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Publications (10 of 32) Show all publications
Paul, S., Jenistova, A., Vosough, F., Berntsson, E., Mörman, C., Jarvet, J., . . . Barth, A. (2023). 13C- and 15N-labeling of amyloid-β and inhibitory peptides to study their interaction via nanoscale infrared spectroscopy. Communications Chemistry, 6(1), Article ID 163.
Open this publication in new window or tab >>13C- and 15N-labeling of amyloid-β and inhibitory peptides to study their interaction via nanoscale infrared spectroscopy
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2023 (English)In: Communications Chemistry, E-ISSN 2399-3669, Vol. 6, no 1, article id 163Article in journal (Refereed) Published
Abstract [en]

Interactions between molecules are fundamental in biology. They occur also between amyloidogenic peptides or proteins that are associated with different amyloid diseases, which makes it important to study the mutual influence of two polypeptides on each other's properties in mixed samples. However, addressing this research question with imaging techniques faces the challenge to distinguish different polypeptides without adding artificial probes for detection. Here, we show that nanoscale infrared spectroscopy in combination with C-13, N-15-labeling solves this problem. We studied aggregated amyloid-& beta; peptide (A & beta;) and its interaction with an inhibitory peptide (NCAM1-PrP) using scattering-type scanning near-field optical microscopy. Although having similar secondary structure, labeled and unlabeled peptides could be distinguished by comparing optical phase images taken at wavenumbers characteristic for either the labeled or the unlabeled peptide. NCAM1-PrP seems to be able to associate with or to dissolve existing A & beta; fibrils because pure A & beta; fibrils were not detected after mixing. Interactions of proteins or polypeptides with different secondary structures can be studied in a mixture by nanoscale infrared spectroscopy, however, this technique remains challenging for polypeptides with similar secondary structures. Here, the authors demonstrate clear discrimination of two polypeptides from a mixture by scattering-type scanning near-field optical microscopy when one of the components is labeled with C-13- and N-15-isotopes.

National Category
Chemical Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-221129 (URN)10.1038/s42004-023-00955-w (DOI)001042052900001 ()37537303 (PubMedID)2-s2.0-85167397298 (Scopus ID)
Available from: 2023-09-18 Created: 2023-09-18 Last updated: 2023-09-18Bibliographically approved
Berntsson, E., Vosough, F., Noormagi, A., Padari, K., Asplund, F., Gielnik, M., . . . Wärmländer, S. (2023). Characterization of Uranyl (UO22+) Ion Binding to Amyloid Beta (Aβ) Peptides: Effects on Aβ Structure and Aggregation. ACS Chemical Neuroscience, 14(15), 2618-2633
Open this publication in new window or tab >>Characterization of Uranyl (UO22+) Ion Binding to Amyloid Beta (Aβ) Peptides: Effects on Aβ Structure and Aggregation
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2023 (English)In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 14, no 15, p. 2618-2633Article in journal (Refereed) Published
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. 

Keywords
Alzheimer's disease, amyloid aggregation, metal-protein binding, neurodegeneration, heavy metal toxicity
National Category
Neurosciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-221233 (URN)10.1021/acschemneuro.3c00130 (DOI)001035034000001 ()37487115 (PubMedID)2-s2.0-85166386170 (Scopus ID)
Available from: 2023-09-19 Created: 2023-09-19 Last updated: 2023-09-19Bibliographically approved
Biswas, A., Maloverjan, M., Padari, K., Abroi, A., Rätsep, M., Wärmländer, S. K. T., . . . Pooga, M. (2023). Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery. Pharmaceutics, 15(2), Article ID 396.
Open this publication in new window or tab >>Choosing an Optimal Solvent Is Crucial for Obtaining Cell-Penetrating Peptide Nanoparticles with Desired Properties and High Activity in Nucleic Acid Delivery
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2023 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 15, no 2, article id 396Article in journal (Refereed) Published
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.

Keywords
cell-penetrating peptides, solvent, nanoparticle formation, nucleic acid delivery
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-215998 (URN)10.3390/pharmaceutics15020396 (DOI)000940877200001 ()36839718 (PubMedID)2-s2.0-85149152654 (Scopus ID)
Available from: 2023-03-31 Created: 2023-03-31 Last updated: 2023-03-31Bibliographically approved
Gielnik, M., Szymańska, A., Dong, X., Jarvet, J., Svedružić, Ž. M., Gräslund, A., . . . Wärmländer, S. . T. (2023). Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions. Biochemistry, 62(11), 1689-1705
Open this publication in new window or tab >>Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions
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2023 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 62, no 11, p. 1689-1705Article in journal (Refereed) Published
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.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-218066 (URN)10.1021/acs.biochem.3c00129 (DOI)000988877300001 ()37163663 (PubMedID)2-s2.0-85160591106 (Scopus ID)
Available from: 2023-07-25 Created: 2023-07-25 Last updated: 2023-10-12Bibliographically approved
Berntsson, E., Sardis, M., Noormägi, A., Jarvet, J., Roos, P. M., Töugu, V., . . . Wärmländer, S. K. .. (2022). Mercury Ion Binding to Apolipoprotein E Variants ApoE2, ApoE3, and ApoE4: Similar Binding Affinities but Different Structure Induction Effects. ACS Omega, 7(33), 28924-28931
Open this publication in new window or tab >>Mercury Ion Binding to Apolipoprotein E Variants ApoE2, ApoE3, and ApoE4: Similar Binding Affinities but Different Structure Induction Effects
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2022 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 7, no 33, p. 28924-28931Article in journal (Refereed) Published
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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-209191 (URN)10.1021/acsomega.2c02254 (DOI)000846759000001 ()36033665 (PubMedID)
Available from: 2022-09-19 Created: 2022-09-19 Last updated: 2022-09-19Bibliographically approved
Roos, E., Wärmländer, S. K. T., Meyer, J., Sholts, S. B., Jarvet, J., Gräslund, A. & Roos, P. M. (2021). Amyotrophic Lateral Sclerosis After Exposure to Manganese from Traditional Medicine Procedures in Kenya. Biological Trace Element Research, 199, 3618-3624
Open this publication in new window or tab >>Amyotrophic Lateral Sclerosis After Exposure to Manganese from Traditional Medicine Procedures in Kenya
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2021 (English)In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 199, p. 3618-3624Article in journal (Refereed) Published
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.

Keywords
Amyotrophic lateral sclerosis, Manganese, Neurodegeneration, Potassium permanganate, Traditional medicine
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-189353 (URN)10.1007/s12011-020-02501-4 (DOI)000591957100002 ()33230634 (PubMedID)
Available from: 2021-01-21 Created: 2021-01-21 Last updated: 2022-02-25Bibliographically approved
Berntsson, E., Paul, S., Vosough, F., Sholts, S. B., Jarvet, J., Roos, P. M., . . . Wärmländer, S. (2021). Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation. Acta Biochimica Polonica, 68(2), 169-179
Open this publication in new window or tab >>Lithium ions display weak interaction with amyloid-beta (Aβ) peptides and have minor effects on their aggregation
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2021 (English)In: Acta Biochimica Polonica, ISSN 0001-527X, E-ISSN 1734-154X, Vol. 68, no 2, p. 169-179Article in journal (Refereed) Published
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.

Keywords
Alzheimer's disease, protein aggregation, metal-protein binding, neurodegeneration, pharmaceutics
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-196438 (URN)10.18388/abp.2020_5493 (DOI)000659435200003 ()33909969 (PubMedID)
Available from: 2021-09-08 Created: 2021-09-08 Last updated: 2022-10-11Bibliographically approved
Król, S., Österlund, N., Vosough, F., Jarvet, J., Wärmländer, S., Barth, A., . . . Mörman, C. (2021). The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments. iScience, 24(8), Article ID 102852.
Open this publication in new window or tab >>The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments
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2021 (English)In: iScience, E-ISSN 2589-0042 , Vol. 24, no 8, article id 102852Article in journal (Refereed) Published
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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-198433 (URN)10.1016/j.isci.2021.102852 (DOI)000686897200039 ()34381976 (PubMedID)
Available from: 2021-11-09 Created: 2021-11-09 Last updated: 2023-09-04Bibliographically approved
Henning-Knechtel, A., Kumar, S., Wallin, C., Król, S., Wärmländer, S. K. T., Jarvet, J., . . . Magzoub, M. (2020). Designed Cell-Penetrating Peptide Inhibitors of Amyloid-beta Aggregation and Cytotoxicity. Cell Reports Physical Science, 1(2), Article ID 100014.
Open this publication in new window or tab >>Designed Cell-Penetrating Peptide Inhibitors of Amyloid-beta Aggregation and Cytotoxicity
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2020 (English)In: Cell Reports Physical Science, E-ISSN 2666-3864, Vol. 1, no 2, article id 100014Article in journal (Refereed) Published
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.

Keywords
aggregation, Alzheimer’s disease, amyloid-beta peptide, cell-penetrating peptides, drug design, neurodegeneration, oligomers, prion protein, protein engineering, signal sequence
National Category
Chemical Sciences
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-181494 (URN)10.1016/j.xcrp.2020.100014 (DOI)
Available from: 2020-05-06 Created: 2020-05-06 Last updated: 2022-07-27Bibliographically approved
Wallin, C., Friedemann, M., Sholts, S. B., Noormägi, A., Svantesson, T., Jarvet, J., . . . Wärmländer, S. K. T. (2020). Mercury and Alzheimer's Disease: Hg(II) Ions Display Specific Binding to the Amyloid-β Peptide and Hinder Its Fibrillization. Biomolecules, 10(1), Article ID 44.
Open this publication in new window or tab >>Mercury and Alzheimer's Disease: Hg(II) Ions Display Specific Binding to the Amyloid-β Peptide and Hinder Its Fibrillization
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2020 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 10, no 1, article id 44Article in journal (Refereed) Published
Abstract [en]

Brains and blood of Alzheimer's disease (AD) patients have shown elevated mercury concentrations, but potential involvement of mercury exposure in AD pathogenesis has not been studied at the molecular level. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-beta (A beta) peptides aggregated into amyloid fibrils. A beta peptide fibrillization is known to be modulated by metal ions such as Cu(II) and Zn(II). Here, we study in vitro the interactions between A beta peptides and Hg(II) ions by multiple biophysical techniques. Fluorescence spectroscopy and atomic force microscopy (AFM) show that Hg(II) ions have a concentration-dependent inhibiting effect on A beta fibrillization: at a 1:1 A betaHg(II) ratio only non-fibrillar A beta aggregates are formed. NMR spectroscopy shows that Hg(II) ions interact with the N-terminal region of A beta(1-40) with a micromolar affinity, likely via a binding mode similar to that for Cu(II) and Zn(II) ions, i.e., mainly via the histidine residues His6, His13, and His14. Thus, together with Cu(II), Fe(II), Mn(II), Pb(IV), and Zn(II) ions, Hg(II) belongs to a family of metal ions that display residue-specific binding interactions with A beta peptides and modulate their aggregation processes.

Keywords
mercury, Alzheimer's disease, amyloid aggregation, metal-protein binding, neurodegeneration
National Category
Biological Sciences Neurology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-180830 (URN)10.3390/biom10010044 (DOI)000514863200133 ()31892131 (PubMedID)
Available from: 2020-04-16 Created: 2020-04-16 Last updated: 2022-03-23Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-7863-1887

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