capable of transporting large hydrophilic cargoes through a cell membrane. Confocal fluorescence microscopy shows that it transports the protein avidin (67 kDa) into several cell lines. The (1-28) peptide has a strong tendency for aggregation and P-structure formation, particularly in interaction with negatively charged phospholipid membranes. The findings have implications for how prion proteins with uncleaved signal peptides in the N-termini may enter into cells, which is important for infection. The secondary structure conversion into beta-structure may be relevant as a seed for the conversion into the scrapie (PrPSc) form of the protein and its arnyloidic transformation.

  • 6.
    Massad, Tariq
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tanner, Risto
    Tomson, Katrin
    Smirnova, Julia
    Palumaa, Peep
    Sugai, Mariko
    Kohno, Toshiyuki
    Vanatalu, Kalju
    Damberg, Peter
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Maximum entropy reconstruction of joint phi, psi-distribution with a coil-library prior: the backbone conformation of the peptide hormone motilin in aqueous solution from phi and psi-dependent J-couplings2007In: Journal of Biomolecular NMR, ISSN 0925-2738, E-ISSN 1573-5001, Vol. 38, no 2, p. 107-23Article in journal (Refereed)
  • 7. Owen, Michael C.
    et al.
    Gnutt, David
    Gao, Mimi
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Winter, Roland
    Ebbinghaus, Simon
    Strodel, Birgit
    Effects of in vivo conditions on amyloid aggregation2019In: Chemical Society Reviews, ISSN 0306-0012, E-ISSN 1460-4744, Vol. 48, no 14, p. 3946-3996Article, review/survey (Refereed)
    Abstract [en]

    One of the grand challenges of biophysical chemistry is to understand the principles that govern protein misfolding and aggregation, which is a highly complex process that is sensitive to initial conditions, operates on a huge range of length- and timescales, and has products that range from protein dimers to macroscopic amyloid fibrils. Aberrant aggregation is associated with more than 25 diseases, which include Alzheimer's, Parkinson's, Huntington's, and type II diabetes. Amyloid aggregation has been extensively studied in the test tube, therefore under conditions that are far from physiological relevance. Hence, there is dire need to extend these investigations to in vivo conditions where amyloid formation is affected by a myriad of biochemical interactions. As a hallmark of neurodegenerative diseases, these interactions need to be understood in detail to develop novel therapeutic interventions, as millions of people globally suffer from neurodegenerative disorders and type II diabetes. The aim of this review is to document the progress in the research on amyloid formation from a physicochemical perspective with a special focus on the physiological factors influencing the aggregation of the amyloid-beta peptide, the islet amyloid polypeptide, alpha-synuclein, and the hungingtin protein.

  • 8.
    Papadopoulos, E
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Oglecka, K
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mäler, L
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, J
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wright, PE
    Dyson, HJ
    Gräslund, A
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    NMR solution structure of the peptide fragment 1-30, derived from unprocessed mouse Doppel protein, in DHPC micelles.2006In: Biochemistry, ISSN 0006-2960, Vol. 45, no 1, p. 159-66Article in journal (Refereed)
    Abstract [en]

    The downstream prion-like Doppel (Dpl) protein is a homologue related to the prion protein (PrP). Dpl is expressed in the brains of mice that do not express PrP, and Dpl is known to be toxic to neurons. One mode of toxicity has been suggested to involve direct membrane interactions. PrP under certain conditions of cell trafficking retains an uncleaved signal peptide, which may also hold for the much less studied Dpl. For a peptide with a sequence derived from the N-terminal part (1-30) of mouse Dpl (mDpl(1-30)) CD spectroscopy shows about 40% alpha-helical structure in DHPC and SDS micelles. In aqueous solution it is mostly a random coil. The three-dimensional solution structure was determined by NMR for mDpl(1-30) associated with DHPC micelles. 2D 1H NMR spectra of the peptide in q = 0.25 DMPC/DHPC bicelles only showed signals from the unstructured termini, indicating that the structured part of the peptide resides within the lipid bilayer. Together with 2H2O exchange data in the DHPC micelle solvent, these results show an alpha-helix protected from solvent exchange between residues 7 and 19, and suggest that the alpha-helical segment can adopt a transmembrane localization also in a membrane. Leakage studies with entrapped calcein in large unilamellar phospholipid vesicles showed that the peptide is almost as membrane perturbing as melittin, known to form pores in membranes. The results suggest a possible channel formation mechanism for the unprocessed Dpl protein, which may be related to toxicity through direct cell membrane interaction and damage.

  • 9.
    Tiiman, Ann
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Vukojevic, Vladana
    Heterogeneity and Turnover of Intermediates during Amyloid-beta (A beta) Peptide Aggregation Studied by Fluorescence Correlation Spectroscopy2015In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 54, no 49, p. 7203-7211Article in journal (Refereed)
    Abstract [en]

    Self-assembly of amyloid beta (A beta) peptide molecules into large aggregates is a naturally occurring process driven in aqueous solution by a dynamic interplay between hydrophobic interactions among A beta molecules, which promote aggregation, and steric and overall electrostatic hindrance, which stifles it. A beta self-association is entropically unfavorable, as it implies order increase in the system, but under favorable kinetic conditions, the process proceeds at appreciable rates, yielding A beta aggregates of different sizes and structures. Despite the great relevance and extensive research efforts, detailed kinetic mechanisms underlying A beta aggregation remain only partially understood. In this study, fluorescence correlation spectroscopy (FCS) and Thioflavin T (ThT) were used to monitor the time dependent growth of structured aggregates and characterize multiple components during the aggregation of A beta peptides in a heterogeneous aqueous solution. To this aim, we collected data during a relatively large number of observation periods, 30 consecutive measurements lasting 10 s each, at what we consider to be a constant time point in the slow aggregation process. This approach enabled monitoring the formation of nanomolar concentrations of structured amyloid aggregates and demonstrated the changing distribution of amyloid aggregate sizes throughout the aggregation process. We identified aggregates of different sizes with molecular weight from 260 to more than 1 x 10(6) kDa and revealed the hitherto unobserved kinetic turnover of intermediates during A beta aggregation. The effect of different A beta concentrations, A beta:ThT ratios, differences between the 40 (A beta 40) and 42 (A beta 42) residue long variants of A beta, and the effect of stirring were also examined.

  • 10. Tiiman, Ann
    et al.
    Jelic, Vesna
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia..
    Jaremo, Petter
    Bogdanovic, Nenad
    Rigler, Rudolf
    Terenius, Lars
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Vukojevic, Vladana
    Amyloidogenic Nanoplaques in Blood Serum of Patients with Alzheimer's Disease Revealed by Time-Resolved Thioflavin T Fluorescence Intensity Fluctuation Analysis2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 68, no 2, p. 571-582Article in journal (Refereed)
    Abstract [en]

    Background: Biomarkers are central to current research on molecular mechanisms underlying Alzheimer's disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies. Objective: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size. Methods: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size. Results: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects. Conclusion: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids.

  • 11.
    Tiiman, Ann
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oxford, UK.
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Olsson, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lindgren, Joel
    Jarvet, Jϋri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roose, Per
    Sholts, Sabrina B.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Museum of Natural History, USA.
    Rahimipour, Shai
    Abrahams, Jan Pieter
    Eriksson Karlström, Amelie
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Specific Binding of Cu(II) Ions to Amyloid-Beta Peptides Bound to Aggregation-Inhibiting Molecules or SDS Micelles Creates Complexes that Generate Radical Oxygen Species2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 54, no 3, p. 971-982Article in journal (Refereed)
    Abstract [en]

    Aggregation of the amyloid-beta (A beta) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate A beta aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, A beta is found in various cellular locations including membranes. So far, Cu(II)/A beta interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with A beta bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the Z(A beta 3)(12-58) Y18L Affibody molecule). In all studied systems the A beta N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, A beta was found to bind Cu(II) and Zn(II) with the same ligands and the same K-D as in aqueous solution. ROS was generated in all Cu(II)/A beta complexes. These results indicate that binding of A beta to membranes, drugs, and other entities that do not interact with the A beta N-terminal part, appears not to compromise the N-terminal segment's ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS.

  • 12. Vaher, M
    et al.
    Viirlaid, S
    Ehrlich, K
    Mahlapuu, R
    Jarvet, J
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Soomets, U
    Kaljurand,
    Characterization of the antioxidative activity of novel nontoxic neuropeptides by using capillary electrophoresis.2006In: Electrophoresis, ISSN 0173-0835, Vol. 27, no 13, p. 2582-9Article in journal (Refereed)
    Abstract [en]

    In the present study, we have monitored the oxidation process of novel nontoxic neuropeptides and determined its rate constants, which describe the antioxidative potential of the peptides. A capillary electrophoretic method was implemented which ensures the simultaneity of analysis of reactants and products in a short time of analysis. The rate constants of oxidation of the four novel peptides, 4-methoxy-L-tyrosinyl-gamma-L-glutamyl-L-cysteinyl-glycine (UPF1), D-serinyl-gamma-L-glutamyl-L-cysteinyl-glycine (UPF6), 4-methoxy-L-tyrosinyl-alpha-L-glutamyl-L-cysteinyl-glycine and D-serinyl-alpha-L-glutamyl-L-cysteinyl-glycine, designed by us, were compared with those of oxidation of glutathione (reduced glutathione) by using capillary electrophoresis. The second-order rate constants were similar for all peptides if the oxidation was carried out with hydrogen peroxide (k(II) = 0.208 - 0.236 x 10(3)/M.min). The rate constants were also determined for the mixtures of peptides. When the oxidation is caused by hydroxyl radical (OH*), the gamma-glutamate containing peptides (UPF1 and UPF6) exhibited two to four times higher antioxidative activity (k(II) = 4.428 and 2.152 x 10(3)/M.min, respectively). The results suggest that the antioxidative potential of the peptides studied is not determined by the formation of disulphide bridge alone.

  • 13.
    Wallin, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hiruma, Yoshitaka
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Huvent, Isabelle
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Abrahams, Jan Pieter
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lippens, Guy
    Luo, Jinghui
    The Neuronal Tau Protein Blocks in Vitro Fibrillation of the Amyloid-beta (A beta) Peptide at the Oligomeric Stage2018In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 26, p. 8138-8146Article in journal (Refereed)
    Abstract [en]

    In Alzheimer's disease, amyloid-beta (A beta) plaques and tau neurofibrillary tangles are the two pathological hallmarks. The co-occurrence and combined reciprocal pathological effects of A beta and tau protein aggregation have been observed in animal models of the disease. However, the molecular mechanism of their interaction remain unknown. Using a variety of biophysical measurements, we here show that the native full-length tau protein solubilizes the A beta(40) peptide and prevents its fibrillation. The tau protein delays the amyloid fibrillation of the A beta(40) peptide at substoichiometric ratios, showing different binding affinities toward the different stages of the aggregated A beta(40) peptides. The A beta monomer structure remains random coil in the presence of tau, as observed by nuclear magnetic resonance (NMR), circular dichroism (CD) spectroscopy and photoinduced cross-linking methods. We propose a potential interaction mechanism for the influence of tau on A beta fibrillation.

  • 14.
    Wallin, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kulkarni, Yashraj S.
    Abelein, Axel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet, Sweden.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Liao, Qinghua
    Strodel, Birgit
    Olsson, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oxford, UK.
    Abrahams, Jan Pieter
    Sholts, Sabrina B.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Museum of Natural History, USA.
    Roos, Per M.
    Kamerlin, Shina C. L.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Characterization of Mn(II) ion binding to the amyloid-beta peptide in Alzheimer's disease2016In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 38, p. 183-193Article in journal (Refereed)
    Abstract [en]

    Growing evidence links neurodegenerative diseases to metal exposure. Aberrant metal ion concentrations have been noted in Alzheimer's disease (AD) brains, yet the role of metals in AD pathogenesis remains unresolved. A major factor in AD pathogenesis is considered to be aggregation of and amyloid formation by amyloid-beta (A beta) peptides. Previous studies have shown that A beta displays specific binding to Cu(II) and Zn(II) ions, and such binding has been shown to modulate A beta aggregation. Here, we use nuclear magnetic resonance (NMR) spectroscopy to show that Mn(II) ions also bind to the N-terminal part of the A beta(1-40) peptide, with a weak binding affinity in the milli- to micromolar range. Circular dichroism (CD) spectroscopy, solid state atomic force microscopy (AFM), fluorescence spectroscopy, and molecular modeling suggest that the weak binding of Mn(II) to A beta may not have a large effect on the peptide's aggregation into amyloid fibrils. However, identification of an additional metal ion displaying A beta binding reveals more complex AD metal chemistry than has been previously considered in the literature.

  • 15.
    Wallin, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oxford, UK.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The Amyloid-beta Peptide in Amyloid Formation Processes: Interactions with Blood Proteins and Naturally Occurring Metal Ions2017In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 57, no 7-8, p. 674-685Article, review/survey (Refereed)
    Abstract [en]

    This review describes interactions between the amyloid- peptide (A) involved in Alzheimer's disease (AD) and endogenous metal ions and proteins, with an emphasis on future potential drug therapies and targets. AD is characterised by loss of neurons, memory, and cognitive functions, and by formation of cerebral senile plaque deposits. These plaques consist mainly of aggregated A peptides. AD pathology includes a) on the molecular level imbalanced concentrations of A peptides and metal ions, and formation of amyloid structures, and b) on the physiological level a combination of inflammatory responses and oxidative stress effects causing neuronal death. Interestingly, certain blood proteins and metal ions can affect the A amyloid aggregation process. These interactions are the topics of the present review. A deeper understanding of these interactions could facilitate new therapeutic strategies against AD. Previous therapeutic approaches and trials are also briefly described.

  • 16.
    Wallin, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sholts, Sabrina B.
    Österlund, Nicklas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Luo, Jinghui
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roos, Per M.
    Ilag, Leopold
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Alzheimer's disease and cigarette smoke components: effects of nicotine, PAHs, and Cd(II), Cr(III), Pb(II), Pb(IV) ions on amyloid-beta peptide aggregation2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 14423Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is a significant risk factor for Alzheimer’s disease (AD), which is associated with extracellular brain deposits of amyloid plaques containing aggregated amyloid-β (Aβ) peptides. Aβ aggregation occurs via multiple pathways that can be influenced by various compounds. Here, we used AFM imaging and NMR, fluorescence, and mass spectrometry to monitor in vitro how Aβ aggregation is affected by the cigarette-related compounds nicotine, polycyclic aromatic hydrocarbons (PAHs) with one to five aromatic rings, and the metal ions Cd(II), Cr(III), Pb(II), and Pb(IV). All PAHs and metal ions modulated the Aβ aggregation process. Cd(II), Cr(III), and Pb(II) ions displayed general electrostatic interactions with Aβ, whereas Pb(IV) ions showed specific transient binding coordination to the N-terminal Aβ segment. Thus, Pb(IV) ions are especially prone to interact with Aβ and affect its aggregation. While Pb(IV) ions affected mainly Aβ dimer and trimer formation, hydrophobic toluene mainly affected formation of larger aggregates such as tetramers. The uncharged and hydrophilic nicotine molecule showed no direct interactions with Aβ, nor did it affect Aβ aggregation. Our Aβ interaction results suggest a molecular rationale for the higher AD prevalence among smokers, and indicate that certain forms of lead in particular may constitute an environmental risk factor for AD.

  • 17. Wang, Chao
    et al.
    Klechikov, Alexey G.
    Gharibyan, Anna L.
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. National Institute of Chemical Physics & Biophysics (NICPB), Estonia.
    Zhao, Lina
    Jia, Xueen
    Shankar, S. K.
    Olofsson, Anders
    Brännström, Thomas
    Mu, Yuguang
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Morozova-Roche, Ludmilla A.
    The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade2014In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 127, no 4, p. 507-522Article in journal (Refereed)
    Abstract [en]

    Pro-inflammatory S100A9 protein is increasingly recognized as an important contributor to inflammation-related neurodegeneration. Here, we provide insights into S100A9 specific mechanisms of action in Alzheimer's disease (AD). Due to its inherent amyloidogenicity S100A9 contributes to amyloid plaque formation together with A beta. In traumatic brain injury (TBI) S100A9 itself rapidly forms amyloid plaques, which were reactive with oligomer-specific antibodies, but not with A beta and amyloid fibrillar antibodies. They may serve as precursor-plaques for AD, implicating TBI as an AD risk factor. S100A9 was observed in some hippocampal and cortical neurons in TBI, AD and non-demented aging. In vitro S100A9 forms neurotoxic linear and annular amyloids resembling A beta protofilaments. S100A9 amyloid cytotoxicity and native S100A9 pro-inflammatory signaling can be mitigated by its co-aggregation with A beta, which results in a variety of micron-scale amyloid complexes. NMR and molecular docking demonstrated transient interactions between native S100A9 and A beta. Thus, abundantly present in AD brain pro-inflammatory S100A9, possessing also intrinsic amyloidogenic properties and ability to modulate A beta aggregation, can serve as a link between the AD amyloid and neuroinflammatory cascades and as a prospective therapeutic target.

  • 18.
    Westerlund, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Moran, Sean D.
    Privett, Heidi K.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hay, Sam
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Jarvet, Juri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gibney, Brian R.
    Tommos, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Making a single-chain four-helix bundle for redox chemistry studies2008In: Protein Engineering Design & Selection, ISSN 1741-0126, E-ISSN 1741-0134, Vol. 21, no 11, p. 645-652Article in journal (Refereed)
    Abstract [en]

    The construction and characteristics of the stable and well-structured alpha W-4 protein are described. The 117-residue, single-chain protein has a molecular weight of 13.1 kDa and is designed to fold into a four-helix bundle. Experimental characterization of the expressed and purified protein shows a 69.8 +/- 0.8% helical content over a 5.5-10.0 pH range. The protein is thermostable with a T-M > 355 K and has a free energy of unfolding as measured by chemical denaturation of -4.7 kcal mol(-1) at 25 degrees C and neutral pH. One-dimensional (1D) proton and 2D N-15-HSQC spectra show narrow, well-dispersed spectral lines consistent with a uniquely structured alpha-helical protein. Analytical ultracentrifugation and NMR data show that the protein is monomeric over a broad protein concentration range. The 324 nm emission maximum of the unique Trp-106 is consistent with a sequestered position of the aromatic residue. Additionally, differential pulse voltammetry characterization indicates an elevated peak potential for Trp-106 when the protein is folded (pH range 7.0-8.5) relative to partly unfolded (pH range 11.4-13.2). The oxidation of Trp-106 is coupled to proton release as shown by a 53 +/- 3 mV/pH unit dependence of the peak potential over the 7.0-8.5 pH range.

  • 19.
    Wärmländer, Sebastian
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tiiman, Ann
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Tallinn Technical University, Estonia.
    Abelein, Axel
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Luo, Jinghui
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Leiden University, Netherlands.
    Söderberg, Kajsa L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Biophysical Studies of the Amyloid beta-Peptide: Interactions with Metal Ions and Small Molecules2013In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 14, no 14, p. 1692-1704Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is the most common of the protein misfolding (amyloid) diseases. The deposits in the brains of afflicted patients contain as a major fraction an aggregated insoluble form of the so-called amyloid beta-peptides (A beta peptides): fragments of the amyloid precursor protein of 39-43 residues in length. This review focuses on biophysical studies of the A beta peptides: that is, of the aggregation pathways and intermediates observed during aggregation, of the molecular structures observed along these pathways, and of the interactions of A beta with Cu and Zn ions and with small molecules that modify the aggregation pathways. Particular emphasis is placed on studies based on high-resolution and solid-state NMR methods. Theoretical studies relating to the interactions are also included. An emerging picture is that of A beta peptides in aqueous solution undergoing hydrophobic collapse together with identical partners. There then follows a relatively slow process leading to more ordered secondary and tertiary (quaternary) structures in the growing aggregates. These aggregates eventually assemble into elongated fibrils visible by electron microscopy. Small molecules or metal ions that interfere with the aggregation processes give rise to a variety of aggregation products that may be studied in vitro and considered in relation to observations in cell cultures or in vivo. Although the heterogeneous nature of the processes makes detailed structural studies difficult, knowledge and understanding of the underlying physical chemistry might provide a basis for future therapeutic strategies against the disease. A final part of the review deals with the interactions that may occur between the A beta peptides and the prion protein, where the latter is involved in other protein misfolding diseases.

  • 20.
    Österlund, Nicklas
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Kulkarni, Yashraj S.
    Misiaszek, Agata D.
    Wallin, Cecilia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Krüger, Dennis M.
    Liao, Qinghua
    Mashayekhy Rad, Farshid
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Jarvet, Jüri
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Strodel, Birgit
    Wärmländer, Sebastian K. T. S.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ilag, Leopold L.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Kamerlin, Shina C. L.
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Amyloid-beta Peptide Interactions with Amphiphilic Surfactants: Electrostatic and Hydrophobic Effects2018In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 9, no 7, p. 1680-1692Article in journal (Refereed)
    Abstract [en]

    The amphiphilic nature of the amyloid-beta (A beta) peptide associated with Alzheimer's disease facilitates various interactions with biomolecules such as lipids and proteins, with effects on both structure and toxicity of the peptide. Here, we investigate these peptide-amphiphile interactions by experimental and computational studies of A beta(1-40) in the presence of surfactants with varying physicochemical properties. Our findings indicate that electrostatic peptide-surfactant interactions are required for coclustering and structure induction in the peptide and that the strength of the interaction depends on the surfactant net charge. Both aggregation-prone peptide-rich coclusters and stable surfactant-rich coclusters can form. Only A beta(1-40) monomers, but not oligomers, are inserted into surfactant micelles in this surfactant-rich state. Surfactant headgroup charge is suggested to be important as electrostatic peptide-surfactant interactions on the micellar surface seems to be an initiating step toward insertion. Thus, no peptide insertion or change in peptide secondary structure is observed using a nonionic surfactant. The hydrophobic peptide-surfactant interactions instead stabilize the A beta monomer, possibly by preventing self-interaction between the peptide core and C terminus, thereby effectively inhibiting the peptide aggregation process. These findings give increased understanding regarding the molecular driving forces for A beta aggregation and the peptide interaction with amphiphilic biomolecules.

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