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  • 1.
    Abelein, Axel
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Juri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. National Institute of Chemical Physics and Biophysics, Estonia.
    Luo, Jinghui
    Tiiman, Ann
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    The hairpin conformation of the amyloid beta peptide is an important structural motif along the aggregation pathway2014Inngår i: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, nr 4-5, s. 623-634Artikkel, forskningsoversikt (Fagfellevurdert)
    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. Bartelink, Eric J.
    et al.
    Sholts, Sabrina B.
    Milligan, Colleen F.
    Van Deest, Traci L.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Linköping University, Sweden.
    A Case of Contested Cremains Analyzed Through Metric and Chemical Comparison2015Inngår i: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 60, nr 4, s. 1068-1073Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Since the 1980s, cremation has become the fastest growing area of the U.S. funeral industry. At the same time, the number of litigations against funeral homes and cremation facilities has increased. Forensic anthropologists are often asked to determine whether the contents of an urn are actually cremated bone, and to address questions regarding the identity of the remains. This study uses both metric and chemical analyses for resolving a case of contested cremains. A cremains weight of 2021.8 g was predicted based on the decedent's reported stature and weight. However, the urn contents weighed 4173.5 g. The urn contents also contained material inconsistent with cremains (e.g., moist sediment, stones, ferrous metal). Analysis using XRD and SEM demonstrated that the urn contained thermally altered bone as well as inorganic material consistent with glass fiber cement. Although forensically challenging, cremains cases such as this one can be resolved using a multidisciplinary approach.

  • 3.
    Berntsson, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Paul, Suman
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vosough, Faraz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Sholts, Sabrina B.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roos, Per M.
    Barth, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation2021Inngår i: Acta Biochimica Polonica, ISSN 0001-527X, E-ISSN 1734-154X, Vol. 68, nr 2, s. 169-179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alzheimer’s disease (AD) is an incurable disease and the main cause of age-related dementia worldwide, despite decades of research. Treatment of AD with lithium (Li) has shown promising results, but the underlying mechanism is unclear. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. The plaques contain also metal ions of e.g. Cu, Fe, and Zn, and such ions are known to interact with Aβ peptides and modulate their aggregation and toxicity. The interactions between Aβ peptides and Li+ions have however not been well investigated. Here, we use a range of biophysical techniques to characterize in vitro interactions between Aβ peptides and Li+ions. We show that Li+ions display weak and non-specific interactions with Aβ peptides, and have minor effects on Aβ aggregation. These results indicate that possible beneficial effects of Li on AD pathology are not likely caused by direct interactions between Aβ peptides and Li+ions.

  • 4.
    Berntsson, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Sardis, Merlin
    Noormägi, Andra
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Roos, Per M.
    Töugu, Vello
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Palumaa, Peep
    Wärmländer, Sebastian K.T.S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mercury Ion Binding to Apolipoprotein E Variants ApoE2, ApoE3, and ApoE4: Similar Binding Affinities but Different Structure Induction Effects2022Inngår i: ACS Omega, E-ISSN 2470-1343, Vol. 7, nr 33, s. 28924-28931Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mercury intoxication typically produces more severe outcomes in people with the APOE-ε4 gene, which codes for the ApoE4 variant of apolipoprotein E, compared to individuals with the APOE-ε2 and APOE-ε3 genes. Why the APOE-ε4 allele is a risk factor in mercury exposure remains unknown. One proposed possibility is that the ApoE protein could be involved in clearing of heavy metals, where the ApoE4 protein might perform this task worse than the ApoE2 and ApoE3 variants. Here, we used fluorescence and circular dichroism spectroscopies to characterize the in vitro interactions of the three different ApoE variants with Hg(I) and Hg(II) ions. Hg(I) ions displayed weak binding to all ApoE variants and induced virtually no structural changes. Thus, Hg(I) ions appear to have no biologically relevant interactions with the ApoE protein. Hg(II) ions displayed stronger and very similar binding affinities for all three ApoE isoforms, with KD values of 4.6 μM for ApoE2, 4.9 μM for ApoE3, and 4.3 μM for ApoE4. Binding of Hg(II) ions also induced changes in ApoE superhelicity, that is, altered coil–coil interactions, which might modify the protein function. As these structural changes were most pronounced in the ApoE4 protein, they could be related to the APOE-ε4 gene being a risk factor in mercury toxicity.

  • 5.
    Berntsson, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vosough, Faraz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Noormagi, Andra
    Padari, Kärt
    Asplund, Fanny
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gielnik, Maciej
    Paul, Suman
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Tõugu, Vello
    Roos, Per M.
    Kozak, Maciej
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Barth, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Pooga, Margus
    Palumaa, Peep
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Characterization of Uranyl (UO22+) Ion Binding to Amyloid Beta (Aβ) Peptides: Effects on Aβ Structure and Aggregation2023Inngår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 14, nr 15, s. 2618-2633Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions, including Alzheimer’s disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is the deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aβ aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aβ production, and these metals bind to Aβ peptides and modulate their aggregation. The possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aβ peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aβ peptides with affinities in the micromolar range, induce structural changes in Aβ monomers and oligomers, and inhibit Aβ fibrillization. This suggests a possible link between AD and U exposure, which could be further explored by cell, animal, and epidemiological studies. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation. 

  • 6.
    Berntsson, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Vosough, Faraz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Svantesson, Teodor
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Pansieri, Jonathan
    Iashchishyn, Igor A.
    Ostojic, Lucija
    Dong, Xiaolin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Paul, Suman
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Roos, Per M.
    Barth, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Morozova-Roche, Ludmilla A.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur.
    Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides2023Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 13, nr 1, artikkel-id 3341Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-beta (A beta) peptides, and A beta oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with A beta peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods-mainly spectroscopy and imaging techniques-to characterize A beta/Ni(II) interactions in vitro, for different A beta variants: A beta(1-40), A beta(1-40)(H6A, H13A, H14A), A beta(4-40), and A beta(1-42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length A beta monomers. Equimolar amounts of Ni(II) ions retard A beta aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)center dot A beta binding affinity is in the low mu M range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent A beta dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in A beta monomers, while in a membrane-mimicking environment (SDS micelles) coil-coil helix interactions appear to be induced. For SDS-stabilized A beta oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the A beta aggregation processes that are involved in AD brain pathology.

  • 7. Biswas, Abhijit
    et al.
    Maloverjan, Maria
    Padari, Kärt
    Abroi, Aare
    Rätsep, Margus
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. CellPept Sweden AB, Sweden.
    Kisand, Vambola
    Löhmus, Rünno
    Pooga, Margus
    Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery2023Inngår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 15, nr 2, artikkel-id 396Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cell-penetrating peptides (CPPs) are highly promising transfection agents that can deliver various compounds into living cells, including nucleic acids (NAs). Positively charged CPPs can form non-covalent complexes with negatively charged NAs, enabling simple and time-efficient nanoparticle preparation. However, as CPPs have substantially different chemical and physical properties, their complexation with the cargo and characteristics of the resulting nanoparticles largely depends on the properties of the surrounding environment, i.e., solution. Here, we show that the solvent used for the initial dissolving of a CPP determines the properties of the resulting CPP particles formed in an aqueous solution, including the activity and toxicity of the CPP–NA complexes. Using different biophysical methods such as dynamic light scattering (DLS), atomic force microscopy (AFM), transmission and scanning electron microscopy (TEM and SEM), we show that PepFect14 (PF14), a cationic amphipathic CPP, forms spherical particles of uniform size when dissolved in organic solvents, such as ethanol and DMSO. Water-dissolved PF14, however, tends to form micelles and non-uniform aggregates. When dissolved in organic solvents, PF14 retains its α-helical conformation and biological activity in cell culture conditions without any increase in cytotoxicity. Altogether, our results indicate that by using a solvent that matches the chemical nature of the CPP, the properties of the peptide–cargo particles can be tuned in the desired way. This can be of critical importance for in vivo applications, where CPP particles that are too large, non-uniform, or prone to aggregation may induce severe consequences.

  • 8. Boutrup, Joy
    et al.
    Franzén, Mari-Louise
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Two 15th century openwork braids of silk and metal thread from Riddarholmen Church and Alvastra Abbey in Sweden2013Inngår i: Fornvännen, ISSN 0015-7813, E-ISSN 1404-9430, Vol. 108, nr 1, s. 23-32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Historical Museum in Stockholm holds two interesting Medieval braids, one from Riddarholmen Church and one from Alvastra Abbey. Both are made of red silk and metal thread, probably with a loop-manipulation braiding technique that can produce openwork braids resembling lace. The braid from Riddarholmen can be linked to funerary textiles, as it was found during the opening in 1915-16 of the purported tomb of King Magnus Birgersson Ladulås (Barnlock). The other braid was excavated in 1949 at Alvastra Abbey and is probably a fastening loop. In this study, we present the results of a technical and material comparison of the two braids.

  • 9. Bulut, Ozgur
    et al.
    Petaros, Anja
    Hizliol, Ismail
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Linköping University, Sweden; University of California in Los Angeles, USA.
    Hekimoglu, Baki
    Sexual dimorphism in frontal bone roundness quantified by a novel 3D-based and landmark-free method2016Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 261, s. 162.e1-162.e5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this study we present a novel and landmark-free method for quantifying shape differences between male and female frontal bones. CT scans were recorded for 80 male and 80 female Turkish hospital patients, age 25-40. The frontal bones were first isolated from the 3D models by digital cutting along the bordering sutures, and then aligned to a CAD-based sphere. This allowed us to quantify the amount of frontal bone overlapping with the sphere (on average 43.2 +/- 6.5% for males and 33.9 +/- 6.6% for females, the difference is significant at p < 0.0001), and to identify areas of shape difference and deviation from the sphere surface in male and female bones. The larger proportion of spherical frontal bone surface in males challenges the common description of the female forehead as rounder''. Based on the overlap data, we developed discriminant functions able to correctly classify 77.5% of the frontal bone models as male/female. This demonstrates that 3D-based and landmark-free approaches to statistical shape analysis may become a viable alternative to the currently dominating landmark-based approaches for shape investigation.

  • 10. Carvalho, Alexandra T. P.
    et al.
    Gouveia, Leonor
    Kanna, Charan Raju
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Platts, Jamie A.
    Kamerlin, Shina Caroline Lynn
    Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation2014Inngår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, nr 12, s. 1604-1612Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.

  • 11. Chemerovski-Glikman, Marina
    et al.
    Rozentur-Shkop, Eva
    Richman, Michal
    Grupi, Asaf
    Getler, Asaf
    Cohen, Haim Y.
    Shaked, Hadassa
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Haas, Elisha
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Chill, Jordan H.
    Rahimipour, Shai
    Self-Assembled Cyclic D,L-alpha-Peptides as Generic Conformational Inhibitors of the alpha-Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies2016Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, nr 40, s. 14236-14246Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Many peptides and proteins with large sequences and structural differences self-assemble into disease-causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross-interaction. Here, we demonstrate how the self-assembled, cyclic D,L-alpha-peptide CP-2, which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson's disease associated alpha-synuclein (alpha-syn) aggregation to toxic oligomers by an, off-pathway mechanism. We show that CP-2 interacts with the N-terminal and the non-amyloid-beta component region of alpha-syn, which are responsible for alpha-syn's membrane intercalation and self-assembly, thus changing the overall conformation of alpha-syn. CP-2 also remodels alpha-syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular alpha-syn in neuronal cells overexpressing alpha-syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.

  • 12. Dong, Xiaolin
    et al.
    Svantesson, Teodor
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Sholts, Sabrina B.
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Copper ions induce dityrosine-linked dimers in human but not in murine islet amyloid polypeptide (IAPP/amylin)2019Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 510, nr 4, s. 520-524Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 13. Drew, Rose
    et al.
    Warmländer, Sebastian K. T. S.
    Stockholms universitet, Humanistiska fakulteten, Institutionen för arkeologi och antikens kultur.
    Children aboard the 17th c. warship Kronan? Four non-adult hip bones found among the skeletal remains2020Inngår i: Fornvännen, ISSN 0015-7813, E-ISSN 1404-9430, Vol. 115, nr 4, s. 285-286Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In Britain, warships did not officially exclude women until the early 19th c. (Hacker 1981, p.657). The non-adult skeletons reported here indicate similar traditions in Sweden, as family members appear to have accompanied Swedish navy sailors and/or soldiers even aboard the large military ships of the 17th century.

  • 14. Frković, Vedran
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Linköping University, Sweden.
    Petaros, Anja
    Španjol-Pandelo, Iva
    Ažman, Josip
    Finger width as a measure of femoral block puncture site: an ultrasonographic anatomical-anthropometric study2015Inngår i: Journal of clinical anesthesia, ISSN 0952-8180, E-ISSN 1873-4529, Vol. 27, nr 7, s. 553-557Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Study objective: Femoral nerve blockade is a regional anesthetic procedure that may be used in prehospital and emergency settings in cases of femoral trauma. Its speed and performance depend on how well the puncture site can be accurately located, something that usually is achieved via visible landmarks and/or by combining various universal preestablished measurements. Most of these methods have been derived from cadaver studies, which often suffer limitations in clinical settings. To facilitate a quick and easy determination of the puncture site, we here attempt to find an in vivo anthropometric measure that closely corresponds to the distance between the femoral artery and femoral nerve.

    Design: This is a prospective observational study.

    Patients: The study includes 67 patients presenting for elective surgery.

    Measurements: The distance from the femoral nerve to the femoral artery, projected to the skin, was measured by a 13-MHz ultrasonographic linear probe. Anthropometric measurements of the width of the hand fingers were carried out at the distal interphalangeal joints.

    Results: The distance from the femoral artery to the femoral nerve projected to the skin was found to closely correspond to the width of the fifth finger of the dominant hand measured at the distal interphalangeal joint.

    Conclusion: Because it relies on individual anthropometric information, this finding offers an individualized approach to determining the puncture site in a given patient. We believe that such an approach can improve and simplify femoral nerve blockade procedures in prehospital and emergency settings.

  • 15.
    Ghalebani, Leila
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wahlström, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielsson, Jens
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    pH-dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid-beta peptide2012Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 421, nr 3, s. 554-560Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metal ions like Cu(II) and Zn(II) are accumulated in Alzheimer's disease amyloid plaques. The amyloid-beta (A beta) peptide involved in the disease interacts with these metal ions at neutral pH via ligands provided by the N-terminal histidines and the N-terminus. The present study uses high-resolution NMR spectroscopy to monitor the residue-specific interactions of Cu(II) and Zn(II) with N-15- and C-13,N-15-labeled A beta(1-40) peptides at varying pH levels. At pH 7.4 both ions bind to the specific ligands, competing with one another. At pH 5.5 Cu(II) retains its specific histidine ligands, while Zn(II) seems to lack residue-specific interactions. The low pH mimics acidosis which is linked to inflammatory processes in vivo. The results suggest that the cell toxic effects of redox active Cu(II) binding to AD may be reversed by the protective activity of non-redox active Zn(II) binding to the same major binding site under non-acidic conditions. Under acidic conditions, the protective effect of Zn(II) may be decreased or changed, since Zn(II) is less able to compete with Cu(II) for the specific binding site on the AD peptide under these conditions.

  • 16. Gielnik, Maciej
    et al.
    Szymańska, Aneta
    Dong, Xiaolin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Svedružić, Željko M.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kozak, Maciej
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions2023Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 62, nr 11, s. 1689-1705Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Misfolding of the cellular prion protein (PrPC) is associated with the development of fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). Metal ions appear to play a crucial role in PrPC misfolding. PrPC is a combined Cu(II) and Zn(II) metal-binding protein, where the main metal-binding site is located in the octarepeat (OR) region. Thus, the biological function of PrPC may involve the transport of divalent metal ions across membranes or buffering concentrations of divalent metal ions in the synaptic cleft. Recent studies have shown that an excess of Cu(II) ions can result in PrPC instability, oligomerization, and/or neuroinflammation. Here, we have used biophysical methods to characterize Cu(II) and Zn(II) binding to the isolated OR region of PrPC. Circular dichroism (CD) spectroscopy data suggest that the OR domain binds up to four Cu(II) ions or two Zn(II) ions. Binding of the first metal ion results in a structural transition from the polyproline II helix to the β-turn structure, while the binding of additional metal ions induces the formation of β-sheet structures. Fluorescence spectroscopy data indicate that the OR region can bind both Cu(II) and Zn(II) ions at neutral pH, but under acidic conditions, it binds only Cu(II) ions. Molecular dynamics simulations suggest that binding of either metal ion to the OR region results in the formation of β-hairpin structures. As the formation of β-sheet structures can be a first step toward amyloid formation, we propose that high concentrations of either Cu(II) or Zn(II) ions may have a pro-amyloid effect in TSE diseases.

  • 17. Gielnik, Maciej
    et al.
    Taube, Michał
    Zhukova, Lilia
    Zhukov, Igor
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Svedružić, Željko
    Kwiatek, Wojciech M.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kozak, Maciej
    Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein2021Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikkel-id 21703Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cellular prion protein (PrP(C)) is a mainly alpha-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrP(C) can undergo a structural transition into a toxic, beta-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrP(C) binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrP(C) and Zn(II) ions. Binding of a single Zn(II) ion to the PrP(C) N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal alpha-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrP(C) can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrP(C).

  • 18. Gielnik, Maciej
    et al.
    Zhukova, Lilia
    Zhukov, Igor
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kozak, Maciej
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The engineered peptide construct NCAM1-Aβ inhibits fibrillization of the human prion protein (PrP)2022Inngår i: Acta Biochimica Polonica, ISSN 0001-527X, E-ISSN 1734-154X, Vol. 69, nr 1, s. 257-261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In prion diseases, the prion protein (PrP) becomes misfolded and forms fibrillar aggregates that are responsible for prion infectivity and pathology. So far, no drug or treatment procedures have been approved for prion disease treatment. We have previously shown that engineered cell-penetrating peptide constructs can reduce the amount of prion aggregates in infected cells. However, the molecular mechanism underlying this effect is unknown. Here, we use atomic force microscopy (AFM) imaging to show that the amyloid aggregation and fibrillization of the human PrP protein can be inhibited by equimolar amounts of the 25 residues long engineered peptide construct NCAM1-Aβ. 

  • 19. Gingerich, Joseph A. M.
    et al.
    Sholts, Sabrina B.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Stanford, Dennis
    Fluted point manufacture in eastern North America: an assessment of form and technology using traditional metrics and 3D digital morphometrics2014Inngår i: World archaeology, ISSN 0043-8243, E-ISSN 1470-1375, Vol. 46, nr 1, s. 101-122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Differences in Paleoindian projectile point morphology have previously been used to define technologies, infer colonization patterns, propose chronological and regional boundaries. In this study, we evaluate the effectiveness of traditional linear measurements and ratios, flake scar angles, and 3D model-based flake contours for the statistical differentiation of projectile point type(s) and reduction technique. Sixty-three fluted bifaces from eastern North America and fourteen replicate Clovis points are analyzed. Discriminant analysis shows that 3D model-based Fourier descriptors of flake scar contours are less successful than traditional metrics in correctly differentiating styles, but more successful in identifying individual knappers. Changes in the symmetry of front and back flake scars between Clovis and later fluted point styles indicate a possible shift in reduction techniques. These findings demonstrate the usefulness of both traditional and modern morphometric variables to quantify biface morphology, and address questions about social interaction and technological change in Pleistocene North America.

  • 20. Henning-Knechtel, Anja
    et al.
    Kumar, Sunil
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Król, Sylwia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Esposito, Gennaro
    Kirmizialtin, Serdal
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hamilton, Andrew D.
    Magzoub, Mazin
    Designed Cell-Penetrating Peptide Inhibitors of Amyloid-beta Aggregation and Cytotoxicity2020Inngår i: Cell Reports Physical Science, E-ISSN 2666-3864, Vol. 1, nr 2, artikkel-id 100014Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyloid proteins and peptides are a major contributing factor to the development of various neurodegenerative disorders, including Alzheimer’s and prion diseases. Previously, a designed cell-penetrating peptide (CPP) comprising a hydrophobic signal sequence followed by a prion protein (PrP)-derived polycationic sequence (PrP23–28: KKRPKP) was shown to have potent anti-prion properties. Here, we extend this approach toward the amyloid-beta (Aβ) peptide amyloid formation, which is associated with Alzheimer’s disease. We characterized the interactions of the CPP with Aβ using complementary in vitro and in silico experiments. We report that the CPP stabilizes Aβ in a non-amyloid state and inhibits Aβ-induced neurotoxicity. Moreover, replacing PrP23–28 with a corresponding segment from Aβ results in a construct with similar CPP functionality and antagonism of Aβ aggregation and neurotoxicity. Our findings reveal a general underlying principle for inhibition of pathogenic protein aggregation that may facilitate the design of CPP-based therapeutics for amyloid diseases.

  • 21. Horvath, Istvan
    et al.
    Iashchishyn, Igor A.
    Moskalenko, Roman A.
    Wang, Chao
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kovacs, Gabor G.
    Morozova-Roche, Ludmilla A.
    Co-aggregation of pro-inflammatory S100A9 with alpha-synuclein in Parkinson's disease: ex vivo and in vitro studies2018Inngår i: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, artikkel-id 172Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease. This is the first report on the co-aggregation of alpha-synuclein (alpha-syn) and S100A9 both in vitro and ex vivo in PD brain. Methods: Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and alpha-syn location and aggregation. In vitro studies revealing S100A9 and alpha-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. Results: Co-localized and co-aggregated S100A9 and alpha-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also observed in Lewy bodies in PD frontal lobe (Braak stages 4-6). Lewy bodies were characterized by ca. 10-23 mu m outer diameter, with S100A9 and alpha-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and alpha-syn were shown to interact with each other via the alpha-syn C-terminus with an apparent dissociation constant of ca. 5 mu M. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of alpha-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers. Conclusions: We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving alpha-syn and S100A9 and leading to PD, similar to the effect of S100A9 and A beta co-aggregation in Alzheimer's disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues.

  • 22. Koski, Lassi
    et al.
    Berntsson, Elina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Vikström, Max
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Roos, Per M.
    Metal ratios as possible biomarkers for amyotrophic lateral sclerosis2023Inngår i: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 78, artikkel-id 127163Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown aetiology. Metals have been suspected to contribute to ALS pathogenesis since mid-19th century, yet studies on measured metal concentrations in ALS patients have often yielded conflicting results, with large individual variation in measured values. Calculating metal concentration ratios can unveil possible synergistic effects of neurotoxic metals in ALS pathogenesis. The aim of this study was to investigate if ratios of different metal concentrations in cerebrospinal fluid (CSF) and blood plasma, respectively, differ between ALS patients and healthy controls.

    Methods: Cerebrospinal fluid and blood plasma were collected from 17 ALS patients and 10 controls. Samples were analysed for 22 metals by high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS), and all possible 231 metal ratios calculated in each body fluid.

    Results: Fifty-three metal ratios were significantly elevated in ALS cases as compared to controls (p < 0.05); five in blood plasma, and 48 in CSF. The finding of fewer elevated ratios in blood plasma may indicate specific transport of metals into the central nervous system. The elevated metal ratios in CSF include Cd/Se (p = 0.031), and 16 ratios with magnesium, such as Mn/Mg (p = 0.005) and Al/Mg (p = 0.014).

    Conclusion: Metal ratios may be used as biomarkers in ALS diagnosis and as guidelines for preventive measures.

  • 23. Koski, Lassi
    et al.
    Ronnevi, Cecilia
    Berntsson, Elina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Roos, Per M.
    Metals in ALS TDP-43 Pathology2021Inngår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, nr 22, artikkel-id 12193Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.

  • 24.
    Król, Sylwia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Österlund, Nicklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Vosough, Faraz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Barth, Andreas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ilag, Leopold Luna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Magzoub, Mazin
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mörman, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments2021Inngår i: iScience, E-ISSN 2589-0042 , Vol. 24, nr 8, artikkel-id 102852Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Substantial research efforts have gone into elucidating the role of protein misfolding and self-assembly in the onset and progression of Alzheimer’s disease (AD). Aggregation of the Amyloid-β (Aβ) peptide into insoluble fibrils is closely associated with AD. Here, we use biophysical techniques to study a peptide-based approach to target Aβ amyloid aggregation. A peptide construct, NCAM-PrP, consists of a largely hydrophobic signal sequence linked to a positively charged hexapeptide. The NCAM-PrP peptide inhibits Aβ amyloid formation by forming aggregates which are unavailable for further amyloid aggregation. In a membrane-mimetic environment, Aβ and NCAM-PrP form specific heterooligomeric complexes, which are of lower aggregation states compared to Aβ homooligomers. The Aβ:NCAM-PrP interaction appears to take place on different aggregation states depending on the absence or presence of a membrane-mimicking environment. These insights can be useful for the development of potential future therapeutic strategies targeting Aβ at several aggregation states.

  • 25. Leshem, Guy
    et al.
    Richman, Michal
    Lisniansky, Elvira
    Antman-Passig, Merav
    Habashi, Maram
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rahimipour, Shai
    Photoactive chlorin e6 is a multifunctional modulator of amyloid-β aggregation and toxicity via specific interactions with its histidine residues2019Inngår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 10, nr 1, s. 208-217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The self-assembly of A to -sheet-rich neurotoxic oligomers is a main pathological event leading to Alzheimer's disease (AD). Selective targeting of A oligomers without affecting other functional proteins is therefore an attractive approach to prevent the disease and its progression. In this study, we report that photodynamic treatment of A in the presence of catalytic amounts of chlorin e6 can selectively damage A and inhibit its aggregation and toxicity. Chlorin e6 also reversed the amyloid aggregation process in the dark by binding its soluble and low molecular weight oligomers, as shown by thioflavin T (ThT) fluorescence and photoinduced cross-linking of unmodified protein (PICUP) methods. Using HSQC NMR spectroscopy, ThT assays, amino acid analysis, SDS/PAGE, and EPR spectroscopy, we show that catalytic amounts of photoexcited chlorin e6 selectively damage the A histidine residues H6, H13, and H14, and induce A cross-linking by generating singlet oxygen. In contrast, photoexcited chlorin e6 was unable to cross-link ubiquitin and -synuclein, demonstrating its high selectivity for A. By binding to the A histidine residues, catalytic amounts of chlorin e6 can also inhibit the Cu2+-induced aggregation and toxicity in darkness, while at stoichiometric amounts it acts as a chelator to reduce the amount of free Cu2+. This study demonstrates the great potential of chlorin e6 as a multifunctional agent for treatment of AD, and shows that the three N-terminal A histidine residues are a suitable target for A-specific drugs.

  • 26. Lindgren, Joel
    et al.
    Segerfeldt, Patrik
    Sholts, Sabrina B.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Karlström, Amelie Eriksson
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Engineered non-fluorescent Affibody molecules facilitate studies of the amyloid-beta (A beta) peptide in monomeric form: Low pH was found to reduce A beta/Cu(II) binding affinity2013Inngår i: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 120, s. 18-23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aggregation of amyloid-beta (A beta) peptides into oligomers and amyloid plaques in the human brain is considered a causative factor in Alzheimer's disease (AD). As metal ions are over-represented in AD patient brains, and as distinct A beta aggregation pathways in presence of Cu(II) have been demonstrated, metal binding to A beta likely affects AD progression. A beta aggregation is moreover pH-dependent, and AD appears to involve inflammatory conditions leading to physiological acidosis. Although metal binding specificity to A beta varies at different pH's, metal binding affinity to A beta has so far not been quantitatively investigated at sub-neutral pH levels. This may be explained by the difficulties involved in studying monomeric peptide properties under aggregation-promoting conditions. We have recently devised a modified Affibody molecule, Z(A beta 3)(12-58), that binds A beta with sub-nanomolar affinity, thereby locking the peptide in monomeric form without affecting the N-terminal region where metal ions bind. Here, we introduce non-fluorescent A beta-binding Affibody variants that keep A beta monomeric while only slightly affecting the A beta peptide's metal binding properties. Using fluorescence spectroscopy, we demonstrate that Cu(II)/A beta(1-40) binding is almost two orders of magnitude weaker at pH 5.0 (apparent K-D = 51 mu M) than at pH 7.3 (apparent K-D = 0.86 mu M). This effect is arguably caused by protonation of the histidines involved in the metal ligandation. Our results indicate that engineered variants of Affibody molecules are useful for studying metal-binding and other properties of monomeric A beta under various physiological conditions, which will improve our understanding of the molecular mechanisms involved in AD.

  • 27. Luo, Jinghui
    et al.
    Mohammed, Inayathulla
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Hiruma, Yoshitaka
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    Endogenous Polyamines Reduce the Toxicity of Soluble A beta Peptide Aggregates Associated with Alzheimer's Disease2014Inngår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, nr 6, s. 1985-1991Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Polyamines promote the formation of the A beta peptide amyloid fibers that are a hallmark of Alzheimer's disease. Here we show that polyamines interact with nonaggregated A beta peptides, thereby reducing the peptide's hydrophobic surface. We characterized the associated conformational change through NMR titrations and molecular dynamics simulations. We found that even low concentrations of spermine, sperimidine, and putrescine fully protected SH-SY5Y (a neuronal cell model) against the most toxic conformational species of AA even at an A beta oligomer concentration that would otherwise kill half of the cells or even more. These observations lead us to conclude that polyamines interfere with the more toxic prefibrillar conformations and might protect cells by promoting the structural transition of A beta toward its less toxic fibrillar state that we reported previously. Since polyamines are present in brain fluid at the concentrations where we observed all these effects, their activity needs to be taken into account in understanding the molecular processes related to the development of Alzheimer's disease.

  • 28. Luo, Jinghui
    et al.
    Otero, José M
    Yu, Chien-Hung
    Wärmländer, Sebastian K T S
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Overhand, Mark
    Abrahams, Jan Pieter
    Inhibiting and Reversing Amyloid-β Peptide (1-40) Fibril Formation with Gramicidin S and Engineered Analogues2013Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, nr 51, s. 17338-17348Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In Alzheimer's disease, amyloid-β (Aβ) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β-sheet conformation, binds to the Aβ peptide hairpin-stacked fibril through β-sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four-times higher than that of the natural product was identified.

  • 29. Luo, Jinghui
    et al.
    Wärmlander, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    Alzheimer Peptides Aggregate into Transient Nanoglobules That Nucleate Fibrils2014Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 53, nr 40, s. 6302-6308Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Protein/peptide oligomerization, cross-beta strand fibrillation, and amyloid deposition play a critical role in many diseases, but despite extensive biophysical characterization, the structural and dynamic details of oligomerization and fibrillation of amyloidic peptides/proteins remain to be fully clarified. Here, we simultaneously monitored the atomic, molecular, and mesoscopic states of aggregating Alzheimer's amyloid beta (A beta) peptides over time, using a slow aggregation protocol and a fast aggregation protocol, and determined the cytotoxicity of the intermediate states. We show that in the early stage of fast fibrillation (the lag phase) the A beta peptides coalesced into apparently unstructured globules (15-200 nm in diameter), which slowly grew larger. Then a sharp transition occurred, characterized by the first appearance of single fibrillar structures of approximately >= 100 nm. These fibrils emerged from the globules. Simultaneously, an increase was observed for the cross-beta strand conformation that is characteristic of the fibrils that constitute mature amyloid. The number and size of single fibrils rapidly increased. Eventually, the fibrils coalesced into mature amyloid. Samples from the early lag phase of slow fibrillation conditions were especially toxic to cells, and this toxicity sharply decreased when fibrils formed and matured into amyloid. Our results suggest that the formation of fibrils may protect cells by reducing the toxic structures that appear in the early lag phase of fibrillation.

  • 30. Luo, Jinghui
    et al.
    Wärmlander, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Yu, Chien-Hung
    Muhammad, Kamran
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    The A beta peptide forms non-amyloid fibrils in the presence of carbon nanotubes2014Inngår i: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 6, nr 12, s. 6720-6726Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Carbon nanotubes have specific properties that make them potentially useful in biomedicine and biotechnology. However, carbon nanotubes may themselves be toxic, making it imperative to understand how carbon nanotubes interact with biomolecules such as proteins. Here, we used NMR, CD, and ThT/fluorescence spectroscopy together with AFM imaging to study pH-dependent molecular interactions between single walled carbon nanotubes (SWNTs) and the amyloid-beta (A beta) peptide. The aggregation of the A beta peptide, first into oligomers and later into amyloid fibrils, is considered to be the toxic mechanism behind Alzheimer's disease. We found that SWNTs direct the A beta peptides to form a new class of beta-sheet-rich yet non-amyloid fibrils.

  • 31. Luo, Jinghui
    et al.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    Human lysozyme inhibits the in vitro aggregation of A beta peptides, which in vivo are associated with Alzheimer's disease2013Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 49, nr 58, s. 6507-6509Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alzheimer's disease is a neurodegenerative disorder characterized by accumulation of A beta peptide aggregates in the brain. Using ThT fluorescence assays, AFM imaging, NMR and CD spectroscopy, and MD modeling we show that lysozyme - a hydrolytic enzyme abundant in human secretions - completely inhibits the aggregation of A beta peptides at equimolar lysozyme : A beta peptide ratios.

  • 32. Luo, Jinghui
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    Cross-interactions between the Alzheimer Disease Amyloid-beta Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis2016Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, nr 32, s. 16485-16493Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-beta (A beta) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A beta and other amyloid proteins.

  • 33. Luo, Jinghui
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    Non-chaperone Proteins Can Inhibit Aggregation and Cytotoxicity of Alzheimer Amyloid beta Peptide2014Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, nr 40, s. 27766-27775Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: A amyloid formation is associated with Alzheimer disease. Results: Non-chaperone proteins prevent amyloid formation and reduce the cytotoxicity of the A peptide. Conclusion: Non-chaperone proteins may affect the onset and development of Alzheimer disease by interfering with A peptide aggregation. Significance: Non-chaperone proteins can function as a chaperone protein to regulate the pathway of the A fibrillation in proteostasis providing a new strategy in the treatment of Alzheimer disease. Many factors are known to influence the oligomerization, fibrillation, and amyloid formation of the A peptide that is associated with Alzheimer disease. Other proteins that are present when A peptides deposit in vivo are likely to have an effect on these aggregation processes. To separate specific versus broad spectrum effects of proteins on A aggregation, we tested a series of proteins not reported to have chaperone activity: catalase, pyruvate kinase, albumin, lysozyme, -lactalbumin, and -lactoglobulin. All tested proteins suppressed the fibrillation of Alzheimer A(1-40) peptide at substoichiometric ratios, albeit some more effectively than others. All proteins bound non-specifically to A, stabilized its random coils, and reduced its cytotoxicity. Surprisingly, pyruvate kinase and catalase were at least as effective as known chaperones in inhibiting A aggregation. We propose general mechanisms for the broad-spectrum inhibition A fibrillation by proteins. The mechanisms we discuss are significant for prognostics and perhaps even for prevention and treatment of Alzheimer disease.

  • 34. Luo, Jinghui
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    Reciprocal Molecular Interactions between the A beta Peptide Linked to Alzheimer's Disease and Insulin Linked to Diabetes Mellitus Type II2016Inngår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 7, nr 3, s. 269-274Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Clinical studies indicate diabetes mellitus type II (DM) doubles the risk that a patient will also develop Alzheimer's disease (AD). DM is caused by insulin resistance and a relative lack of active insulin. AD is characterized by the deposition of amyloid beta (A beta) peptide fibrils. Prior to fibrillating, A beta forms intermediate, prefibrillar oligomers, which are more cytotoxic than the mature A beta fibrils. Insulin can also form amyloid fibrils. In vivo studies have revealed that insulin promotes the production of A beta, and that soluble A beta competes with insulin for the insulin receptor. Here, we report that monomeric insulin interacted with soluble A beta and that both molecules reciprocally slowed down the aggregation kinetics of the other. Prefibrillar oligomers of A beta that eventually formed in the presence of insulin were less cytotoxic than A beta oligomers formed in the absence of insulin. Mature A beta fibrils induced fibrillation of soluble insulin, but insulin aggregates did not promote A beta fibrillation. Our study indicates that direct molecular interactions between insulin and A beta may contribute to the strong link between DM and AD.

  • 35. Luo, Jinghui
    et al.
    Yu, Chien-Hung
    Yu, Huixin
    Borstnar, Rok
    Kamerlin, Shina C. L.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Abrahams, Jan Pieter
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Cellular Polyamines Promote Amyloid-Beta (A beta) Peptide Fibrillation and Modulate the Aggregation Pathways2013Inngår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 4, nr 3, s. 454-462Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (A beta) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric A beta(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 mu M spermine (normal intracellular concentration is similar to 1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce A beta(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of A beta peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.

  • 36. Neiss, Michael
    et al.
    Sholts, Sabrina B.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. University of California, USA.
    New applications of 3D modeling in artefact analysis: three case studies of Viking Age brooches2016Inngår i: Archaeological and Anthropological Sciences, ISSN 1866-9557, E-ISSN 1866-9565, Vol. 8, nr 4, s. 651-662Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Three-dimensional (3D) laser scanning is a nondestructive and versatile technique that provides archaeologists with 3D models of archaeological and ethnographic objects. We have previously shown that 3D models facilitate shape analysis of archaeological bones and stone tools, due to the high measurement accuracy inherent in the latest generation of 3D laser scanners. Here, we explore the utility of 3D modeling as a tool for analyzing Viking Age metal artefacts with complex morphologies. Four highly ornate Viking Age brooches from Scandinavia and Russia were digitized with a portable laser scanner, and the resulting 3D models were used in three case studies of (a) artefact reconstruction, (b) tool mark analysis, and (c) motif documentation. The results revealed both strengths and limitations of the employed techniques. 3D modeling proved to be very well suited for artefact reconstruction and was helpful also in the stylistic and motif analysis. The tool mark analysis was only partially successful, due to the resolution limits of the laser scanner used. 3D-based motif analysis of a grandiose Scandinavian-style brooch from Yelets, Russia, identified an anthropomorphic figure with a bird-like body that previously has been overlooked. This figure may be a Rurikid coat of arms, possibly linking the object to a princely household and providing further evidence for a connection between Scandinavia and the Rurikids. As 3D technology keeps improving, we expect that additional applications for 3D modeling in archaeology will be developed, likely leading to many new findings when old objects are re-analyzed with modern techniques. However, our results indicate that 3D modeling cannot completely replace traditional artefact analysis-instead, we argue that the two approaches are best used in combination.

  • 37. Noormägi, Andra
    et al.
    Golubeva, Tatjana
    Berntsson, Elina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Tallinn University of Technology, Estonia.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Tõugu, Vello
    Palumaa, Peep
    Direct Competition of ATCUN Peptides with Human Serum Albumin for Copper(II) Ions Determined by LC-ICP MS2023Inngår i: ACS Omega, E-ISSN 2470-1343, Vol. 8, nr 37, s. 33912-33919Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Copper is an indispensable biometal, primarily serving as a redox-competent cofactor in numerous proteins. Apart from preformed copper-binding sites within the protein structures, small peptide motifs exist called ATCUN, which are composed of an N-terminal tripeptide XZH, able to bind Cu(II) ions in exchangeable form. These motifs are common for serum albumin, but they are also present in a wide range of proteins and peptides. These proteins and peptides can be involved in copper metabolism, and copper ions can affect their biological role. The distribution of copper between the ATCUN peptides, including truncated amyloid-β (Aβ) peptides Aβ4–42 and Aβ11–42, which may be involved in Alzheimer’s disease pathogenesis, is mainly determined by their concentrations and relative Cu(II)-binding affinities. The Cu(II)-binding affinity (log Kd) of several ATCUN peptides, determined by different methods and authors, varies by more than three orders of magnitude. This variation may be attributed to the chemical properties of peptides but can also be influenced by the differences in methods and experimental conditions used for the determination of Kd. In the current study, we performed direct competition experiments between selected ATCUN peptides and HSA by using an LC-ICP MS-based approach. We demonstrated that ATCUN and truncated Aβ peptides Aβ4–16 and Aβ11–15 bind Cu(II) ions with an affinity similar to that for HSA. Our results demonstrate that ATCUN motifs cannot compete with excess HSA for the binding of Cu(II) ions in the blood and cerebrospinal fluid. 

  • 38. Olowoyo, J. O.
    et al.
    Tshoni, U. A.
    Kobyana, A. S.
    Lion, G. N.
    Mugivhisa, L. L.
    Koski, L.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Roos, P. M.
    Blood lead concentrations in exposed forecourt attendants and taxi drivers in parts of South Africa2024Inngår i: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 81, artikkel-id 127348Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Leaded fuel was banned in South Africa in 2006, in order to improve human health and reduce environmental pollution. Lead (Pb) has been suggested to contribute to the development of neurodegenerative disorders, and the role of respiratory exposure to Pb from petrol fumes should not be neglected in this context. In addition to Pb, petrol contains various harmful chemicals including other neurotoxic metals and hydrocarbons.

    Objectives and Methods: Here, we investigated concentrations of Pb and other metals in blood from petrol station forecourt attendants (n = 38), taxi drivers (n = 21), and unexposed controls (n = 36). Taxi drivers and forecourt attendants were divided into three groups each, based on number of years worked. A questionnaire was designed to investigate the health status of the participants. Blood samples were collected by medical professionals and analyzed for metal concentrations by ICP-MS.

    Results: A positive correlation between number of years worked and Pb blood concentrations was found. The highest Pb concentration (60.2 µg/L) was observed in a forecourt attendant who had worked 11–20 years, and the average Pb concentration in this group (24.5 µg/L) was significantly (p < 0.05) higher than in forecourt attendants who had worked 2–5 years (10.4 µg/L). Some individuals had elevated concentrations of manganese, arsenic, cadmium, chromium and cobalt, yet not significantly elevated at the group level. The blood levels of arsenic appeared to be related to smoking. Mood swings, dizziness, headaches and tiredness were reported by the workers.

    Conclusion: Blood Pb concentrations in petrol station forecourt attendants and taxi drivers exposed to leaded petrol are elevated and correlate to exposure time. A health monitoring program should be erected for all individuals working in these industries, and preventive measures should be implemented to eliminate metal exposure from petrol.

  • 39. Owen, Michael C.
    et al.
    Gnutt, David
    Gao, Mimi
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Winter, Roland
    Ebbinghaus, Simon
    Strodel, Birgit
    Effects of in vivo conditions on amyloid aggregation2019Inngår i: Chemical Society Reviews, ISSN 0306-0012, E-ISSN 1460-4744, Vol. 48, nr 14, s. 3946-3996Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

  • 40. Pansieri, Jonathan
    et al.
    Ostojic, Lucija
    Iashchishyn, Igor A.
    Magzoub, Mazin
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Mai, Nguyen
    Smirnovas, Vytautas
    Svedruzic, Zeljko
    Morozova-Roche, Ludmilla A.
    Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs2019Inngår i: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, nr 7, s. 1410-1417Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyloid cascade and neuroinflammation are hallmarks of neurodegenerative diseases, and pro-inflammatory S100A9 protein is central to both of them. Here, we have shown that NCAM1 peptide constructs carrying polycationic sequences derived from A beta peptide (KKLVFF) and PrP protein (KKRPKP) significantly promote the S100A9 amyloid self-assembly in a concentration-dependent manner by making transient interactions with individual S100A9 molecules, perturbing its native structure and acting as catalysts. Since the individual molecule misfolding is a rate-limiting step in S100A9 amyloid aggregation, the effects of the NCAM1 construct on the native S100A9 are so critical for its amyloid self-assembly. S100A9 rapid self assembly into large aggregated clumps may prevent its amyloid tissue propagation, and by modulating S100A9 aggregation as a part of the amyloid cascade, the whole process may be effectively tuned.

  • 41. Petaros, Anja
    et al.
    Garvi, Heather M.
    Sholts, Sabrina B.
    Schlager, Stefan
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. UCLA, USA; Linköping University, Sweden.
    Sexual dimorphism and regional variation in human frontal bone inclination measured via digital 3D models2017Inngår i: Legal Medicine, ISSN 1344-6223, E-ISSN 1873-4162, Vol. 29, s. 53-61Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The frontal bone is one of the most sexually dimorphic elements of the human skull, due to features such as the glabella, frontal eminences, and frontal inclination. While glabella is frequently evaluated in procedures to estimate sex in unknown human skeletal remains, frontal inclination has received less attention. In this study we present a straightforward, quick, and reproducible method for measuring frontal inclination angles from glabella and supraglabella. Using a sample of 413 human crania from four different populations (U.S. Whites, U.S. Blacks, Portuguese, and Chinese), we test the usefulness of the inclination angles for sex estimation and compare their performance to traditional methods of frontal inclination assessment. Accuracy rates in the range 75-81% were achieved for the U.S. White, U.S. Black, and Portuguese groups. For Chinese the overall accuracy was lower, i.e. 66%. Although some regional variation was observed, a cut-off value of 78.2 for glabellar inclination angles separates female and male crania from all studied populations with good accuracy. As inclination angles measured from glabella captures two sexually dimorphic features (i.e. glabellar prominence and frontal inclination) in a single measure, the observed clear male/female difference is not unexpected. Being continuous variables, inclination angles are suitable for use in statistical methods for sex estimations.

  • 42. Petaros, Anja
    et al.
    Sholts, Sabrina B.
    Slaus, Mario
    Bosnar, Alan
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Linköping University, Sweden; University of California in Los Angeles, USA.
    Evaluating sexual dimorphism in the human mastoid process: A viewpoint on the methodology2015Inngår i: Clinical anatomy (New York, N.Y. Print), ISSN 0897-3806, E-ISSN 1098-2353, Vol. 28, nr 5, s. 593-601Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mastoid process is one of the most sexually dimorphic features in the human skull, and is therefore often used to identify the sex of skeletons. Numerous techniques for assessing variation in the size and shape of the mastoid process have been proposed and implemented in osteological research, but its complex form still presents difficulties for consistent and effective analysis. In this article, we compare the different techniques and variables that have been used to define, measure, and visually score sexual dimorphism in the mastoid process. We argue that the current protocols fail to capture the full morphological range of this bony projection, and suggest ways of improving and standardizing them, regarding both traditional and 3D-based approaches. Clin. Anat. 28:593-601, 2015.

  • 43. Petaros, Anja
    et al.
    Sholts, Sabrina B.
    Čavka, Mislav
    Šlaus, Mario
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. UCLA, USA; Linköping University, Sweden.
    Sexual dimorphism in mastoid process volumes measured from 3D models of dry crania from mediaeval Croatia2021Inngår i: Homo (Stuttgart), ISSN 0018-442X, E-ISSN 1618-1301, Vol. 72, nr 2, s. 113-127Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    3D analysis of skeletal volumes has become an important field in digital anthropology studies. The volume of the mastoid process has been proposed to display significant sexual dimorphism, but it has a complex shape and to date no study has quantified the full mastoid volume for sex estimation purposes. In this study we compared three different ways to isolate the volume of the mastoid process from digital 3D models of dry crania, and then evaluated the performance of the three different volume definitions for sex estimation purposes. A total of 170 crania (86 male, 84 females) excavated from five medieval Croatian sites were CT-scanned and used to produce 3D stereolitographic models. The three different isolation techniques were based on various anatomical landmarks and planes, as well as the anatomy of the mastoid process itself. Measurements of the three different mastoid volumes yielded different accuracies and precisions. Interestingly, anatomical structures were sometimes more useful than classical landmarks as demarcators of mastoid volume. For all three volume definitions, male mastoid volumes were significantly larger than female volumes, in both relative and absolute numbers. Sex estimation based on mastoid volume showed a slightly higher precision and better accuracy (71% correct classifications) than visual scoring techniques (67%) and linear distance measurements (69%) of the mastoid process. Sex estimation based on cranial size performed even better (78%), and multifactorial analysis (cranium size + mastoid volume) reached up to 81% accuracy. These results show that measurements of the mastoid volume represent a promising metric to be used in multifactorial approaches for sex estimation of human remains.

  • 44. Rajkovic, Andrei
    et al.
    Kanchugal, Sandesh
    Abdurakhmanov, Eldar
    Howard, Rebecca
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wärmländer, Sebastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Erwin, Joseph
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Barrera Saldaña, Hugo A.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Danielson, Helena
    Coulbourn Flores, Samuel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Swedish University of Agricultural Sciences, Sweden.
    Amino acid substitutions in human growth hormone affect coiled-coil content and receptor binding2023Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 18, nr 3, artikkel-id e0282741Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The interaction between human Growth Hormone (hGH) and hGH Receptor (hGHR) has basic relevance to cancer and growth disorders, and hGH is the scaffold for Pegvisomant, an anti-acromegaly therapeutic. For the latter reason, hGH has been extensively engineered by early workers to improve binding and other properties. We are particularly interested in E174 which belongs to the hGH zinc-binding triad; the substitution E174A is known to significantly increase binding, but to now no explanation has been offered. We generated this and several computationally-selected single-residue substitutions at the hGHR-binding site of hGH. We find that, while many successfully slow down dissociation of the hGH-hGHR complex once bound, they also slow down the association of hGH to hGHR. The E174A substitution induces a change in the Circular Dichroism spectrum that suggests the appearance of coiled-coiling. Here we show that E174A increases affinity of hGH against hGHR because the off-rate is slowed down more than the on-rate. For E174Y (and certain mutations at other sites) the slowdown in on-rate was greater than that of the off-rate, leading to decreased affinity. The results point to a link between structure, zinc binding, and hGHR-binding affinity in hGH.

  • 45. Richman, Michal
    et al.
    Wilk, Sarah
    Chemerovski, Marina
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Wahlström, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rahimipour, Shai
    In Vitro and Mechanistic Studies of an Antiamyloidogenic Self-Assembled Cyclic D,L-alpha-Peptide Architecture2013Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 135, nr 9, s. 3474-3484Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Misfolding of the A beta protein and its subsequent aggregation into toxic oligomers are related to Alzheimer's disease. Although peptides of various sequences can self-assemble into amyloid structures, these structures share common three-dimensional features that may promote their cross-reaction. Given the significant similarities between amyloids and the architecture of self-assembled cyclic D,L-alpha-peptide, we hypothesized that the latter may bind and stabilize a nontoxic form of A beta thereby preventing its aggregation into toxic forms. By screening a focused library of six-residue cyclic D,L-alpha-peptides and optimizing the activity of a lead peptide, we found one cyclic D,L-alpha-peptide (CP-2) that interacts strongly with A beta and inhibits its aggregation. In transmission electron microscopy, optimized thioflavin T and cell survival assays, CP-2 inhibits the formation of A beta aggregates, entirely disassembles preformed aggregated and fibrillar A beta, and protects rat pheochromocytoma PC12 cells from A beta toxicity, without inducing any toxicity by itself. Using various immunoassays, circular dichroism spectroscopy, photoinduced cross-linking of unmodified proteins (PICUP) combined with SDS/PAGE, and NMR, we probed the mechanisms underlying CP-2's antiamyloidogenic activity. NMR spectroscopy indicates that CP-2 interacts with A beta through its self-assembled conformation and induces weak secondary structure in A beta. Upon coincubation, CP-2 changes the aggregation pathway of A beta and alters its oligomer distribution by stabilizing small oligomers (1-3 mers). Our results support studies suggesting that toxic early oligomeric states of A beta may be composed of antiparallel beta-peptide structures and that the interaction of A beta with CP-2 promotes formation of more benign parallel beta-structures. Further studies will show whether these kinds of abiotic cyclic D,L-alpha-peptides are also beneficial as an intervention in related in vivo models.

  • 46. Roos, Elin
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. UCLA, USA.
    Meyer, Jeremy
    Sholts, Sabrina B.
    Jarvet, Jüri
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. The National Institute of Chemical Physics and Biophysics, Estonia.
    Gräslund, Astrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Roos, Per M.
    Amyotrophic Lateral Sclerosis After Exposure to Manganese from Traditional Medicine Procedures in Kenya2021Inngår i: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 199, s. 3618-3624Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss and widespread muscular atrophy. Despite intensive investigations on genetic and environmental factors, the cause of ALS remains unknown. Recent data suggest a role for metal exposures in ALS causation. In this study we present a patient who developed ALS after a traditional medical procedure in Kenya. The procedure involved insertion of a black metal powder into several subcutaneous cuts in the lower back. Four months later, general muscle weakness developed. Clinical and electrophysiological examinations detected widespread denervation consistent with ALS. The patient died from respiratory failure less than a year after the procedure. Scanning electron microscopy and X-ray diffraction analyses identified the black powder as potassium permanganate (KMnO4). A causative relationship between the systemic exposure to KMnO4 and ALS development can be suspected, especially as manganese is a well-known neurotoxicant previously found to be elevated in cerebrospinal fluid from ALS patients. Manganese neurotoxicity and exposure routes conveying this toxicity deserve further attention.

  • 47. Saage, Ragnar
    et al.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Cotsen Institute of Archaeology, UCLA, USA.
    Metal residues in 5th c. BCE-13th c. CE Estonian tools for non-ferrous metal casting2018Inngår i: Journal of Archaeological Science: Reports, ISSN 2352-409X, E-ISSN 2352-4103, Vol. 19, s. 35-51Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This paper investigates Estonian tools for non-ferrous metal casting in the form of crucibles, moulds, and casting ladles dating to the Estonian Iron Age (500 BCE-1227 CE), adding elemental analysis and 3D modelling to the traditional typological comparison. In contrast to the neighbouring countries of Russia, Latvia, and Sweden, no comprehensive study has previously been published on this subject for Estonian material. The typological analysis sets Iron Age Estonia in the same metalworking tradition as that of other eastern Baltic countries and Northwestern Russia. However, some classes of casting tools present in Scandinavian and Slavonic areas have so far not been encountered in the Estonian archaeological record. The elemental analysis included qualitative pXRF analysis of 175 artefacts and detailed residue analysis using SEM-EDS of thirteen selected artefacts. This analysis identified for the first time Estonian Iron Age casting tools - crucibles - used for casting gold and silver. Most of the investigated crucibles were used for casting various copper alloys, while the casting ladles and most of the stone moulds were used for casting pewter. Casting of pewter and precious metals only occurred in regional centres such as hill forts and strongholds, while copper alloys were cast in all parts of Estonia. In addition to clarifying fundamental questions about Estonian Iron Age metal casting, this study also lays a foundation for using modern analytical techniques in future investigations of Estonian metalworking traditions.

  • 48. Shearer, Brian M.
    et al.
    Sholts, Sabrina B.
    Garvin, Heather M.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. University of California, USA; Linköping University, Sweden.
    Sexual dimorphism in human browridge volume measured from 3D models of dry crania: A new digital morphometrics approach2012Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 222, nr 1-3, s. 400.e1-400.e5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sex estimation from the human skull is often a necessary step when constructing a biological profile from unidentified human remains. Traditional methods for determining the sex of a skull require observers to rank the expression of sexually dimorphic skeletal traits by subjectively assessing their qualitative differences. One of these traits is the prominence of the glabellar region above the browridge. In this paper, the volume of the browridge region was measured from digital 3D models of 128 dry crania ( 65 female, 63 male). The 3D models were created with a desktop laser scanner, and the browridge region of each 3D model was isolated using geometric planes defined by cranial landmarks. Statistical analysis of browridge-to-cranium volume ratios revealed significant differences between male and female crania. Differences were also observed between geographically distinct populations, and between temporally distinct populations from the same locale. The results suggest that in the future, sex determination of human crania may be assisted by quantitative computer-based volume calculations from 3D models, which can provide increased objectivity and repeatability when compared to traditional forensic techniques. The method presented in this paper can easily be extended to other volumetric regions of the human cranium.

  • 49. Sholts, Sabrina B.
    et al.
    Gingerich, Joseph A. M.
    Schlager, Stefan
    Stanford, Dennis J.
    Wärmländer, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. University of California Los Angeles, California.
    Tracing social interactions in Pleistocene North America via 3D model analysis of stone tool asymmetry2017Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 12, nr 7, artikkel-id e0179933Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stone tools, often the sole remnant of prehistoric hunter-gatherer behavior, are frequently used as evidence of ancient human mobility, resource use, and environmental adaptation. In North America, studies of morphological variation in projectile points have provided important insights into migration and interactions of human groups as early as 12-13 kya. Using new approaches to 3D imaging and morphometric analysis, we here quantify bifacial asymmetry among early North American projectile point styles to better understand changes in knapping technique and cultural transmission. Using a sample of 100 fluted bifaces of Clovis and post-Clovis styles in the eastern United States ca. 13,100-9,000 cal BP (i.e., Clovis, Debert-Vail, Bull Brook, Michaud-Neponset/Barnes, and Crowfield), we employed two different approaches for statistical shape analysis: our previously presented method for analysis of 2D flake scar contours, and a new approach for 3D surface analysis using spherical harmonics (SPHARM). Whereas bifacial asymmetry in point shape does not vary significantly across this stylistic sequence, our measure of asymmetric flake scar patterning shows temporal variation that may signify the beginning of regionalization among early New World colonists.

  • 50. Sholts, Sabrina B.
    et al.
    Smith, Kevin
    Wallin, Cecilia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Ahmed, Trifa Mohammad
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Wärmlander, Sebastian K. T. S.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. UCLA, USA.
    Ancient water bottle use and polycyclic aromatic hydrocarbon (PAH) exposure among California Indians: a prehistoric health risk assessment2017Inngår i: Environmental Health, E-ISSN 1476-069X, Vol. 16, artikkel-id 61Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Polycyclic aromatic hydrocarbons (PAHs) are the main toxic compounds in natural bitumen, a fossil material used by modern and ancient societies around the world. The adverse health effects of PAHs on modern humans are well established, but their health impacts on past populations are unclear. It has previously been suggested that a prehistoric health decline among the native people living on the California Channel Islands may have been related to PAH exposure. Here, we assess the potential health risks of PAH exposure from the use and manufacture of bitumen-coated water bottles by ancient California Indian societies. Methods: We replicated prehistoric bitumen-coated water bottles with traditional materials and techniques of California Indians, based on ethnographic and archaeological evidence. In order to estimate PAH exposure related to water bottle manufacture and use, we conducted controlled experiments to measure PAH contamination 1) in air during the manufacturing process and 2) in water and olive oil stored in a completed bottle for varying periods of time. Samples were analyzed with gas chromatography/mass spectrometry (GC/MS) for concentrations of the 16 PAHs identified by the US Environmental Protection Agency (EPA) as priority pollutants. Results: Eight PAHs were detected in concentrations of 1-10 mu g/m(3) in air during bottle production and 50-900 ng/L in water after 2 months of storage, ranging from two-ring (naphthalene and methylnaphthalene) to four-ring (fluoranthene) molecules. All 16 PAHs analyzed were detected in olive oil after 2 days (2 to 35 mu g/kg), 2 weeks (3 to 66 mu g/kg), and 2 months (5 to 140 mu g/kg) of storage. Conclusions: For ancient California Indians, water stored in bitumen-coated water bottles was not a significant source of PAH exposure, but production of such bottles could have resulted in harmful airborne PAH exposure.

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