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Publications (10 of 25) Show all publications
Gharibyan, A., Jayaweera, S. W., Lehmann, M., Anan, I. & Olofsson, A. (2022). Endogenous Human Proteins Interfering with Amyloid Formation. Biomolecules, 12(3), Article ID 446.
Open this publication in new window or tab >>Endogenous Human Proteins Interfering with Amyloid Formation
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2022 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 12, no 3, article id 446Article, review/survey (Refereed) Published
Abstract [en]

Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
Alpha-synuclein, Amyloid inhibition, Amyloid-beta, Apolipoprotein E, BRICHOS, Clusterin, Endogenous proteins, IAPP, Transthyretin
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-193407 (URN)10.3390/biom12030446 (DOI)000775848600001 ()2-s2.0-85126704016 (Scopus ID)
Available from: 2022-03-31 Created: 2022-03-31 Last updated: 2023-09-05Bibliographically approved
Bharate, J. B., Ådén, J., Gharibyan, A., Adolfsson, D. E., Jayaweera, S. W., Singh, P., . . . Almqvist, F. (2021). K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones. Organic and biomolecular chemistry, 19(44), 9758-9772
Open this publication in new window or tab >>K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones
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2021 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 19, no 44, p. 9758-9772Article in journal (Refereed) Published
Abstract [en]

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.

Place, publisher, year, edition, pages
The Royal Society of Chemistry, 2021
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-189516 (URN)10.1039/D1OB01580J (DOI)000714122800001 ()34730163 (PubMedID)2-s2.0-85120001225 (Scopus ID)
Funder
Swedish Research Council, 2017-02339; 2017-00695; 2018-04589Knut and Alice Wallenberg Foundation, 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Foundation for Strategic Research, SB12-0070NIH (National Institutes of Health), (R01AI134847-01A1
Available from: 2021-11-15 Created: 2021-11-15 Last updated: 2023-08-09Bibliographically approved
Jayaweera, S. W., Surano, S., Pettersson, N., Oskarsson, E., Lettius, L., Gharibyan, A. L., . . . Olofsson, A. (2021). Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation. Biomolecules, 11(3), Article ID 411.
Open this publication in new window or tab >>Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation
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2021 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 11, no 3, article id 411Article in journal, Editorial material (Refereed) Published
Abstract [en]

Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
IAPP, TTR, amylin, amyloid, diabetes, islet amyloid polypeptide, thioflavin T, transthyretin
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-182798 (URN)10.3390/biom11030411 (DOI)000633423800001 ()33802170 (PubMedID)2-s2.0-85103862637 (Scopus ID)
Funder
The Swedish Brain Foundation, FO2018-0334Stiftelsen Olle Engkvist Byggmästare, 199-0469Stiftelsen Gamla Tjänarinnor, 2018-00718
Available from: 2021-05-05 Created: 2021-05-05 Last updated: 2023-09-05Bibliographically approved
Tyagi, M., Adolfsson, D. E., Singh, P., Ådén, J., Jayaweera, S. W., Gharibyan, A., . . . Almqvist, F. (2021). Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones. Journal of Organic Chemistry, 86(23), 16582-16592
Open this publication in new window or tab >>Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones
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2021 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 86, no 23, p. 16582-16592Article in journal (Refereed) Published
Abstract [en]

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2021
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-189656 (URN)10.1021/acs.joc.1c01875 (DOI)000752848600030 ()34767366 (PubMedID)2-s2.0-85119436020 (Scopus ID)
Funder
Swedish Research Council, 2017-02339Swedish Research Council, 2017-00695Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070NIH (National Institute of Health), (R01AI134847-01A1Familjen Erling-Perssons Stiftelse
Available from: 2021-11-18 Created: 2021-11-18 Last updated: 2023-09-05Bibliographically approved
Islam, T., Gharibyan, A. L., Golchin, S. A., Pettersson, N., Brännström, K., Hedberg, I., . . . Olofsson, A. (2020). Apolipoprotein E impairs amyloid-β fibril elongation and maturation. The FEBS Journal, 287(6), 1208-1219
Open this publication in new window or tab >>Apolipoprotein E impairs amyloid-β fibril elongation and maturation
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2020 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 287, no 6, p. 1208-1219Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is strongly linked to amyloid depositions of the Aβ peptide (Aβ). The lipid-binding protein apolipoprotein E (ApoE) has been found to interfere with Aβ amyloid formation and to exert a strong clinical impact to the pathology of AD. The APOE gene exists in three allelic isoforms represented by APOE ε2, APOE ε3, and APOE ε4. Carriers of the APOE ε4 variant display a gene dose-dependent increased risk of developing the disease. Aβ amyloids are formed via a nucleation-dependent mechanism where free monomers are added onto a nucleus in a template-dependent manner. Using a combination of surface plasmon resonance and thioflavin-T assays, we here show that ApoE can target the process of fibril elongation and that its interference effectively prevents amyloid maturation. We expose a complex equilibrium where the concentration of ApoE, Aβ monomers, and the amount of already formed Aβ fibrils will affect the relative proportion and formation rate of mature amyloids versus alternative assemblies. The result illustrates a mechanism which may affect both the clearance rate of Aβ assemblies in vivo and the population of cytotoxic Aβ assemblies.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2020
Keywords
abeta, amyloid, apolipoprotein E, elongation, surface plasmon resonance
National Category
Basic Medicine Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
biological chemistry
Identifiers
urn:nbn:se:umu:diva-165305 (URN)10.1111/febs.15075 (DOI)000519662100010 ()31571352 (PubMedID)2-s2.0-85075677418 (Scopus ID)
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2023-03-24Bibliographically approved
Gharibyan, A., Islam, T., Pettersson, N., Golchin, S. A., Lundgren, J., Johansson, G., . . . Olofsson, A. (2020). Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity. Biomolecules, 10(1), Article ID 134.
Open this publication in new window or tab >>Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity
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2020 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 10, no 1, article id 134Article in journal (Refereed) Published
Abstract [en]

Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
apolipoprotein E, IAPP amyloid, Thioflavin T, pericytes, cytotoxicity
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-168881 (URN)10.3390/biom10010134 (DOI)000514863200033 ()31947546 (PubMedID)2-s2.0-85077999664 (Scopus ID)
Funder
The Swedish Brain Foundation, FO2018-0334Swedish Research Council, 199-0469Stiftelsen Gamla Tjänarinnor, 2018-00718
Available from: 2020-03-19 Created: 2020-03-19 Last updated: 2023-03-24Bibliographically approved
Adolfsson, D. E., Tyagi, M., Singh, P., Deuschmann, A., Ådén, J., Gharibyan, A., . . . Almqvist, F. (2020). Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils. Journal of Organic Chemistry, 85(21), 14174-14189
Open this publication in new window or tab >>Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
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2020 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 85, no 21, p. 14174-14189Article in journal (Other academic) Published
Abstract [en]

A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
Keywords
Nanofibers, Column chromatography, Peptides and proteins, Mixtures, Alkyls
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-174531 (URN)10.1021/acs.joc.0c01699 (DOI)000589941700068 ()2-s2.0-85095859796 (Scopus ID)
Funder
Swedish Research Council, 2017-02339Swedish Research Council, 2017-00695Swedish Research Council, 2018-04589Knut and Alice Wallenberg Foundation, KAW 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineThe Kempe Foundations, SMK-1755Swedish Foundation for Strategic Research , SB12-0070NIH (National Institute of Health), R01AI134847-01A1
Note

Previously included in thesis in manuscript form.

Available from: 2020-08-26 Created: 2020-08-26 Last updated: 2023-03-24Bibliographically approved
Islam, T., Gharibyan, A. L., Lee, C. C. & Olofsson, A. (2019). Morphological analysis of Apolipoprotein E binding to A beta Amyloid using a combination of Surface Plasmon Resonance, Immunogold Labeling and Scanning Electron Microscopy. BMC Biotechnology, 19(1), Article ID 97.
Open this publication in new window or tab >>Morphological analysis of Apolipoprotein E binding to A beta Amyloid using a combination of Surface Plasmon Resonance, Immunogold Labeling and Scanning Electron Microscopy
2019 (English)In: BMC Biotechnology, E-ISSN 1472-6750, Vol. 19, no 1, article id 97Article in journal (Refereed) Published
Abstract [en]

Background: Immunogold labeling in combination with transmission electron microscopy analysis is a technique frequently used to correlate high-resolution morphology studies with detailed information regarding localization of specific antigens. Although powerful, the methodology has limitations and it is frequently difficult to acquire a stringent system where unspecific low-affinity interactions are removed prior to analysis.

Results: We here describe a combinatorial strategy where surface plasmon resonance and immunogold labeling are used followed by a direct analysis of the sensor-chip surface by scanning electron microscopy. Using this approach, we have probed the interaction between amyloid-beta fibrils, associated to Alzheimer's disease, and apolipoprotein E, a well-known ligand frequently found co-deposited to the fibrillar form of A beta in vivo. The results display a lateral binding of ApoE along the amyloid fibrils and illustrates how the gold-beads represent a good reporter of the binding.

Conclusions: This approach exposes a technique with generic features which enables both a quantitative and a morphological evaluation of a ligand-receptor based system. The methodology mediates an advantage compared to traditional immunogold labeling since all washing steps can be monitored and where a high stringency can be maintained throughout the experiment.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
A beta, ApoE, Immunogold, Surface plasmon resonance, SPR, Scanning electron microscopy, SEM, Fibrils, Morphology, Abeta
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:umu:diva-168577 (URN)10.1186/s12896-019-0589-4 (DOI)000513564300001 ()31829176 (PubMedID)2-s2.0-85076369978 (Scopus ID)
Funder
The Dementia Association - The National Association for the Rights of the DementedThe Swedish Brain Foundation
Available from: 2020-03-03 Created: 2020-03-03 Last updated: 2024-01-10Bibliographically approved
Brännström, K., Gharibyan, A. L., Islam, T., Iakovleva, I., Nilsson, L., Lee, C. C., . . . Olofsson, A. (2018). Scanning electron microscopy as a tool for evaluating morphology of amyloid structures formed on surface plasmon resonance chips. Data in Brief, 19, 1166-1170
Open this publication in new window or tab >>Scanning electron microscopy as a tool for evaluating morphology of amyloid structures formed on surface plasmon resonance chips
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2018 (English)In: Data in Brief, E-ISSN 2352-3409, Vol. 19, p. 1166-1170Article in journal (Refereed) Published
Abstract [en]

We demonstrate the use of Scanning Electron microscopy (SEM) in combination with Surface Plasmon Resonance (SPR) to probe and verify the formation of amyloid and its morphology on an SPR chip. SPR is a technique that measures changes in the immobilized weight on the chip surface and is frequently used to probe the formation and biophysical properties of amyloid structures. In this context it is of interest to also monitor the morphology of the formed structures. The SPR chip surface is made of a layer of gold, which represent a suitable material for direct analysis of the surface using SEM. The standard SPR chip used here (CM5-chip, GE Healthcare, Uppsala, Sweden) can easily be disassembled and directly analyzed by SEM. In order to verify the formation of amyloid fibrils in our experimental conditions we analyzed also in-solution produced structures by using Transmission Electron Microscopy (TEM). For further details and experimental findings, please refer to the article published in Journal of Molecular Biology, (Brännström K. et al., 2018) [1].

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-149049 (URN)10.1016/j.dib.2018.05.129 (DOI)000449869100149 ()30228999 (PubMedID)2-s2.0-85047834173 (Scopus ID)
Note

Refers to: Kristoffer Brännström, Tohidul Islam, Anna L. Gharibyan, Irina Iakovleva, Lina Nilsson, Cheng Choo Lee, Linda Sandblad, Annelie Pamrén, Anders Olofsson. The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation. Journal of Molecular Biology, Volume 430, Issue 13, 22 June 2018, Pages 1940-1949

Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2023-08-25Bibliographically approved
Hakobyan, G., Davtyan, H., Harutyunyan, K., Alexanyan, K., Amirkhanyan, Y., Gharibyan, A. L., . . . Tadevosyan, Y. (2018). Similarities in blood mononuclear cell membrane phospholipid profiles during malignancy. Medical Sciences, 6(4), Article ID 105.
Open this publication in new window or tab >>Similarities in blood mononuclear cell membrane phospholipid profiles during malignancy
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2018 (English)In: Medical Sciences, ISSN 2076-3271, Vol. 6, no 4, article id 105Article in journal (Refereed) Published
Abstract [en]

Phospholipids (PLs), key elements of cellular membranes, are regulated reciprocally with membrane proteins and can act as sensors for alterations in physiological or pathological states of cells including initiation and development of cancer. On the other hand, peripheral blood mononuclear cells (MNCs) play an important role in antitumor immune response by reacting to cancerous modifications in distant organs. In the current study, we tested the hypothesis that tumor initiation and development are reflected in the alteration pattern of the MNC PL component. We analyzed MNC membrane PL fractions in samples from healthy individuals and from patients with diverse types of cancers to reveal possible alterations induced by malignancy. Compared to healthy controls, the cancer samples demonstrated shifts in several membrane PL profiles. In particular, when analyzing cancer data pooled together, there were significantly higher levels in lysophosphatidylcholine, phosphatidylcholine, and phosphatidylethanolamine fractions, and significantly lower quantities in phosphatidylinositol, phosphatidylserine, and phosphatidic acid fractions in cancer samples compared to controls. The levels of sphingomyelins and diphosphatidylglycerols were relatively unaffected. Most of the differences in PLs were sustained during the analysis of individual cancers such as breast cancer and chronic lymphocytic leukemia. Our findings suggest the presence of a common pattern of changes in MNC PLs during malignancy.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
cancers, mononuclear cells, plasma membrane, phospholipids, biomarkers
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-154242 (URN)10.3390/medsci6040105 (DOI)30477187 (PubMedID)2-s2.0-85098660961 (Scopus ID)
Available from: 2018-12-14 Created: 2018-12-14 Last updated: 2023-07-24Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9070-6215

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